Biology subjects

Duan, S.

Publications and source records attributed to Duan, S..

66 records · Page 4Linked to original sources

bioRxiv2020

Tropomyosin in mugwort cross-reacts to house dust mite, eliciting non-Th2 response in allergic rhinitis patients sensitized to house dust mite

BackgroundMugwort and house dust mite (HDM) are two of the most common inhalant allergens in Asia; however, whether or not mugwort affects polysensitized HDM+ allergic rhinitis (AR) patients has not been elucidated. MethodsOverall, 15884 AR outpatients were assessed for clinical status. Amino acid sequences of mugwort were determined by mass spectrometry. Afterward, cross-reactivity between mugwort tropomyosin and Dermatophagoides pteronyssinus 10 (Der p10) was analysed by ELISA inhibition and basophils activation experiments. To compare immunologic responses eliciting by two different tropomyosins, peripheral blood mononuclear cells (PBMCs) of HDM-monosensitized patients were stimulated by mugwort, HDM, Der p10 and synthetic peptides representing mugwort tropomyosin respectively. ResultsPolysensitized HDM+AR patients were mainly sensitized to cat and mugwort, and the positive rate of monosensitized HDM+AR out-clinic patients was increased during the mugwort pollen season. Mugwort tropomyosin protein had similar structural domains to HDM tropomyosin, Der p10. ELISA inhibition experiment showed synthetic mugwort tropomyosin peptide inhibited IgE binding to Der p10; mugwort tropomyosin peptide activated basophils which were primed by HDM-specific IgE. Unlike HDM and Derp 10, mugwort and mugwort tropomyosin mainly induced IFN-{gamma} and IL-17, release in PBMCs of monosensitized HDM+AR patients, but not IL-5. ConclusionsPan-allergen tropomyosin is a major protein accounting for the cross-reactivity between mugwort and HDM, which reminds HDM+ patients to reduce mugwort exposure in mugwort pollen season in virtue of the tropomyosin induced mild inflammation.

immunology↗

bioRxiv2020

Extracellular Vesicle-Mediated Purinergic Signaling Contributes to Host Microenvironment Plasticity and Metastasis in Triple Negative Breast Cancer

Metastasis accounts for over 90% of cancer-related deaths. The mechanisms guiding this process remain unclear. Secreted nucleoside diphosphate kinase A and B (NDPK) support breast cancer metastasis. Proteomic evidence confirms their presence in breast cancer-derived extracellular vesicles (EVs). We investigated the role of EV-associated NDPK in modulating the host microenvironment in favor of pre-metastatic niche formation. We measured NDPK expression and activity in EVs isolated from triple-negative breast cancer (MDA-MB-231) and non-tumorigenic mammary epithelial (HME1) cells using flow cytometry, western blot, and ATP assay. We evaluated the effects of EV-associated NDPK on endothelial cell migration, vascular remodeling, and metastasis. We further assessed MDA-MB-231 EV induced-proteomic changes in support of pre-metastatic lung niche formation. NDPK-B expression and phosphotransferase activity were enriched in MDA-MB-231 EVs that promote vascular endothelial cell migration and disrupt monolayer integrity. MDA-MB-231 EV-treated mice demonstrate pulmonary vascular leakage and enhanced experimental lung metastasis, whereas treatment with an NDPK inhibitor or a P2Y1 purinoreceptor antagonist blunts these effects. We identified perturbations to the purinergic signaling pathway in experimental lungs, lending evidence to support a role for EV-associated NDPK-B in lung pre-metastatic niche formation and metastatic outgrowth.

cancer biology↗

bioRxiv2020

A Substantia Innominata-midbrain Circuit Controls a General Aggressive State

While aggressive behaviors are universal and essential for survival, uncontrollable and abnormal aggressive behaviors in animals or humans may have severe adverse consequences or social costs. Neural circuits regulating specific forms of aggression under defined conditions have been described, but how brain circuits govern a general aggressive response remains unknown. Here, we found that posterior substantia innominata (pSI) neurons responded to several aggression-provoking cues with the graded activity of differential dynamics, predicting the aggressive state and the topography of aggression in mice. Activation of pSI neurons projecting to the periaqueductal gray (PAG) increased aggressive arousal and robustly initiated/promoted all the types of aggressive behavior examined in an activity level-dependent manner. Inactivation of the pSI circuit largely blocked diverse aggressive behaviors but not mating. By encoding a general aggressive response, the pSI-PAG circuit universally drives multiple aggressive behaviors and may provide a potential target for alleviating human pathological aggression. In BriefZhu et al. find that the posterior substantia innominata neurons universally drive aggressive behaviors by representing aggressive state and topography of aggression in mice. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/047670v2_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@19d72org.highwire.dtl.DTLVardef@7cc4corg.highwire.dtl.DTLVardef@1f5c3dborg.highwire.dtl.DTLVardef@d9743_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIpSI neuronal dynamics reflect aggressive state and the topography of aggression C_LIO_LIThe pSI-PAG circuit promotes arousal and elicits thirteen aggressive behaviors C_LIO_LIThe pSI controls various aggressive behaviors in an activity level-dependent manner C_LIO_LIInactivation of the pSI circuit blocks diverse aggressive behaviors but not mating C_LI

neuroscience↗

bioRxiv2020

Reconstruction of the Hypothalamo-Neurohypophysial System and Functional Dissection of Magnocellular Oxytocin Neurons in the Brain

The hypothalamo-neurohypophysial system (HNS), comprising hypothalamic magnocellular neuroendocrine cells (MNCs) and the neurohypophysis, plays a pivotal role in regulating reproduction and fluid homeostasis by releasing oxytocin and vasopressin into the bloodstream. However, it remains incompletely understood on its structure and whether it contributes to the central actions of oxytocin and vasopressin. Using viral tracing and whole brain imaging, we reconstructed the three-dimensional architecture of the HNS and uncovered that subsets of MNCs collaterally project to multiple extrahypothalamic regions. Moreover, selective activation of magnocellular oxytocin neurons promoted peripheral oxytocin release and facilitated central oxytocin-mediated social interactions. Further, MNCs-released oxytocin in the caudate putamen enhanced locomotion to orchestrate social investigation. Our work reveals the previously unrecognized complexity of the HNS and provides structural and functional evidence for MNCs in coordinating both peripheral and central oxytocin-mediated actions, which will shed light on the mechanistic understanding of oxytocin-related psychiatric diseases.

neuroscience↗

bioRxiv2019

Lesions of canine prostate underwent laser ablation, radiofrequency ablation, and microwave ablation: Lesions shapes and clinical significances

ObjectiveTo explore the shapes and clinical significances of the lesions of canine prostate underwent laser ablation (LA), radiofrequency ablation (RFA), and microwave ablation (MWA).\n\nMethodsHere, 6 male Beagle dogs were randomly assigned to LA, RFA, and MWA groups, respectively. The ablations were conducted with the doses commonly applied in clinical practice (LA: 3 W/1200 J; RFA and MWA: 30 W/120 s) for one region in the left and right lobes of the prostate, which totally resulted in 12 lesions. An energy transmitter was inserted via the perineum under the guidance of transrectal ultrasound (TRUS) and the ablation process was observed dynamically. After ablation, the efficacy was assessed by contrast-enhanced ultrasonography (CEUS), and transverse diameter (TRD), anteroposterior diameter (APD), and longitudinal diameter (TRD) were measured. Then, the volume (V) was calculated according to the following formulae, V = 1/6 x {pi} x (MLD x APD x LD), and ratio (R) R =[(MLD + APD)/2 x LD], which was used to show the shape of the lesion (The closer R is to 1, the more spherical it is).\n\nResultsThe shapes and sizes of the lesions underwent the three techniques varied under the clinically commonly used doses. The R values, reflecting the changes in shapes of lesions, were 0.89{+/-}0.02, 0.72{+/-}0.01, and 0.65{+/-}0.03 for RFA, MWA, and LA, respectively, which were significantly different (P =0.027). The volumes of the lesions underwent the three ablation techniques significantly varied as well (P=0.001), which were 2.17{+/-}0.10, 1.51{+/-}0.20, and 0.79{+/-}0.07 ml for MWA, LA, and RFA, respectively. Conclusion: The above-mentioned three techniques could be used for ablation of prostate cancer using the clinically commonly used doses. The shapes of the lesions underwent the three ablation techniques varied evidently, with the lesions received RFA and LA were more spherical and oval, respectively, while the shapes of lesions underwent MWA were between spherical and oval. The lesions received MWA and RFA had the largest and smallest sizes, respectively, while sizes of lesions underwent LA were in the middle. These findings may assist physicians to select an appropriate therapeutic method for treatment of prostate disease.

cancer biology↗

bioRxiv2019

GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) is a deadly form of breast cancer due to the development of resistance to chemotherapy affecting over 30% of patients. New therapeutics and companion biomarkers are urgently needed. Recognizing the elevated expression of glucose transporter 1 (GLUT1, encoded by SLC2A1) and associated metabolic dependencies in TNBC, we investigated the vulnerability of TNBC cell lines and patient-derived samples to GLUT1 inhibition. We report that genetic or pharmacological inhibition of GLUT1 with BAY-876 impairs the growth of a subset of TNBC cells displaying high glycolytic and lower oxidative phosphorylation (OXPHOS) rates. Pathway enrichment analysis of gene expression data implicates E2F Targets pathway activity as a surrogate of OXPHOS activity. Furthermore, the protein levels of retinoblastoma tumor suppressor (RB1) are strongly correlated with the degree of sensitivity to GLUT1 inhibition in TNBC, where RB1-negative cells are insensitive to GLUT1 inhibition. Collectively, our results highlight a strong and targetable RB1-GLUT1 metabolic axis in TNBC and warrant clinical evaluation of GLUT1 inhibition in TNBC patients stratified according to RB1 protein expression levels.

cancer biology↗

bioRxiv2018

A Chemical Toolbox for the Study of Bromodomains and Epigenetic Signaling

Bromodomains (BRDs) are evolutionary conserved epigenetic protein interaction modules which recognize (\"read\") acetyl-lysine, however their role(s) in regulating cellular states and their potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set of 25 chemical probes, selective tool small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate the selectivity of this probe-set using BROMOscan(R) and demonstrate the utility of the set using studies of muscle cell differentiation and triple negative breast cancer (TNBC). We identified cross talk between histone acetylation and the glycolytic pathway resulting in a vulnerability of TNBC cell lines to inhibition of BRPF2/3 BRDs under conditions of glucose deprivation or GLUT1 inhibition. This chemical probe set will serve as a resource for future applications in the discovery of new physiological roles of bromodomain proteins in normal and disease states, and as a toolset for bromodomain target validation.

cell biology↗

bioRxiv2018

Active information maintenance in working memory by a sensory cortex

Working memory is a critical function of the brain to maintain and manipulate information over delay periods of seconds. Sensory areas have been implicated in working memory; however, it is debated whether the delay-period activity of sensory regions is actively maintaining information or passively reflecting top-down inputs. We hereby examined the anterior piriform cortex, an olfactory cortex, in head-fixed mice performing a series of olfactory working memory tasks. Information maintenance is necessary in these tasks, especially in a dual-task paradigm in which mice are required to perform another distracting task while actively maintaining information during the delay period. Optogenetic suppression of the piriform cortex activity during the delay period impaired performance in all the tasks.Furthermore, electrophysiological recordings revealed that the delay-period activity of the anterior piriform cortex encoded odor information with or without the distracting task.Thus, this sensory cortex is critical for active information maintenance in working memory.

neuroscience↗

bioRxiv2018

Mapping and Analysis of QTL for Early Maturity Trait in Tetraploid Potato (Solanum tuberosum L.)

Maturity is one of the important traits of potato. In order to get the genetic segment of potato early maturity trait, a tetraploid potato maturity segregation population of Zhongshu 19 x Zhongshu 3 was used for genetic analysis through the combination of high throughput simplified genome sequencing (2b-RAD) and bulked segregation analysis (BSA). A genetic segment related to the early maturity trait at the 3.7~4.2 Mb locus on the short arm of chromosome 5 was obtained and eight markers were developed based on this segment, while five of them were closely linked to the early maturity trait loci. Moreover, 42 SSR markers were developed based on the reference sequence of DM. Finally, a genetic map of chromosome 5 contained 50 markers was constructed using the Tetraploidmap software. The total map length was 172 cM with an average genetic distance of 3.44 cM. Combining with phenotypic data of the segregation population, we mapped the early maturity trait QTL with the contribution of 33.55% on the short arm of chromosome 5, located at 84cM between the flanking markers SSR5-85-1 and SCAR5-8 with the physical interval of 471kb. Gene annotation showed that there exist 34 genes in this region, 12 of them are unknown function. Among the other 22 annotated genes, E3 ubiquitin ligase gene PUB14 may be related to maturity and regulate tuber formation. Our fine mapping of the early maturity QTL made a solid foundation for cloning of the early maturity controlled gene or genes.\n\nKey messageEarly maturity site was mapped using a tetraploid potato segregation population derived from cv. Zhongshu 19 and Zhongshu 3. One major QTL with 33.55% contribution to early maturity was fine mapped in physical interval of 471kb on chromosome 5.

genetics↗

bioRxiv2018

ATRAID, a genetic factor that regulates the clinical action of nitrogen-containing bisphosphonates on bone.

Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFFs) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase (FDPS), resulting in defects in protein prenylation. Yet it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene, ATRAID. Loss of ATRAID function results in selective resistance to N-BP-mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation. ATRAID is required for alendronate inhibition of osteoclast function, and ATRAID-deficient mice have impaired therapeutic responses to alendronate in both postmenopausal and senile (old age) osteoporosis models. Lastly, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF. ATRAID is one of three genes that contain rare non-synonymous coding variants in patients with ONJ or AFF that is also differentially expressed in poor outcome groups of patients treated with N-BPs. We functionally validated this patient variation in ATRAID as conferring cellular hypersensitivity to N-BPs. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people. One Sentence SummaryATRAID is essential for responses to the commonly prescribed osteoporosis drugs nitrogen-containing bisphosphonates. OverlineBONE

genomics↗

bioRxiv2018

MLL1 minimal catalytic complex is a dynamic conformational ensemble susceptible to pharmacological allosteric disruption

Histone H3K4 methylation is an epigenetic mark associated with actively transcribed genes. This modification is catalyzed by the mixed lineage leukaemia (MLL) family of histone methyltransferases including MLL1, MLL2, MLL3, MLL4, SET1A and SET1B. Catalytic activity of MLL proteins is dependent on interactions with additional conserved proteins but the structural basis for subunit assembly and the mechanism of regulation is not well understood. We used a hybrid methods approach to study the assembly and biochemical function of the minimally active MLL1 complex (MLL1, WDR5 and RbBP5). A combination of small angle X-ray scattering (SAXS), cross-linking mass spectrometry (XL-MS), NMR spectroscopy, and computational modeling were used to generate a dynamic ensemble model in which subunits are assembled via multiple weak interaction sites. We identified a new interaction site between the MLL1 SET domain and the WD40 repeat domain of RbBP5, and demonstrate the susceptibility of the catalytic function of the complex to disruption of individual interaction sites.

biophysics↗

bioRxiv2018

ErbB4 deletion in noradrenergic neurons in the locus coeruleus induces mania-like behavior via elevated catecholamines

Dysfunction of the noradrenergic (NE) neurons is implicated in the pathogenesis of manic-depressive psychosis (MDP). ErbB4 is highly expressed in NE neurons, and its genetic variation has been linked to MDP; however, how ErbB4 regulates NE neuronal function and contributes to MDP pathogenesis is unclear. Here we find that conditional deletion of ErbB4 in locus coeruleus (LC) NE neurons increases neuronal spontaneous firing through NMDA receptor hyperfunction, and elevates catecholamines in the cerebrospinal fluid (CSF). Furthermore, ErbB4-deficient mice present mania-like behaviors, including hyperactivity, reduced anxiety and depression, and increased sucrose preference. These behaviors are completely rescued by the anti-manic drug lithium or antagonists of catecholaminergic receptors. Our study demonstrates the critical role of ErbB4 signaling in regulating LC-NE neuronal function, reinforcing the view that dysfunction of the NE system may contribute to the pathogenesis of mania-associated disorder.

neuroscience↗