Biology subjects

Cui, L.

Publications and source records attributed to Cui, L..

At least 73 records · Page 4Linked to original sources

bioRxiv2022

ApoE4 causes severe COVID-19 outcomes via downregulation of ACE2

The coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); host cell entry by this virus relies on the interaction between the receptor-binding domain (RBD) of its spike glycoprotein and the angiotensin-converting enzyme 2 (ACE2) receptor on cell membranes. In addition to serving as a receptor for SARS-CoV-2, ACE2 was originally discovered as a protective factor in the renin-angiotensin system (RAS) that catalyses the degradation of angiotensin II (Ang II) to Ang 1-7, which is involved in multiple organ pathology. Recent genetic and clinical studies reported that ApoE4 expression is associated with increased susceptibility to SARS-CoV-2 infection and the development of severe COVID-19, but the underlying mechanism is currently unclear. In the present study, by using immunofluorescence staining, molecular dynamics simulations, proximity ligation assay (PLA) and coimmunoprecipitation (Co-IP) combined with a biolayer interferometry (BLI) assay, we found that ApoE interacts with both the spike protein and ACE2 but does not show obvious isoform-dependent binding effects. These data suggest that ApoE4 increases SARS-CoV-2 infectivity in a manner that may not depend on differential interactions with the spike protein or ACE2. Importantly, further immunoblotting and immunofluorescence staining results showed that ApoE4 significantly downregulates ACE2 protein expression in vitro and in vivo and subsequently decreases the conversion of Ang II to Ang 1-7, which could worsen tissue lesions; these findings provide a possible explain by which ApoE4 exacerbates COVID-19 disease.

neuroscience↗

bioRxiv2022

Causal contributions to sensory-based decision-making by cell-type specific circuits in the tail striatum

The striatum comprises distinct types of neurons giving rise to the direct and indirect basal ganglia pathways and local circuits. A large amount of work has been focusing on cell-type specific striatal circuits in the context of movement control, proposing several models on their functional roles. But it remains to be elucidated how the cell-type specific striatal circuits contribute to decision-making behavior and whether the existing models apply. Here, we investigate the causal roles of the cell-type specific circuits in the posterior tail of the dorsal striatum (TS) of mice in an auditory-guided decision-making behavior. Transient unilateral activation of the direct- or indirect-pathway striatal spiny projection neurons (dSPNs or iSPNs) both biased decisions in opposite directions. These effects, however, were not due to a direct influence on movement, but was specific to the decision period preceding action execution. Optogenetic inactivation of dSPNs and iSPNs revealed their opposing causal contributions to decisions. At the local circuit level, simutaneous optical recording and manipulation of dSPNs and iSPNs revealed their antagnizing interactions. Inactivation of PV interneurons, a common inhibitory input to both dSPNs and iSPNs, facilitated contraversive choices, supporting a causal contribution of coordinated striatal circuits. Using a neural circuit model, we further demonstrated the computational implemenation of the causal circuit mechanism. Our results indicate that while the causal roles of the cell-type specific striatal circuits in decision-making largely agree with classic models in movement control, they show decision task-related specificity involving local circuit coordination.

neuroscience↗

bioRxiv2022

Chromosomal assembly of the flat oyster (Ostrea edulis L.) genome as a new genetic ressource for aquaculture

The European flat oyster (Ostrea edulis L.) is the endemic species of the European coasts. Its exploitation has been reduced during the last decades, because of the appearance of two parasites that have led to the collapse of the stocks and the strong decline of the natural oyster beds. O. edulis has been the subject of numerous studies and programs in population genetics and on the presence of the parasites Bonamia ostreae and Marteilia refringens. These studies investigated the effects of these parasites mainly on immunity at the molecular and cellular levels. Several genetic selection programs especially related to resistance to the parasite have been initiated. Within the framework of a European project (PERLE 2) which aims to produce genetic lines of O. edulis with hardiness traits (growth, survival, resistance) for the purpose of repopulating natural oyster beds in Brittany and reviving the culture of this species on the foreshore, obtaining a reference genome has proved to be essential as done recently in many bivalve species of aquaculture interest. Here, we present a chromosome-level genome assembly and annotation for the European flat oyster, generated by combining PacBio technology, Illumina, 10X linked and Hi-C sequencing. The finished assembly is 887.2 Mb with a scaffold-N50 of 97.1 Mb scaffolded on the expected 10 pseudo-chromosomes. Annotation of the genome revealed the presence of 35962 protein-coding genes. We analyzed in details the transposable elements (TE) diversity in the flat oyster genome, highlight some specificities in tRNA and miRNA composition and provide first insights in the molecular response of O. edulis to M. refringens. This genome will serve as a reference for genomic studies on O. edulis to better understand its basic physiology or developing genetic markers in breeding projects for aquaculture or natural reef restoration.

genomics↗

bioRxiv2022

Within-patient evolution of plasmid-mediated antimicrobial resistance

Antibiotic resistance (AMR) in bacteria is a major threat to public health, and one of the key elements in the spread and evolution of AMR in clinical pathogens is the transfer of conjugative plasmids. The drivers of AMR evolution have been extensively studied in vitro, but the evolution of plasmid-mediated AMR in vivo remains poorly explored. Here, we tracked the evolution of the clinically-relevant plasmid pOXA-48, which confers resistance to the last-resort antibiotics carbapenems, in a large collection of enterobacterial clones isolated from the gut of hospitalised patients. Combining genomic and experimental approaches, we first characterized plasmid diversity and the genotypic and phenotypic effects of multiple plasmid mutations on a common genetic background. Second, using cutting-edge genomic editing in wild-type multidrug resistant enterobacteria, we dissected three cases of within-patient plasmid-mediated AMR evolution. Our results revealed, for the first time, compensatory evolution of plasmid-associated fitness cost, as well as the evolution of enhanced plasmid-mediated AMR, in bacteria evolving within the gut of hospitalised patients. Crucially, we observed that the evolution of plasmid-mediated AMR in vivo involves a pivotal trade-off between resistance levels and bacterial fitness. This study highlights the need to develop new evolution-informed approaches to tackle plasmid-mediated AMR dissemination.

evolutionary biology↗

bioRxiv2022

Trophoblast and blood vessel organoid cultures recapitulate the role of WNT2B in promoting intravillous vascularization in human intrauterine and ectopic pregnancy

Tubal ectopic pregnancy (TEP), a pregnancy complication caused by aberrant implantation in fallopian tubes, accounts for 9-13% pregnancy-related deaths. The lack of models for human TEP hampers the understanding of its pathological mechanisms. Here, we employed multiple models to investigate the crosstalk between human trophoblast development and intravillous vascularization. We found that the severity of TEP, the size of placental villi, and the depth of trophoblast invasion are correlated with the extent of intravillous vascularization. We identified a key pro-angiogenic factor secreted by trophoblasts, WNT2B, that promotes villous vasculogenesis, angiogenesis, and vascular network expansion. In an organoid coculture model consisting of trophoblast organoids and blood vessel organoids, knockdown of WNT2B in trophoblast organoids compromises their pro-angiogenic effect on the development of blood vessel organoids. These organoid-based models reveal an important role for WNT-mediated angiogenesis in pregnancies and could be employed to investigate the commutations between trophoblasts and endothelial/endothelial progenitor cells.

cell biology↗

bioRxiv2022

Metabolism of glucose activates TORC1 through multiple mechanisms in Saccharomyces cerevisiae

Target of Rapamycin Complex 1 (TORC1) is a conserved eukaryotic protein complex that links the presence of nutrients with cell growth. In Saccharomyces cerevisiae, TORC1 activity is positively regulated by the presence of amino acids and glucose in the medium. However, mechanisms underlying nutrient-induced TORC1 activation remain poorly understood. By utilizing a TORC1 activation assay, we demonstrate that differential metabolism of glucose activates TORC1 through three distinct pathways in yeast. The first canonical Rag GTPase-dependent pathway requires conversion of glucose to fructose 1,6-bisphosphate which activates TORC1 via the Rag GTPase heterodimer Gtr1GTP/Gtr2GDP. The second non-canonical Rag GTPase-dependent pathway requires conversion of glucose to glucose 6-phosphate which activates TORC1 via Gtr1GTP/Gtr2GTP. The third Rag GTPase-independent pathway requires complete glycolysis and vacuolar ATPase reassembly for TORC1 activation. Glucose-induced TORC1 activation can be uncoupled from glucose-induced AMPK inactivation. We have established a roadmap to deconstruct the link between glucose metabolism and TORC1 activation.

genetics↗

bioRxiv2022

Global Spatial Transcriptome of Macaque Brain at Single-Cell Resolution

Global profile of gene expression at single-cell resolution remains to be determined for primates. Using a recently developed technology ("Stereo-seq"), we have obtained a comprehensive single-cell spatial transcriptome map at the whole-brain level for cynomolgus monkeys, with [~]600 genes per cell for 10 m-thick coronal sections (up to 15 cm2 in size). Large-scale single-nucleus RNA-seq analysis for [~]1 million cells helped to identify cell types corresponding to Stereo-seq gene expression profiles, providing a 3-D cell type atlas of the monkey brain. Quantitative analysis of Stereo-seq data revealed molecular fingerprints that mark distinct neocortical layers and subregions, as well as domains within subcortical structures including hippocampus, thalamus, striatum, cerebellum, hypothalamus and claustrum. Striking whole-brain topography and coordinated patterns were found in the expression of genes encoding receptors and transporters for neurotransmitters and neuromodulators. These results pave the way for cellular and molecular understanding of organizing principles of the primate brain.

cell biology↗

bioRxiv2022

Novel Murine models of Mania and Depression

Neuropathological mechanisms triggering manic syndrome or manic episodes in bipolar disorder remain poorly characterised, as the research progress is severely limited by the paucity of appropriate animal models. Here we developed a novel manic mice model by combining a series of chronic unpredictable rhythm disturbances (CURD), which include disruption of circadian rhythm, sleep deprivation, exposure to cone light, with subsequent interference of followed spotlight, stroboscopic illumination, high temperature stress, noise disturbance and foot shock. To validate this novel manic model, we used multiple behavioural and cell biology approaches comparing the CURD-model with healthy controls and depressed mice. The depression model was created by an exposure to an improved chronic unpredictable mild stress, which we defined as chronic unpredictable mild restraint (CUMR). A novel manic mice model induced by environmental stressors and free from genetic or pharmacological interventions will benefit research into pathological mechanisms of mania.

animal behavior and cognition↗

bioRxiv2022

Decoding the temporal dynamics of affective scene processing

Natural images containing affective scenes are used extensively to investigate the neural mechanisms of visual emotion processing. Functional fMRI studies have shown that these images activate a large-scale distributed brain network that encompasses areas in visual, temporal, and frontal cortices. The underlying spatial and temporal dynamics among these network structures, however, remain to be characterized. We recorded simultaneous EEG-fMRI data while participants passively viewed affective images from the International Affective Picture System (IAPS). Applying multivariate pattern analysis to decode EEG data, and representational similarity analysis to fuse EEG data with simultaneously recorded fMRI data, we found that: (1) ~100 ms after picture onset, perceptual processing of complex visual scenes began in early visual cortex, proceeding to ventral visual cortex at ~160 ms, (2) between ~200 and ~300 ms (pleasant pictures: ~200 ms; unpleasant pictures: ~260 ms), affect-specific neural representations began to form, supported mainly by areas in occipital and temporal cortices, and (3) affect-specific neural representations, lasting up to ~2 s, were stable and exhibited temporally generalizable activity patterns. These results suggest that affective scene representations in the brain are formed in a valence-dependent manner and are sustained by recurrent neural interactions among distributed brain areas.

neuroscience↗

bioRxiv2022

Molecular basis of broad neutralization against SARS-CoV-2 variants including Omicron by a human antibody

Omicron, a newly emerging SARS-CoV-2 variant, carried a large number of mutations in the spike protein leading to an unprecedented evasion from many neutralizing antibodies (nAbs). Here, we performed a head-to-head comparison of Omicron with other existing highly evasive variants in terms of their reduced sensitivities to antibodies, and found that Omicron variant is significantly more evasive than Beta and Mu variants. Of note, some key mutations occur in the conserved epitopes identified previously, especially in the binding sites of Class 4 nAbs, contributing to the increased Ab evasion. We also reported a broadly nAb (bnAb), VacW-209, which effectively neutralized all tested SARS-CoV-2 variants and even SARS-CoV. Finally, we determined six cryo-electron microscopy structures of VacW-209 complexed with the spike ectodomains of wild-type, Delta, Mu, C.1.2, Omicron, and SARS-CoV, and revealed the molecular basis of the broadly neutralizing activities of VacW-209 against SARS-CoV-2 variants. Overall, Omicron has once again raised the alarm over virus variation with significantly compromised neutralization. BnAbs targeting more conserved epitopes among variants will continue to play a key role in pandemic control and prevention. One sentence summaryStructural and functional analyses reveal that a human antibody named VacW-209 confers broad neutralization against SARS-CoV-2 variants including Omicron by recognizing a highly conserved epitope.

immunology↗

bioRxiv2021

Asymmetrical choice-related ensemble activity in direct and indirect-pathway striatal neurons drives perceptual decisions

Sensory-guided decision-making is a vital brain function critically depending on the striatum, a key brain structure transforming sensorimotor information into actions. However, how the two opposing striatal pathways work in concert to select actions during decision-making remains controversial. Here, using cell-type specific two-photon imaging and optogenetic perturbations from the posterior dorsal striatum during decision-making behavior in mice, we uncover the population coding and causal mechanisms of the direct- and indirect-pathway spiny projection neurons (dSPNs and iSPNs) in decision-related action selection. Unexpected from prevailing models, we found that both dSPNs and iSPNs contain divergent subpopulations representing competing choices, and exhibit ensemble-level asymmetry: stronger contralateral dominance in dSPNs than in iSPNs. Such multi-ensemble competition/cooperation causally contributes to decision-related action selection, as supported by systematic optogenetic manipulations and verified by computational modeling. Our results unravel a multi-ensemble coordination mechanism in the striatum for action selection during decision-making.

neuroscience↗

bioRxiv2021

Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models

The mouse is a useful preclinical species for evaluating disease etiology due to the availability of a wide variety of genetically modified strains and the ability to perform disease-modifying manipulations. In order to better characterize atrial fibrillation (AF), we profiled several commonly used murine AF models. We initially evaluated a pharmacological model of acute carbachol (CCh) treatment plus atrial burst pacing in C57BL/6 mice. In an effort to observe micro-reentrant circuits indicative of authentic AF, we employed optical mapping imaging in isolated mouse hearts. While CCh reduced atrial refractoriness and increased atrial tachyarrhythmia vulnerability, the left atrial (LA) excitation patterns were rather regular without reentrant circuits or wavelets. Therefore, the atrial tachyarrhythmia resembled high frequency atrial flutter, not typical AF per se. We next examined both a chronic angiotensin II (Ang II) infusion model and the surgical model of transverse aortic constriction (TAC), which have both been reported to induce atrial and ventricular structural changes that serve as a substrates for micro-reentrant AF. Although we observed some extent of atrial remodeling such as fibrosis or enlarged LA diameter, burst pacing-induced atrial tachyarrhythmia vulnerability did not differ from control mice in either model. This again suggested that an AF-like pathophysiology is difficult to demonstrate in the mouse. To continue searching for a valid murine AF model, we studied mice with a cardiac-specific deficiency (KO) in liver kinase B1 (Cardiac-LKB1), which has been reported to exhibit spontaneous AF. Indeed, the electrocardiograms (ECG) of conscious Cardiac-LKB1 KO mice exhibited no P waves and had irregular RR intervals, which are characteristics of AF. Histological evaluation of Cardiac-LKB1 KO mice revealed dilated and fibrotic atria, again consistent with AF. However, atrial electrograms and optical mapping revealed that electrical activity was limited to the sino-atrial node area with no electrical conduction into the atrial myocardium beyond. Thus, Cardiac-LKB KO mice have severe atrial myopathy or atrial standstill, but not AF. In summary, the atrial tachyarrhythmias we observed in the four murine models were distinct from typical human AF, which often exhibits micro- or macro-reentrant atrial circuits. Our results suggest that the four murine AF models we examined are poor representations of human AF, and raise a cautionary note about the use of any murine model to study AF.

physiology↗

bioRxiv2021

Transcriptome and metabolome analyses reveal pathways associated with fruit color in plum (Prunus salicina Lindl.)

BackgroundIn order to reveal the mechanism of fruit color changes in plum, two common plum cultivars Changli84 (Ch84, red fruit) and Dahuangganhe (D, yellow fruit) in Northeast China were selected as plant materials. Transcriptome sequencing and metabonomic analyzing were performed at three different developmental stages: young fruit stage, colour-change stage, and maturation stage. Results"Flavonoid biosynthesis" was significantly enriched in the KEGG analysis. Some DEGs in "Flavonoid biosynthesis" pathway had an opposite trend between the two cultivars, such as CHS, DFR and FLS. Also, transcriptional control of MBW (MYB-bHLH-WD) protein complexes showed a close relationship with plum fruit color, especially the expression of MYBs and bHLHs. In the current study, procyanidin B1 and B2 had the highest level at young fruit stage in Ch84 and the content of procyanidin B2 decreased sharply at the color change stage. Conversely, the content of cyanidin increased with the growth of fruit and reached the peak at the maturation stage. ConclusionThe content of procyanidin B1 and B2 in plums at young fruit stage might be the leading factors of the matured fruit color. At the maturation stage, the cyanidin produced by procyanidins keeps the color of the fruit red. Correspondingly, genes in "flavonoid biosynthesis" pathway play critical roles in regulating the accumulation of anthocyanin in plum.

plant biology↗

bioRxiv2021

CALIPER: A software for blood-free parametric Patlak mapping using PET/MRI input function.

Routine clinical use of absolute PET quantification techniques is limited by the need for serial arterial blood sampling for input function and more importantly by the lack of automated pharmacokinetic analysis tools that can be readily implemented in clinic with minimal effort. PET/MRI provides the ability for absolute quantification of PET probes without the need for serial arterial blood sampling using image-derived input functions (IDIFs). Here we introduce caliPER, a modular and scalable software for simplified pharmacokinetic modelling of PET probes with irreversible uptake or binding based on PET/MR IDIFs and Patlak Plot analysis. caliPER generates regional values or parametric maps of net influx rate (Ki) using reconstructed dynamic PET images and anatomical MRI aligned to PET for IDIF vessel delineation. We evaluated the performance of caliPER for blood-free region-based and pixel-wise Patlak analyses of [18F] FDG by comparing caliPER IDIF to serial arterial blood input functions and its application in imaging brain glucose hypometabolism in Frontotemporal dementia. IDIFs corrected for partial volume errors including spill-out and spill-in effects were similar to arterial blood input functions with a general bias of around 6-8%, even for arteries <5 mm. The Ki and cerebral metabolic rate of glucose estimated using caliPER IDIF were similar to estimates using arterial blood sampling (<2%) and within limits of whole brain values reported in literature. Overall, caliPER is a promising tool for irreversible PET tracer quantification and can simplify the ability to perform parametric analysis in clinical settings without the need for blood sampling. HighlightsO_LIcaliPER is an adaptable image processing software for extracting image-derived input functions and generating parametric maps of irreversible PET tracer uptake. C_LIO_LIAnatomical (T1-weighted/T2-weighted/time-of-flight angiography) MRI carefully aligned to PET provides a robust approach for delineation of vessels on PET, eliminating the need for serial blood sampling for input functions. C_LIO_LIApplication of caliPER in modelling glucose uptake in patients with Frontotemporal dementia, demonstrates the feasibility of absolute quantification of cerebral metabolic rate of glucose in clinical populations. C_LI

bioinformatics↗

bioRxiv2021

Genome-wide identification and characterization of DNA/RNA differences associated with Fusarium graminearum infection in wheat

RNA editing (DNA/RNA differences) as a post-transcriptional modification approach to enrich genetic information, plays the crucial role in regulating diverse biological processes in eukaryotes. Although it has been extensively studied in plant chloroplast and mitochondria genome, RNA editing in plant nuclear genome, especially those associated with Fusarium head blight (FHB), is not well studied at present. Here, we investigated the DNA/RNA differences associated with FHB through a novel method by comparing the RNA-seq data from Fusarium-infected and control samples from 4 wheat genotypes. A total of 187 DNA/RNA differences were identified in 36 wheat genes, representing the first landscape of the FHB-responsive RNA editome in wheat. Furthermore, all of these 36 edited genes were located in the FHB related co-expression gene modules, which may involve in regulating FHB response. Finally, the effects of DNA/RNA differences were systematically investigated to show that they could cause the change of RNA structure and protein structure in edited genes. In particular, the G to C editing (chr3A_487854715) in TraesCS3A02G263900, which is the orthology of OsRACK1, resulted that it was targeted by tae-miR9664-3p to control its expression in different genotype through different editing efficiency, suggesting RNA editing could mediate miRNA to participate in the regulation network of FHB tolerance. This study reported the first wheat DNA/RNA differences associated with FHB, which not only contribute to better understand the molecular basis underlying FHB tolerance, but also shed light on improving FHB tolerance through epigenetic method in wheat and beyond.

plant biology↗

bioRxiv2021

A self-immolative linker for heparanase activatable probe

Substrate-based probes utilize known substrate specificity parameters to create a probe that can be activated by a target enzyme. In developing probes for heparanase, an endo-{beta}-glucuronidase, we previously reported that small, inactive substrate-based probes could be electronically tuned by incorporating electron-withdrawing atoms on the aromatic aglycone fluorophore, ortho- to the cleaved glycosidic bond. However, the installation of electron-withdrawing groups directly onto established fluorophores or other reporters complicates the synthesis of new heparanase probes. In this work we report a new design strategy to expand the toolkit of heparanase imaging probes, in which the installation of an electronically tuned benzyl alcohol linker restored the activity of a previously inactive heparanase probe using 4-methylumbelliferone as the fluorescent reporter, suggesting such a linker can provide a scaffold for facile development of activatable heparanase probes bearing a variety of imaging moieties.

biochemistry↗

bioRxiv2021

A Versatile Linker for Probes Targeting Hydrolases via In Situ labeling

Hydrolases are important molecules that are involved in a wide range of biological functions and their activities are tightly regulated in healthy or diseased states. Detecting or imaging the activities of hydrolases, therefore, can reveal underlying molecular mechanisms in the context of cells to organisms, and their correlation with different physiological conditions can therefore be used in diagnosis. Due to the nature of hydrolases, substrate-based probes can be activated in their catalytic cycles, and cleavage of covalent bonds frees reporter moieties. For test-tube type bulk detection, spatial resolution is not a measure of importance, but for cell- or organism-based detection or imaging, spatial resolution is a key factor for probe sensitivity that influences signal-to-background ratio. One strategy to improve spatial resolution of the probes is to form a covalent linkage between the reporter moiety and intracellular proteins upon probe activation by the enzyme. In this work, we developed a generalizable linker chemistry that would allow in situ labeling of various imaging moieties via quinone methide species. To do so, we synthesized probes containing a monofluoromethyl or a difluoromethyl groups for {beta}-galactosidase activation, while using fluorescein as a fluorescent reporter. The labeling efficacy of these two probes was evaluated in vitro. The probe bearing a monofluormethyl group exhibited superior labeling efficiency in imaging {beta}-galactosidase activity in living cells. This study provides a versatile linker for applying quinone methide chemistry in the development of hydrolase-targeting probes involving in situ labeling.

biochemistry↗

bioRxiv2021

Endogenous RNA editing of a nuclear gene BOSS triggers flowering in tomato

RNA editing is defined as the production of transcripts with RNA sequences different from those of the DNA template. Most of previous RNA editing studies have focused on organelles, while RNA editing of nuclear transcripts is largely unknown. Here, we describe the first example of nuclear transcript RNA editing in plant, the BOSS RNA editing regulates tomato flowering. The SNP (SNP1) located in the 5UTR of BOSS gene (the Balancer of SP and SFT) is associated with tomato early flowering, and two transcripts of BOSS produced by SNP1 associated RNA editing show functional differentiation, where BOSS-{beta} transcript promotes flowering while BOSS- does not. Furthermore, these two transcripts of BOSS are shown to regulate SP (anti-florigen) pathway at transcription level in the shoot apical meristem (SAM). Our findings reveal a new layer of complexity in the control of plant stem cell proliferation and provide the evidence of RNA-editing of a single gene for flowering, suggesting that molecular breeding programs to increase the RNA-editing efficiency may improve the productivity of tomatoes and other agricultural organisms.

plant biology↗