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Tian, Q.

Publications and source records attributed to Tian, Q..

At least 37 records · Page 2Linked to original sources

Impact of anatomic variability and other vascular factors on lamina cribrosa hypoxia

Insufficient oxygenation in the lamina cribrosa (LC) may contribute to axonal damage and glaucomatous vision loss. To understand the range of susceptibilities to glaucoma, we aimed to identify key factors influencing LC oxygenation and examine if these factors vary with anatomical differences between eyes. We reconstructed 3D, eye-specific LC vessel networks from histological sections of four healthy monkey eyes. For each network, we generated 125 models varying vessel radius, oxygen consumption rate, and arteriole perfusion pressure. Using hemodynamic and oxygen supply modeling, we predicted blood flow distribution and tissue oxygenation in the LC. ANOVA assessed the significance of each parameter. Our results showed that vessel radius had the greatest influence on LC oxygenation, followed by anatomical variations. Arteriole perfusion pressure and oxygen consumption rate were the third and fourth most influential factors, respectively. The LC regions are well perfused under baseline conditions. These findings highlight the importance of vessel radius and anatomical variation in LC oxygenation, providing insights into LC physiology and pathology. Pathologies affecting vessel radius may increase the risk of LC hypoxia, and anatomical variations could influence susceptibility. Conversely, increased oxygen consumption rates had minimal effects, suggesting that higher metabolic demands, such as those needed to maintain intracellular transport despite elevated intraocular pressure, have limited impact on LC oxygenation.

bioengineering↗

RNADiffFold: Generative RNA Secondary Structure Prediction using Discrete Diffusion Models

RNA molecules are essential macromolecules that perform diverse biological functions in living beings. Precise prediction of RNA secondary structures is instrumental in deciphering their complex three-dimensional architecture and functionality. Traditional methodologies for RNA structure prediction, including energy-based and learning-based approaches, often depict RNA secondary structures from a static perspective and rely on stringent a priori constraints. Inspired by the success of diffusion models, in this work, we introduce RNADiffFold, an innovative generative prediction approach of RNA secondary structures based on multinomial diffusion. We reconceptualize the prediction of contact maps as akin to pixel-wise segmentation and accordingly train a denoising model to refine the contact maps starting from a noise-infused state progressively. We also devise a potent conditioning mechanism that harnesses features extracted from RNA sequences to steer the model toward generating an accurate secondary structure. These features encompass one-hot encoded sequences, probabilistic maps generated from a pre-trained scoring network, and embeddings and attention maps derived from RNA-FM. Experimental results on both within- and cross-family datasets demonstrate RNADiffFolds competitive performance compared with current state-of-the-art methods. Additionally, RNADiffFold has shown a notable proficiency in capturing the dynamic aspects of RNA structures, a claim corroborated by its performance on datasets comprising multiple conformations.

bioinformatics↗

Multicore-fiber microendoscopy for functional cellular in-organ imaging

Microendoscopy enables minimally invasive investigations of organs even within small cavities. Conventional microendoscopy is limited by probe size and often restricted to a single excitation wavelength. We developed and characterized a multichannel microendoscope as thin as 360 {micro}m and recorded functional cellular signals in-situ using custom written software for image processing. The endoscope had an effective resolution of 4.64 {micro}m and resolved subcellular structures of neurons. The system enabled analysis of in-situ calcium responses in murine tracheal brush cells and kidney podocytes. Additionally, ratiometric redox responses were recorded in whole, explanted organs and pancreatic islet culture. The flexibility and simplicity of our approach for imaging a variety of tissues and organs paves the way for in-vivo, longitudinal studies with cellular resolution.

bioengineering↗

Dynamic floral scent profile of Epiphyllum oxypetalum and the cytosolic biosynthesis of trans-Geraniol through mevalonate pathway

O_LIEpiphyllum oxypetalum, a renowned ornamental species in Cactaceae, releases attractive fragrance during its infrequent, transient and nocturnal flowering, the nature and biosynthesis of the volatiles for this floral scent, however, remained unexplored. C_LIO_LIEmploying volatilomic, transcriptomic and biochemical approaches, we systematically characterized the composition, emission dynamics and biosynthesis of E. oxypetalum floral scent. C_LIO_LIFloral scent composition was highly dynamic, with trans-geraniol comprising 72.54% of the total emission at full bloom, followed by benzyl alcohol (12.96%) and methyl salicylate (3.75%), which predominantly emanated from petals and sepals. Transcriptomic analysis and inhibition assay using pathway-specific inhibitors revealed the mevalonate (MVA) pathway as the precursor source for trans-geraniol biosynthesis. Together with elevated expression of both cytosol-localized geraniol pyrophosphate synthase EoGDPS and geraniol synthase EoTPSa1, we elucidated an unusual cytosolic biosynthesis route for geraniol in E. oxypetalum petals. C_LIO_LIOur study on E. oxypetalum scent emission and its biosynthesis offers a comprehensive profile of cactus floral scent profiles and presents a rare case of cytosolic geraniol biosynthesis using MVA pathway-derived substrates. These findings underline the unique metabolism of cactus flower volatiles, which hold a promise to be applied in the development of novel perfumes. C_LI

plant biology↗

ERas-Null Mice Generated Directly from Embryonic Stem Cells in a Lipid-rich Medium Enable the Discovery of A Novel Role in Craniofacial Development

Generating mice entirely from embryonic stem cells (ESCs) via tetraploid complementation, termed all-ESC mice, is considered the gold standard for pluripotency testing. In this study, we examined the effects of our newly reported lipid-rich 2i/LIF medium (2iLA) on ESCs for genetic engineering. As a proof of principle, we targeted the ERas gene using the 2iLA medium, since ERas-null mice displayed no noticeable phenotype in a previously developed mouse model through chimeras. We demonstrated that the 2iLA medium effectively supports the creation of both male and female ERas-null all-ESC mice, emphasizing the advantages of this culture medium. Unexpectedly, we observed that ERas-null all-ESC mice produced with the 2iLA medium exhibited a non-Mendelian lethal craniofacial anomaly, which can be mitigated by using the lipid-free 2i/LIF medium. Our findings not only highlight the potential of the 2iLA medium for gene targeting but also reveal a novel lipid-associated role of the ERas gene in craniofacial development. Our system offers a unique alternative for studying developmental gene functions unachievable with traditional methods and provides a novel platform for the rapid construction of mouse models. Graphic AbstractAll-ESC pups from wild-type (WT) ESCs cultured in lipid-rich 2iLA medium are normal. In contrast, both male and female ERas-null isogenic all-ESC pups produced from ESCs in 2iLA medium display a non-Mendelian craniofacial anomaly. This phenotype is alleviated when the ESCs are grown in a lipid-free 2iL medium. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/565209v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@c2dd48org.highwire.dtl.DTLVardef@14dbd07org.highwire.dtl.DTLVardef@b54a86org.highwire.dtl.DTLVardef@2fcdd5_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

Rolling 2D Bioelectronic film into 1D: a Suturable Long-term Implantable Soft Microfiber

Long-term implantable bioelectronics can efficiently evaluate the function of the nervous system. 1D fiber-shaped devices require small surgical incisions significantly benefiting long-term biocompatibility. We report a strategy of rolling to reduce the dimension of bioelectronic devices from 2D film to 1D microfiber. The soft and stretchable multifunctional microfiber accommodates more than 60-channel longitudinally-distributed electrodes for bio-electric and -mechanical monitoring. It can be sutured into muscle with tiny incision for 8-month bio-electrical monitoring in rats. Importantly, after 13-month implantation, the fibroblast encapsulation around the fiber is negligible. Moreover, it can wander inside a brain under magnetic field. This strategy not only opens up the study of multi-channel and -function soft and stretchable fiber-shaped sensors but offers a platform for minimally-invasive implantable bioelectronics. One-Sentence SummaryThe rolling enables stretchable electrode array along one single microfiber and multimodal long-term in-vivo monitoring.

neuroscience↗

omicsMIC: a Comprehensive Benchmarking Platform for Robust Comparison of Imputation Methods in Mass Spectrometry-based Omics Data

Mass spectrometry is a powerful and widely used tool for generating proteomics, lipidomics, and metabolomics profiles, which is pivotal for elucidating biological processes and identifying biomarkers. However, missing values in spectrometry-based omics data may pose a critical challenge for the comprehensive identification of biomarkers and elucidation of the biological processes underlying human complex disorders. To alleviate this issue, various imputation methods for mass spectrometry-based omics data have been developed. However, a comprehensive and systematic comparison of these imputation methods is still lacking, and researchers are frequently confronted with a multitude of options without a clear rationale for method selection. To address this pressing need, we developed omicsMIC (mass spectrometrybased omics with Missing values Imputation methods Comparison platform), an interactive platform that provides researchers with a versatile framework to simulate and evaluate the performance of 28 diverse imputation methods. omicsMIC offers a nuanced perspective, acknowledging the inherent heterogeneity in biological data and the unique attributes of each dataset. Our platform empowers researchers to make data-driven decisions in imputation method selection based on real-time visualizations of the outcomes associated with different imputation strategies. The comprehensive benchmarking and versatility of omicsMIC make it a valuable tool for the scientific community engaged in mass spectrometry-based omics research. OmicsMIC is freely available at https://github.com/WQLin8/omicsMIC.

bioinformatics↗

Deep learning classification of ex vivo human colon tissues using spectroscopic OCT

Screening programs for colorectal cancer (CRC) have had a profound impact on the morbidity and mortality of this disease by detecting and removing early cancers and precancerous adenomas with colonoscopy. However, CRC continues to be the third leading cause of cancer-related mortality in both men and woman, partly because of limitations in colonoscopy-based screening. Thus, novel strategies to improve the efficiency and effectiveness of screening colonoscopy are urgently needed. Here, we propose to address this need using an optical biopsy technique based on spectroscopic optical coherence tomography (OCT). The depth resolved images obtained with OCT are analyzed as a function of wavelength to measure optical tissue properties. The optical properties can be used as input to machine learning algorithms as a means to classify adenomatous tissue in the colon. In this study, biopsied tissue samples from the colonic epithelium are analyzed ex vivo using spectroscopic OCT and tissue classifications are generated using a novel deep learning architecture, informed by machine learning methods including LSTM and KNN. The overall classification accuracy obtained was 88.9%, 76.0% and 97.9% in discriminating tissue type for these methods. Further, we apply an approach using false coloring of en face OCT images based on SOCT parameters and deep learning predictions to enable visual identification of tissue type. This study advances the spectroscopic OCT towards clinical utility for analyzing colonic epithelium for signs of adenoma.

pathology↗

Rapid in-situ diversification rates in Rhamnaceae explain the parallel evolution of high diversity in temperate biomes from global to local scales

O_LIThe macroevolutionary processes that have shaped biodiversity across the temperate realm remain poorly understood and may have resulted from evolutionary dynamics related to diversification rates, dispersal rates, and colonization times, closely coupled with Cenozoic climate change. C_LIO_LIWe integrated phylogenomic, environmental ordination, and macroevolutionary analyses for the cosmopolitan angiosperm family Rhamnaceae to disentangle the evolutionary processes that have contributed to high species diversity within and across temperate biomes. C_LIO_LIOur results show independent colonization of environmentally similar but geographically separated temperate regions mainly during the Oligocene, consistent with the global expansion of temperate biomes. High global, regional, and local temperate diversity was the result of high in-situ diversification rates, rather than high immigration rates or accumulation time, except for Southern China, which was colonized much earlier than other regions. The relatively common lineage dispersals out of temperate hotspots highlights strong source-sink dynamics across the cosmopolitan distribution of Rhamnaceae. C_LIO_LIThe proliferation of temperate environments since the Oligocene may have provided the ecological opportunity for rapid in-situ diversification of Rhamnaceae across the temperate realm. Our study illustrates the importance of high in-situ diversification rates for the establishment of modern temperate biomes and biodiversity hotspots across spatial scales. C_LI

evolutionary biology↗

Role of Articulatory Motor Networks in Perceptual Categorization of Speech Signals: A 7 T fMRI Study

BACKGROUNDThe association between brain regions involved in speech production and those that play a role in speech perception is not yet fully understood. We compared speech production related brain activity with activations resulting from perceptual categorization of syllables using high field 7 Tesla functional magnetic resonance imaging (fMRI) at 1-mm isotropic voxel resolution, enabling high localization accuracy compared to previous studies. METHODSBlood oxygenation level dependent (BOLD) signals were obtained in 20 normal hearing subjects using a simultaneous multi-slice (SMS) 7T echo-planar imaging (EPI) acquisition with whole-head coverage and 1 mm isotropic resolution. In a speech production localizer task, subjects were asked to produce a silent lip-round vowel /u/ in response to the visual cue "U" or purse their lips when they saw the cue "P". In a phoneme discrimination task, subjects were presented with pairs of syllables, which were equiprobably identical or different along an 8-step continuum between the prototypic /ba/ and /da/ sounds. After the presentation of each stimulus pair, the subjects were asked to indicate whether the two syllables they heard were identical or different by pressing one of two buttons. In a phoneme classification task, the subjects heard only one syllable and asked to indicate whether it was /ba/ or /da/. RESULTSUnivariate fMRI analyses using a parametric modulation approach suggested that left motor, premotor, and frontal cortex BOLD activations correlate with phoneme category variability in the /ba/-/da/ discrimination task. In contrast, the variability related to acoustic features of the phonemes were the highest in the right primary auditory cortex. Our multivariate pattern analysis (MVPA) suggested that left precentral/inferior frontal cortex areas, which were associated with speech production according to the localizer task, play a role also in perceptual categorization of the syllables. CONCLUSIONSThe results support the hypothesis that articulatory motor networks in the left hemisphere that are activated during speech production could also have a role in perceptual categorization of syllables. Importantly, high voxel-resolution combined with advanced coil technology allowed us to pinpoint the exact brain regions involved in both perception and production tasks.

neuroscience↗

A new vulnerability to BET inhibition due to enhanced autophagy in BRCA2 deficient pancreatic cancer

Pancreatic cancer is one of the deadliest diseases in human malignancies. Among total pancreatic cancer patients, [~]10% of patients are categorized as familial pancreatic cancer (FPC) patients, carrying germline mutations of the genes involved in DNA repair pathways (e.g., BRCA2). Personalized medicine approaches tailored toward patients mutations would improve patients outcome. To identify novel vulnerabilities of BRCA2-deficient pancreatic cancer, we generated isogenic Brca2-deficient murine pancreatic cancer cell lines and performed high-throughput drug screens. High-throughput drug screening revealed that Brca2-deficient cells are sensitive to Bromodomain and Extraterminal Motif (BET) inhibitors, suggesting that BET inhibition might be a potential therapeutic approach. We found that BRCA2 deficiency increased autophagic flux, which was further enhanced by BET inhibition in Brca2-deficient pancreatic cancer cells, resulting in autophagy-dependent cell death. Our data suggests that BET inhibition can be a novel therapeutic strategy for BRCA2-deficient pancreatic cancer.

cancer biology↗

Phylogenomic Analyses Reveal Widespread Gene Flow During the Early Radiation of Oaks and Relatives (Fagaceae: Quercoideae)

AO_SCPLOWBSTRACTC_SCPLOWOaks (Quercus), one of the most species-rich and ecologically dominant woody plant clades in the Northern Hemisphere, are well known for their propensity to hybridize and form syngameons, complexes where alleles are readily exchanged among closely related species. While hybridization has been extensively studied towards the tips of the oak phylogeny, the extent, timeline, and evolutionary scenarios of hybridization during the early radiation of oaks and related genera (Quercoideae) remain poorly known. Using an expansive new dataset of nuclear and chloroplast sequences (including up to 431 spp.), we conducted a multifaceted phylogenomic investigation of Quercus aimed at characterizing gene-tree and cytonuclear (chloroplast-nuclear) discordance and identifying ancient reticulation in the early evolution of the group. We document extensive nuclear gene-tree and cytonuclear discordance at deep nodes in Quercus and Quercoideae, with Quercus recovered as non-monophyletic in the chloroplast phylogeny. Analyses recovered clear signatures of gene flow against a backdrop of incomplete lineage sorting, with gene flow most prevalent among major lineages of Quercus and Quercoideae during their initial radiation, dated to the early-middle Eocene. Ancestral reconstructions including fossil data suggest that the ancestors of Castanea+Castanopsis, Lithocarpus, and the Old World oak clade co-occurred in North America and Eurasia, while the ancestors of Chrysolepis, Notholithocarpus, and the New World oak clade co-occurred in North America, offering ample opportunity for hybridization in each region. Following this initial phase of radiation and reticulation, we detected multiple niche shifts in Quercus and other Quercoideae genera that likely facilitated their expansion into new habitats arising from post-Eocene climatic changes. Our study shows that hybridization--perhaps in the form of ancient syngameons similar to those seen today--has been a common and important process throughout the evolutionary history of oaks and their close relatives.

evolutionary biology↗

Multiplexed Sequential Imaging in Living Cells with Orthogonal Fluorogenic RNA Aptamer/Dye Pairs

Single-cell detection of multiple target analytes is an important goal in cell biology. However, due to the spectral overlap of common fluorophores, multiplexed fluorescence imaging beyond two-to-three targets inside living cells remains a technical challenge. Herein, we introduce a multiplexed imaging strategy that enables live-cell target detection via sequential rounds of imaging-and-stripping process, which is named as "sequential Fluorogenic RNA Imaging-Enabled Sensor" (seqFRIES). In seqFRIES, multiple orthogonal fluorogenic RNA aptamers are genetically encoded inside cells, and then the corresponding cell membrane permeable dye molecules are added, imaged, and rapidly removed in consecutive detection cycles. As a proof-of-concept, we have identified in this study five in vitro orthogonal fluorogenic RNA aptamer/dye pairs (>10-fold higher fluorescence signals), four of which can be used for highly orthogonal and multiplexed imaging in living bacterial and mammalian cells. After further optimizing the cellular fluorescence activation and deactivation kinetics of these RNA/dye pairs, the whole four-color semi-quantitative seqFRIES process can now be completed in [~]20 min. Meanwhile, seqFRIES-mediated simultaneous detection of two critical signaling molecules, guanosine tetraphosphate and cyclic diguanylate, was also achieved within individual living cells. We expect our validation of this new seqFRIES concept here will facilitate the further development and potential broad usage of these orthogonal fluorogenic RNA/dye pairs for highly multiplexed and dynamic cellular imaging and cell biology studies.

bioengineering↗

The influence of axonal beading and undulation on axonal diameter mapping

We consider the effect of non-cylindrical axonal shape on axonal diameter mapping with diffusion MRI. Practical sensitivity to axon diameter is attained at strong diffusion weightings b, where the deviation from the [Formula] scaling yields the finite transverse diffusivity, which is then translated into axon diameter. While axons are usually modeled as perfectly straight, impermeable cylinders, the local variations in diameter (caliber variation or beading) and direction (undulation) have been observed in microscopy data of human axons. Here we quantify the influence of cellular-level features such as caliber variation and undulation on axon diameter estimation. For that, we simulate the diffusion MRI signal in realistic axons segmented from 3-dimensional electron microscopy of a human brain sample. We then create artificial fibers with the same features and tune the amplitude of their caliber variations and undulations. Numerical simulations of diffusion in fibers with such tunable features show that caliber variations and undulations result in under- and over-estimation of axon diameters, correspondingly; this bias can be as large as 100%. Given that increased axonal beading and undulations have been observed in pathological tissues, such as traumatic brain injury and ischemia, the interpretation of axon diameter alterations in pathology may be significantly confounded.

neuroscience↗

Targeted RNA Condensation in Living Cells via Genetically Encodable Triplet Repeat Tags

Living systems contain various functional membraneless organelles that can segregate selective proteins and RNAs via liquid-liquid phase separation. Inspired by nature, many synthetic compartments have been engineered in vitro and in living cells, mostly focused on protein-scaffolded systems. Herein, we introduce a nature-inspired genetically encoded RNA tag to program cellular condensate formations and recruit non-phase-transition target RNAs to achieve functional modulation. In our system, different lengths of CAG-repeat tags were tested as the self-assembled scaffold to drive multivalent condensate formation. Various selective target messenger RNAs and noncoding RNAs can be compartmentalized into these condensates. With the help of fluorogenic RNA aptamers, we have systematically studied the formation dynamics, spatial distributions, sizes, and densities of these cellular RNA condensates. The regulation functions of these CAG-repeat tags on the cellular RNA localization, lifetime, RNA-protein interactions, and gene expression have also been investigated. Considering the importance of RNA condensation in both health and disease conditions, these genetically encodable modular and self-assembled tags can be potentially widely used for chemical biology and synthetic biology studies.

bioengineering↗

A novel triptolide analog downregulates NF-κB and induces mitochondrial apoptosis pathways in human pancreatic cancer

BackgroundPancreatic cancer is the seventh leading cause of cancer-related death worldwide, and despite advancements in disease management, the 5-year survival rates stands at only 9%. Triptolides have potent anti-tumor activity against different types of cancers, including pancreatic cancer, however poor solubility and toxicity limit their translation into clinical use. MethodsWe synthesized a novel pro-drug of triptolide, (E)-19-[(1-benzoyloxy-1-phenyl)-methylidene]-Triptolide (CK21), and formulated into an emulsion for in vitro and in vivo testing in rats and mice, and using human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids. A time-course transcriptomic profiling of tumor organoids treated with CK21 in vitro was conducted to define its mechanism of action, as well as transcriptomic profiling at a single time point post-CK21 administration in vivo. FindingsIntravenous administration of emulsified CK21 resulted in the stable release of triptolide, and potent anti-proliferative effects on human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids in vitro, and with minimal toxicity in vivo. Time course transcriptomic profiling of tumor organoids treated with CK21 in vitro revealed <10 differentially expressed genes (DEGs) at 3 h and [~]8,000 DEGs at 12 h. Overall inhibition of general RNA transcription was observed, and Ingenuity pathway analysis together with functional cellular assays confirmed inhibition of the NF-{kappa}B pathway, increased oxidative phosphorylation and mitochondrial dysfunction, leading ultimately to increased reactive oxygen species (ROS) production, reduced B-cell-lymphoma protein 2 (BCL2) expression, and mitochondrial-mediated tumor cell apoptosis. InterpretationCK21 is a novel pro-drug of triptolide that exerts potent anti-proliferative effects on human pancreatic tumors by inhibiting the NF-{kappa}B pathway, leading ultimately to mitochondrial-mediated tumor cell apoptosis. FundingThe study of the anti-tumor efficacy of CK21 supported in part by a research grant from Cinkate Pharmaceutical Corp; the funders had no role in the study design, interpretation or decision to publish. Patient-derived pancreatic tumor organoids were a generous gift from the Organoid and Primary Culture Research Core at University of Chicago.

pharmacology and toxicology↗

Rice potassium transporter OsHAK18 mediates phloem K+ loading and redistribution

High-Affinity K+ transporters/K+ Uptake Permeases/K+ Transporters (HAK/KUP/KT) are important pathways mediating K+ transport across cell membrane, which function in maintaining K+ homeostasis during plant growth and stress response. An increasing number of studies have shown that HAK/KUP/KT transporters play important roles in potassium uptake and root-to-shoot translocation. However, whether some HAK/KUP/KT transporters mediate K+ redistribution in phloem remains unknown. In this study, we revealed that a phloem-localized HAK/KUP/KT transporter, OsHAK18 operated as a typical KUP/HAK/KT transporter mediating cell K+ uptake when expressed in yeast, E. coli and Arabidopsis. It was localized at plasma membrane. Disruption of OsHAK18 rendered rice seedlings insensitive to low-K+ stress. Compared with WT, the oshak18 mutants accumulated more K+ in shoots but less K+ in roots, leading to a higher shoot/root ratio of K+ per plant. Although disruption of OsHAK18 doesnt affect root K+ uptake and K+ level in xylem sap, it significantly decreases phloem K+ concentration and inhibits root-to-shoot-to-root K+ translocation in split-root assay. These results reveal that OsHAK18 mediates phloem K+ loading and redistribution, whose disruption is favor of shoot K+ retention under low-K+ stress. Our findings not only reveal a unique function of rice HAK/KUP/KT family member, but also provide a promising strategy to improve rice tolerance under K+ deficiency.

plant biology↗