Biology subjects

Jiang, Y.

Publications and source records attributed to Jiang, Y..

At least 307 records · Page 17Linked to original sources

bioRxiv2023

Daptomycin forms a stable complex with phosphatidylglycerol for selective uptake to bacterial membrane

Daptomycin is a potent lipopeptide antibiotic used in the treatment of live-threatening Gram-positive infections, but the molecular mechanism of its interaction with bacterial membrane remains unclear. Here we show that this interaction is divided into two stages, of which the first is a fast and reversible binding of the drug to phospholipid membrane in milliseconds and the second is a slow and irreversible insertion into membrane in minutes, only in the presence of the bacteria-specific lipid phosphatidylglycerol, to a saturating point where the ratio of the drug to phosphatidylglycerol is 1:2. Fluorescence-based titration showed that the antibiotic simultaneously binds two molecules of phosphatidylglycerol with a nanomolar binding affinity in the presence of calcium ion. The resulting stable complex is easily formed in a test tube and readily isolated from the membrane of drug-treated bacterial cells, strongly supporting a unique drug uptake mechanism in which daptomycin forms a stable multi-component complex with calcium and phosphatidylglycerol. Revelation of this novel uptake mechanism provides fresh insights into the mode of action of daptomycin and paves the way to new strategies to attenuate resistance to the drug.

biochemistry↗

bioRxiv2023

Generalization of deep learning models for predicting spatial gene expression profiles using histology images: A breast cancer case study

Spatial transcriptomics is a breakthrough technology that enables spatially-resolved measurement of molecular profiles in tissues, opening the opportunity for integrated analyses of morphology and transcriptional profiles through paired imaging and gene expression data. However, the high cost of generating data has limited its widespread adoption. Predicting gene expression profiles from histology images only can be an effective and cost-efficient in-silico spatial transcriptomics solution but is computationally challenging and current methods are limited in model performance. To advance research in this emerging and important field, this study makes the following contributions. We first provide a systematic review of deep learning methods for predicting gene expression profiles from histology images, highlighting similarities and differences in algorithm, model architecture, and data processing pipelines. Second, we performed extensive experiments to evaluate the generalization performance of the reviewed methods on several spatial transcriptomics datasets for breast cancer, where the datasets are generated using different technologies. Lastly, we propose several ideas for model improvement and empirically investigate their effectiveness. Our results shed insight on key features in a neural network model that either improve or not the performance of in-silico spatial transcriptomics, and we highlight challenges in developing algorithms with strong generalization performance. Key MessagesO_LIWe comprehensively compared the performance of existing methods for predicting spatial gene expression profiles from histology images C_LIO_LIWe assessed the roles of different algorithms, model architectures, and data processing pipelines to model performance C_LIO_LIWe performed extensive experiments to evaluate the generalization of the models on in-distribution and out-of-distribution spatial transcriptomics datasets C_LIO_LIWe proposed several strategies for improving existing models and empirically investigated their effectiveness C_LI

bioinformatics↗

bioRxiv2023

The brain time estimation system is dynamically assembled by non-temporal perceptual states

To investigate how neural integration of visual signals distorts human time perception, we developed a novel apparent motion paradigm. We found that the higher the frequency of visual events defined by spatial location, the longer the perception duration. At the same visual event frequency, perceptual duration was shorter when motion perception was evoked. We propose that the non-temporal perceptual states dynamically determine which core brain region (read-out system) and which group of activated neurons (timing units) assemble into a time estimation system. Timing units have activation delays in integrating input signals, which results in shorter perceptual time since perceptual duration depends only on the outputs of timing units. The read-out system consumes operating time to accumulate each timing unit, this results in a longer perception time the more timing units are accumulated in the same physical duration. Subsequently, experiments further validated two predictions of our perceptual assembly model.

neuroscience↗

bioRxiv2023

Ontogeny of Projections from the Motor Cortex Governing Whisker and Neck Movements to the Striatum in the Rat

Corticostrial or cortico-basal ganglia circuitry plays an important role in integrating sensory and motor information, developing appropriate goal-directed behavior, promoting the maturation of GABAergic interneurons in the striatum, and regulating the nigrostriatal pathways. Dysfunction of this circuitry has been seen in some movement disorders. However, the dynamic changes of this circuitry in early life are not fully elucidated. Previous studies demonstrated that projections from motor cortices of caudal forelimb and jaw-lip-tongue areas to the striatum developed postnatally with terminal-like fibers evident at postnatal day 7. Here we report the development of the projections from the motor cortex governing whisker and neck movements to the striatum. Corticostriatal projections from this area were mainly ipsilateral and also underwent a progressive, postnatal development. The pyramidal tract and its collaterals to the dorsal striatum appeared on the day of birth (postanatal day 0 (P0)), peaked on P6 in density, and continued to be tuned until P36. The intertelencephalic projections in the dorsolateral striatum were established between P6 and P12 and continued to be refined between P20 and P36. Neurons in this motor cortex sent their axons to the contralateral motor cortex via the corpus callosum at the age between P6 and P12. Our results suggest that the time window between P6 and P12 is critical for the development of the projections from the motor cortex governing whisker and neck movement to the striatum in the rat. The overall process of the development of this circuitry appears to correspond to the functional development of whisker movement and locomotor activities.

neuroscience↗

bioRxiv2023

Inducer of CBF Expression 1 (ICE1) Promotes Cold-enhanced Immunity by Directly Activating Salicylic Acid Signaling

Cold stress affects plant immune responses, and this process may involve the salicylic acid (SA) signaling pathway. However, the underlying mechanism by which low temperature signals coordinate with SA signaling to regulate plant immunity remains not fully understood. Here, we found that low temperatures enhanced the disease resistance of Arabidopsis against Pseudomonas syringae pv. tomato (Pst) DC3000. This process required Inducer of CBF expression 1 (ICE1), the core transcription factor in cold-signal cascades. ICE1 physically interacted with Non-expresser of PR genes 1 (NPR1), the master regulator of the SA signaling pathway. Enrichment of ICE1 on the PR1 promoter and its ability to transcriptionally activate PR1 were enhanced by NPR1. Further analyses revealed that cold stress signals cooperate with SA signals to facilitate plant immunity against pathogen attack in an ICE1-dependent manner. Cold treatment promoted interactions of NPR1 and TGA3 with ICE1, and increased the ability of the ICE1-TGA3 complex to transcriptionally activate PR1. Together, our results characterize a previously unrecognized role of ICE1 as an indispensable regulatory node linking low temperature activated- and SA-regulated immunity. Discovery of a crucial role of ICE1 in coordinating multiple signals associated with immunity broadens our understanding of plant-pathogen interactions.

plant biology↗

bioRxiv2023

Mapping glymphatic solute transportation through the perivascular space of hippocampal arterioles with 14 Tesla MRI

The perivascular space (PVS) plays a crucial role in facilitating the clearance of waste products and the exchange of cerebrospinal fluid and interstitial fluid in the central nervous system. While optical imaging methods identify the glymphatic transport of fluorescent tracers through PVS of surface-diving arteries, their limited depth penetration impedes the study of glymphatic dynamics in deep brain regions. In this study, we introduced a novel high-resolution dynamic contrast-enhanced MRI mapping approach based on single-vessel multi-gradient-echo methods. This technique allowed the differentiation of penetrating arterioles and venules from adjacent parenchymal tissue voxels and enabled the detection of Gd-enhanced signals coupled to PVS of penetrating arterioles in the deep cortex and hippocampus. By directly infusing Gd into the lateral ventricle, we eliminated delays in cerebrospinal fluid flow and focused on PVS Gd transport through PVS of hippocampal arterioles. The study revealed significant PVS-specific Gd signal enhancements, shedding light on glymphatic function in deep brain regions. These findings advance our understanding of brain-wide glymphatic dynamics and hold potential implications for neurological conditions characterized by impaired waste clearance, warranting further exploration of their clinical relevance and therapeutic applications.

neuroscience↗

bioRxiv2023

Evolutionary diversity of the control of the azole response by Tra1 across yeast species

Tra1 is an essential co-activator protein of the yeast SAGA and NuA4 acetyltransferase complexes that regulate gene expression through multiple mechanisms including the acetylation of histone proteins. Tra1 is a pseudokinase of the PIKK family characterized by a C-terminal PI3K domain with no known kinase activity. However, mutations of specific arginine residues to glutamine in the PI3K domains (an allele termed tra1Q3) result in reduced growth and increased sensitivity to multiple stresses. In the opportunistic fungal pathogen Candida albicans, the tra1Q3 allele reduces pathogenicity and increases sensitivity to the echinocandin antifungal drug caspofungin, which disrupts the fungal cell wall. Here, we found that loss of Tra1 function, in contrast to what is seen with caspofungin, increases tolerance to the azole class of antifungal drugs, which inhibits ergosterol synthesis. In C. albicans, tra1Q3 increases expression of genes linked to azole resistance, such as ERG11 and CDR1. CDR1 encodes a multidrug ABC transporter associated with efflux of multiple xenobiotics, including azoles. Consequently, cells carrying tra1Q3 show reduced intracellular accumulation of fluconazole. In contrast, a tra1Q3 S. cerevisiae strain displayed opposite phenotypes: decreased tolerance to azole, decreased expression of the efflux pump PDR5 and increased intracellular accumulation of fluconazole. Therefore, our data provide evidence that Tra1 differentially regulates the antifungal response across yeast species.

genetics↗

bioRxiv2023

Estrogen prevents age-dependent beige adipogenesis failure through NAMPT-controlled ER stress pathway

Thermogenic beige adipocytes are recognized as potential therapeutic targets for combating metabolic diseases. However, the metabolic advantages they offer are compromised with aging. Here, we show that treating mice with estrogen (E2), a hormone that decreases with age, to mice can counteract the aging- related decline in beige adipocyte formation when subjected to cold, while concurrently enhancing energy expenditure and improving glucose tolerance. Mechanistically, we find that nicotinamide phosphoribosyltranferase (NAMPT) plays a pivotal role in facilitating the formation of E2-induced beige adipocytes, which subsequently suppresses the onset of age-related ER stress. Furthermore, we found that targeting NAMPT signaling, either genetically or pharmacologically, can restore the formation of beige adipocytes by increasing the number of perivascular adipocyte progenitor cells. Conversely, the absence of NAMPT signaling prevents this process. In conclusion, our findings shed light on the mechanisms governing the age-dependent impairment of beige adipocyte formation and underscore the E2-NAMPT controlled ER stress as a key regulator of this process. HighlightsO_LIEstrogen restores beige adipocyte failure along with improved energy metabolism in old mice. C_LIO_LIEstrogen enhances the thermogenic gene program by mitigating age-induced ER stress. C_LIO_LIEstrogen enhances the beige adipogenesis derived from SMA+ APCs. C_LIO_LIInhibiting the NAMPT signaling pathway abolishes estrogen-promoted beige adipogenesis. C_LI

physiology↗

bioRxiv2023

WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS

Renal fibrosis is a common pathological endpoint in chronic kidney disease (CKD) that is challenging to reverse. Although myofibroblasts are mainly responsible for the accumulation of a fibrillar collagen-rich extracellular matrix (ECM) in fibrotic kidney, recent studies have unveiled their diversity in terms of proliferative and fibrotic characteristics. This diversity could be linked with the existence of different metabolic states, and myofibroblast metabolic reprogramming may contribute to the pathogenesis and progression of renal fibrosis. Here, we reveal an unexpected role of the E3 ubiquitin-protein ligase WWP2 in the metabolic reprogramming of myofibroblasts during renal fibrosis. The tubulointerstitial expression of WWP2 contributes to the progression of fibrosis in CKD patients, and in pre-clinical murine models of CKD. WWP2 deficiency increases fatty acid oxidation and activates the pentose phosphate pathway, boosting mitochondrial respiration at the expense of glycolysis. This concurrently promotes myofibroblast proliferation and halts pro-fibrotic activation, reducing the severity of kidney fibrosis. Mechanistically, WWP2 suppresses the transcription of PGC-1, a metabolic mediator shaping myofibroblast fibrotic response. Pharmacological interventions targeting PGC-1 reverse the effects of WWP2 on fibrotic myofibroblasts. These findings demonstrate the influence of WWP2 on essential metabolic pathways involved in fibrogenesis, uncovering the WWP2-PGC-1 axis that orchestrates the metabolic reprogramming of myofibroblasts during renal fibrosis. Our study presents a potential novel target for therapeutic intervention in the treatment of chronic kidney disease. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/554242v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1847ffeorg.highwire.dtl.DTLVardef@1ef029aorg.highwire.dtl.DTLVardef@93e0f1org.highwire.dtl.DTLVardef@950d49_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIWWP2 expression is elevated in the tubulointerstitium of fibrotic kidneys and contributes to CKD pathogenesis and progression. C_LIO_LIWWP2 uncouples the pro-fibrotic activation and cell proliferation in renal myofibroblasts. C_LIO_LIWWP2 controls mitochondrial respiration in renal myofibroblasts through the metabolic regulator PGC-1 C_LIO_LIMyofibroblast metabolic reprogramming mediates the effect of WWP2 on fibrotic myofibroblasts. C_LI

cell biology↗

bioRxiv2023

ccTCM: a quantitative component and compound platform for promoting the research of traditional Chinese medicine

Traditional Chinese medicine (TCM) databases play a vital role in bridging the gap between TCM and modern medicine, as well as in promoting the popularity of TCM. Elucidating the bioactive ingredients of Chinese medicinal materials is key to TCM modernization and new drug discovery. However, one drawback of current TCM databases is the lack of quantitative data on the constituents of Chinese medicinal materials. Herein, we present ccTCM, a web-based platform designed to provide a component and compound-content-based resource on TCM and analysis services for medical experts. In terms of design features, ccTCM combines resource distribution, similarity analysis, and molecular-mechanism analysis to accelerate the discovery of bioactive ingredients in TCM. ccTCM contains 273 Chinese medicinal materials commonly used in clinical settings, covering 29 functional classifications. By searching and comparing, we finally adopted 2043 studies, from which we collected the compounds contained in each TCM with content greater than 0.001%, and a total of 1 449 were extracted. Subsequently, we collected 40767 compound-target pairs by integrating multiple databases. Taken together, ccTCM is a versatile platform for that can be used by TCM scientists to perform scientific and clinical TCM studies based on quantified ingredients of Chinese medicinal materials. ccTCM is freely accessible at http://www.cctcm.org.cn.

bioinformatics↗

bioRxiv2023

Large-scale population genomics of Malayan pangolins reveals deep diversification and a new species

BackgroundArchipelagos and oceanic islands often present high percentage of endemism due to rapid speciation. The Malayan pangolin is a species distributing at both mainland (southern Yunnan, China) and oceanic islands via Malayan peninsula, which may result in deep differentiation among populations. In-depth investigation of population structure and genetic consequences for such species is of vital importance for their protection and conservation, practically for the critically endangered Malayan pangolin that is suffering from poaching, illegal trade, and habitat loss. ResultsHere we carried out a large-scale population genomic analysis for Malayan pangolins, and revealed three highly distinct genetic populations in this species, two of which are now being reported for the first time. Based on multiple lines of genomic and morphological evidence, we postulate the existence of a new pangolin species (Manis_1). Genetic diversity and recent inbreeding were both at a moderate level for both Malayan pangolins and Manis_1, but mainland Malayan pangolins presented relatively lower genetic diversity, higher inbreeding and fitness cost than island populations. ConclusionsWe found extremely deep and graded differentiation in Malayan pangolins, with two newly discovered genetic populations and a new pangolin species that is closely related to the Philippine pangolin than the typical Malayan pangolin, but a distant relative of the Indian pangolin. Anthropogenic factors did not significantly weaken the basis of genetic sustainability for Malayan pangolins, but mainland Malayan pangolins should be paid more attention for conservation due to higher genetic risks than island populations.

genomics↗

bioRxiv2023

ASB3 expression aggravates inflammatory bowel disease by targeting TRAF6 protein stability and affecting the intestinal microbiota

E3 ubiquitin ligase (E3) plays a vital role in regulating inflammatory responses by mediating ubiquitination. Previous studies have shown that ankyrin repeat and SOCS box-containing protein 3 (ASB3) is involved in immunomodulatory functions associated with cancer. However, the impact of ASB3 on the dynamic interplay of microbiota and inflammatory responses in inflammatory bowel disease (IBD) is unclear. Here we systematically identify the E3 ligase ASB3 as a facilitative regulator in the development and progression of IBD. ASB3-/- mice are resistant to DSS-induced colitis. I{kappa}B phosphorylation levels and production of proinflammatory factors IL-1{beta}, IL-6, and TNF- were reduced in colonic tissues of ASB3-/- mice compared to WT mice. This colitis-resistant phenotype was suppressed after coprophagic microbial transfer and reversed after combined antibiotic clearance of the microbiota. Mechanistically, ASB3 specifically catalyzes K48-linked polyubiquitination of TRAF6 in IECs. In contrast, in ASB3-deficient organoids, the integrity of the TRAF6 protein is shielded, consequently decelerating the onset of intestinal inflammation. Taken together, Our findings demonstrates that ASB3 is associated with dysregulation of the colitis microbiota and promotes proinflammatory factors production by disrupting the TRAF6 stability. Strategies to limit the protein level of ASB3 in intestinal epithelial cells may help in the treatment of colitis.

immunology↗

bioRxiv2023

Atypical Biological Motion Perception in Children with Attention Deficit Hyperactivity Disorder: Dissociating the Roles of Local Motion and Global Configuration Processing

Perceiving biological motion (BM) is crucial for human survival and social interaction. Many studies have reported impaired BM perception in autism spectrum disorder, which is characterised by deficits in social interaction. Children with attention deficit hyperactivity disorder (ADHD) often exhibit similar difficulties in social interaction. However, few studies have investigated BM perception in children with ADHD. Here, we compared differences in the ability to process local kinematic and global configurational cues, two fundamental abilities of BM perception, between typically developing and ADHD children. We further investigated the relationship between BM perception and social interaction skills measured using the Social Responsiveness Scale and examined the contributions of latent factors (e.g., sex, age, attention, and intelligence) to BM perception. The results revealed that children with ADHD exhibited atypical BM perception. Local and global BM processing showed distinct features. Local BM processing ability was related to social interaction skills, whereas global BM processing ability significantly improved with age. Critically, general BM perception (i.e., both local and global BM processing) may be affected by sustained attentional ability in children with ADHD. This relationship was primarily mediated by reasoning intelligence. These findings elucidate atypical BM perception in ADHD and the latent factors related to BM perception. Moreover, this study provides new evidence that BM perception is a hallmark of social cognition and advances our understanding of the potential roles of local and global processing in BM perception and social cognitive disorders.

neuroscience↗

bioRxiv2023

Multi-level processing of emotions in life motion signals revealed through pupil responses

Perceiving emotions from the movements of other biological entities is critical for human survival and interpersonal interactions. Here, we report that emotional information conveyed by point-light biological motion (BM) triggered automatic physiological responses as reflected in pupil size. Specifically, happy BM evoked larger pupil size than neutral and sad BM, while sad BM induced a smaller pupil response than neutral BM. Moreover, this happy over sad pupil dilation effect is negatively correlated with individual autistic traits. Notably, emotional BM with only local motion features retained could also exert modulations on pupils. Compared with intact BM, both happy and sad local BM evoked stronger pupil responses than neutral local BM starting from an earlier timepoint, with no difference between the happy and sad conditions. These results revealed a fine-grained pupil-related emotional modulation induced by intact BM and a coarse but rapid modulation by local BM, demonstrating multi-level processing of emotions in life motion signals. Taken together, our findings shed new light on BM emotion processing, and highlight the potential of utilizing the emotion-modulated pupil response to facilitate the diagnosis of social cognitive disorders.

neuroscience↗

bioRxiv2023

The super-pangenome of Populus unveil genomic facets for adaptation and diversification in widespread forest trees

Understanding the underlying mechanisms between genome evolution and phenotypic and adaptive innovations is a key goal of evolutionary studies. Poplars are the worlds most widely distributed and cultivated trees, with extensive phenotypic diversity and environmental adaptability. Here we report a genus-level super-pangenome of 19 Populus genomes. After integrating pan-genomes with transcriptomes, methylomes and chromatin accessibility mapping, we reveal that the evolutionary fate of pan-genes and duplicated genes are largely associated with local genomic landscapes of regulatory and epigenetic architectures. Further comparative genomic analyses enabled to identify 142,202 structural variations (SVs) across species, which overlap with substantial genes and play key roles in both phenotypic and adaptive divergence. We experimentally validated a [~]180 bp presence/absence variant located in the promoter of the CUC2 gene, which contributed critically to leaf serration divergence between species. Together, this first super-pangenome resource in forest trees will not only accelerate molecular functional studies and genetic breeding of this globally important tree genus, but also lays a foundation for our understanding of tree biology.

evolutionary biology↗

bioRxiv2023

Chromosomal-level genome assembly of Populus davidiana

Despite the population structure and genetic differentiation of P. davidiana has been reported, little is known about the P. davidiana genome characterization with the genomes assembled at the chromosome level. As one of the most widely distributed and ecologically important tree species in China, P. davidiana is an excellent resource to understand population adaption to climate and environment change. Here we present a high-quality assembly based on long-read sequences and Hi-C data. This assembly is assembled into 19 contiguous chromosomes which provides a powerful tool for future association studies.

genomics↗

bioRxiv2023

Simultaneous Multi-Omics Analysis by Direct Infusion Mass Spectrometry (SMAD-MS)

Combined multi-omics analysis of proteomics, metabolomics, and lipidomics requires separate liquid chromatography-mass spectrometry (LC-MS), which limits throughput and increases costs, hindering the application of mass spectrometry-based multi-omics to large-scale analyses. Here, we present single-injection multi-omics analysis by direct infusion (SMAD), an integrated platform leveraging ion mobility mass spectrometry and self-developed software tools to enable single injection multi-omics analysis without liquid chromatography. SMAD allows quantification of over 9,000 metabolite m/z features and over 1,300 proteins from the same sample in less than five minutes. We validated the efficiency and reliability of SMAD with three case studies. (1) mouse macrophages after M1/M2 polarization and senescence, (2) a pilot drug screen in human cells, and (3) large-scale high-throughput drug screening of mammalian cells in 96-well plates. Finally, relationships between proteomic and metabolomic data are discovered by machine learning and validated.

systems biology↗

bioRxiv2023

Combinatorial selective ER-phagy remodels the ER during neurogenesis

The endoplasmic reticulum (ER) employs a diverse proteome landscape to orchestrate many cellular functions ranging from protein and lipid synthesis to calcium ion flux and inter-organelle communication. A case in point concerns the process of neurogenesis: a refined tubular ER network is assembled via ER shaping proteins into the newly formed neuronal projections to create highly polarized dendrites and axons. Previous studies have suggested a role for autophagy in ER remodeling, as autophagy-deficient neurons in vivo display axonal ER accumulation within synaptic boutons, and the membrane-embedded ER-phagy receptor FAM134B has been genetically linked with human sensory and autonomic neuropathy. However, our understanding of the mechanisms underlying selective removal of ER and the role of individual ER-phagy receptors is limited. Here, we combine a genetically tractable induced neuron (iNeuron) system for monitoring ER remodeling during in vitro differentiation with proteomic and computational tools to create a quantitative landscape of ER proteome remodeling via selective autophagy. Through analysis of single and combinatorial ER-phagy receptor mutants, we delineate the extent to which each receptor contributes to both magnitude and selectivity of ER protein clearance. We define specific subsets of ER membrane or lumenal proteins as preferred clients for distinct receptors. Using spatial sensors and flux reporters, we demonstrate receptor-specific autophagic capture of ER in axons, and directly visualize tubular ER membranes within autophagosomes in neuronal projections by cryo-electron tomography. This molecular inventory of ER proteome remodeling and versatile genetic toolkit provides a quantitative framework for understanding contributions of individual ER-phagy receptors for reshaping ER during cell state transitions.

cell biology↗