Biology subjects

Dai, B.

Publications and source records attributed to Dai, B..

26 records · Page 2Linked to original sources

bioRxiv2021

Targeting glucose metabolism sensitizes pancreatic cancer to MEK inhibition

Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal. A critical unmet need exists to explore essential susceptibilities in PDAC and identify druggable targets for tumor maintenance. This is especially challenging in the context of PDAC, in which activating mutations of KRAS oncogene (KRAS*) dominate the genetic landscape. By using an inducible KrasG12D-driven p53 deficient PDAC mouse model (iKras model), we demonstrate that RAF-MEK-MAPK signaling is the major effector for oncogenic Kras-mediated tumor maintenance. However, MEK inhibition has minimal therapeutic effect as single agent for PDAC both in vitro and in vivo. Although MEK inhibition partially downregulates the transcription of glycolysis genes, it surprisingly fails to suppress the glycolysis flux in PDAC cell, which is a major metabolism effector of oncogenic KRAS. Accordingly, In vivo genetic screen identified multiple glycolysis genes as potential targets that may sensitize tumor cells to MAPK inhibition. Furthermore, inhibition of glucose metabolism with low dose 2-deoxyglucose (2DG) in combination with MEK inhibitor dramatically induces apoptosis in KrasG12D-driven PDAC cell in vitro, inhibits xenograft tumor growth and prolongs the overall survival of genetically engineered mouse PDAC model. Molecular and metabolism analyses indicate that co-targeting glycolysis and MAPK signaling results in apoptosis via induction of lethal ER stress. Together, our work suggests that combinatory inhibition of glycolysis and MAPK pathway may serve as an alternative approach to target KRAS-driven PDAC.

cancer biology↗

bioRxiv2020

DDR1-INDUCED NEUTROPHIL EXTRACELLULAR TRAPS DRIVE PANCREATIC CANCER METASTASIS

Pancreatic ductal adenocarcinoma (PDAC) tumors are characterized by a desmoplastic reaction and dense collagen that is known to promote cancer progression. A central mediator of pro-tumorigenic collagen signaling is the receptor tyrosine kinase discoid domain receptor 1 (DDR1). DDR1 is a critical driver of a mesenchymal and invasive cancer cell PDAC phenotype. Previous studies have demonstrated that genetic or pharmacologic inhibition of DDR1 prevents PDAC tumorigenesis and metastasis. Here, we investigated whether DDR1 signaling has cancer cell non-autonomous effects that promote PDAC progression and metastasis. We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs) and subsequent cancer cell invasion and metastasis. Moreover, we have identified that collagen-induced CXCL5 production was mediated by a DDR1-PKC{theta}-SYK-NF{kappa}B signaling cascade. Together, these results highlight the critical contribution of collagen I-DDR1 interaction in the formation of an immune microenvironment that promotes PDAC metastasis. SummaryDeng et al find that collagen signaling via DDR1 on human pancreatic cancer cells drives production and release of the cytokine, CXCL5, into systemic circulation. CXCL5 then triggers infiltration of neutrophils into the tumor where they promote cancer cell progression.

cancer biology↗

bioRxiv2020

Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of COVID-19 Spike psedotype virus

BackgroundThe novel coronavirus disease (2019-nCoV) has been affecting global health since the end of 2019 and there is no sign that the epidemic is abating. The major issue for controlling the infectious is lacking efficient prevention and therapeutic approaches. Chloroquine (CQ) and Hydroxychloroquine (HCQ) have been reported to treat the disease, but the underlying mechanism remains controversial. PurposeThe objective of this study is to investigate whether CQ and HCQ could be ACE2 blockers and used to inhibit 2019-nCoV virus infection. MethodsIn our study, we used CCK-8 staining, flow cytometry and immunofluorescent staining to evaluate the toxicity and autophagy of CQ and HCQ, respectively, on ACE2 high-expressing HEK293T cells (ACE2h cells). We further analyzed the binding character of CQ and HCQ to ACE2 by molecular docking and surface plasmon resonance (SPR) assays, 2019-nCoV spike pseudotyped virus was also used to observe the viropexis effect of CQ and HCQ in ACE2h cells. ResultsResults showed that HCQ is slightly more toxic to ACE2h cells than CQ. Both CQ and HCQ could bind to ACE2 with KD =(7.31{+/-}0.62)e-7 M and (4.82{+/-}0.87)e-7 M, respectively. They exhibit equivalent suppression effect for the entrance of 2019-nCoV spike pseudotyped virus into ACE2h cells. ConclusionsCQ and HCQ both inhibit the entrance 2019-nCoV into cells by blocking the binding of the virus with ACE2. Our findings provide novel insights into the molecular mechanism of CQ and HCQ treatment effect on virus infection.

biochemistry↗

bioRxiv2020

New and improved GRAB fluorescent sensors for monitoring dopaminergic activity in vivo

The monoamine neuromodulator dopamine (DA) plays a critical role in the brain, and the ability to directly measure dopaminergic activity is essential for understanding its physiological functions. We therefore developed the first red fluorescent GPCR-activation-based DA (GRABDA) sensors and optimized versions of green fluorescent GRABDA sensors following our previous studies. In response to extracellular DA, both the red and green GRABDA sensors have a large increase in fluorescence ({Delta}F/F0 values of 150% and 340%, respectively), with subcellular resolution, subsecond kinetics, and nanomolar to submicromolar affinity. Moreover, both the red and green GRABDA sensors readily resolve evoked DA release in mouse brain slices, detect compartmental DA release in live flies with single-cell resolution, and report optogenetically elicited nigrostriatal DA release as well as mesoaccumbens dopaminergic activity during sexual behavior in freely behaving mice. Importantly, co-expressing red GRABDA with either green GRABDA or the calcium indicator GCaMP6s provides a robust tool for simultaneously tracking neuronal activity and dopaminergic signaling in distinct circuits in vivo.

neuroscience↗

bioRxiv2018

The Relation between Alpha/Beta Oscillations and the Encoding of Sentence induced Contextual Information

Within the sensory domain, alpha/beta oscillations have been frequently linked to the prediction of upcoming sensory input. Here, we investigated whether oscillations at these frequency bands serve as a neural marker in the context of linguistic input prediction as well. Specifically, we hypothesized that if alpha/beta oscillations do index language prediction, their power should modulate during sentence processing, indicating stronger engagement of underlying neuronal populations involved in the linguistic prediction process. Importantly, the modulation should monotonically relate to the degrees of predictability of incoming words based on past context. Specifically, we expected that the more predictable the last word of a sentence, the stronger the alpha/beta power modulation. To test this, we measured neural responses with magnetoencephalography of healthy individuals (of either sex) during exposure to a set of linguistically matched sentences featuring three distinct levels of sentence context constraint (high, medium and low constraint). We observed fluctuations in alpha/beta power before last word onset, and also modulations in M400 amplitude after last word onset that are known to gradually relate to semantic predictability. In line with previous findings, the M400 amplitude was monotonically related to the degree of context constraint, with a high constraining context resulting in the strongest amplitude decrease. In contrast, alpha/beta power was non-monotonically related to context constraints. The strongest power decrease was observed for intermediate constraints, followed by high and low constraints. While the monotonous M400 amplitude modulation fits within a framework of prediction, the non-monotonous oscillatory results are not easily reconciled with this idea.\n\nSIGNIFICANCE STATEMENTNeural activity in the alpha (8-10Hz) and beta (16-20) frequency ranges have been related to the prediction of upcoming sensory input. It remains still debated whether these frequency bands relate to language prediction as well. In this magnetoencephalography study, we recorded alpha/beta oscillatory activity while participants listened to sentences whose ending had varying degree of predictability based on past linguistic information. Our results show that alpha/beta power modulations were non-monotonically related to the degree of linguistic predictability: the strongest modulation of alpha/beta power was observed for intermediate levels of linguistic predictability during sentence reading. Together, the results emphasize that alpha/beta oscillations cannot directly be linked to predictability in language, but potentially relate to attention or control operations during language processing.

neuroscience↗

bioRxiv2018

Population based hospitalization burden of laboratory-confirmed hand, foot and mouth disease caused by multiple enterovirus serotypes in southern China

BackgroundHand, foot and mouth disease (HFMD) is spread widely across Asia, and the hospitalization burden is as yet not well understood. Here, we estimated serotype-specific and age-specific hospitalization rates of HFMD in Southern China.\n\nMethodsWe enrolled pediatric patients admitted to 3/3 county-level hospitals and 3/23 township level hospitals in Anhua county, Hunan (CN) with HFMD, and collected samples to identify enterovirus serotypes by RT-PCRs between October 2013 and September 2016. The information of other eligible but un-enrolled patients were retrospectively collected from the same six hospitals. Monthly number of hospitalizations for all causes was collected from each of 23 township level hospitals to extrapolate hospitalizations associated with HFMD among these.\n\nResultsDuring the three years, an estimated 3,236 pediatric patients were hospitalized with lab-confirmed HFMD, and among these only one patient was severe. The mean hospitalization rates were 660 (95% CI: 638-684) per 100,000 person-years for lab-confirmed HFMD, with higher rates among CV-A16 and CV-A6 associated HFMD (213 vs 209 per 100,000 person-years), and lower among EV-A71, CV-A10 and other enteroviruses associated HFMD (134, 39 and 66 per 100,000 person-years, p<0.001). Children aged 12-23 months had the highest hospitalization rates (3,594/100,000 person-years), followed by those aged 24-35 months (1,828/100,000 person-years) and 6-11 months (1,572/100,000 person-years). Compared with other serotypes, CV-A6-associated hospitalizations were evident at younger ages.\n\nConclusionsOur study indicates a substantial hospitalization burden associated with non-severe HFMD in a rural county in southern China. Future mitigation policies should take into account the disease burden identified, and optimize interventions for HFMD.

epidemiology↗

bioRxiv2018

Altered Bacteria-Fungi Inter-Kingdom Network in Gut of Ankylosing Spondylitis Patients

Intestinal bacterial dysbiosis has been increasingly linked to Ankylosing Spondylitis (AS), which is a prototypic and best studied subtype of Spondyloarthritis (SpA). Fungi and bacteria coexist in human gut and interact with each other, although they have been shown to contribute actively to health or diseases, no studies have investigated whether fungal microbiota in AS patients is perturbed. In this study, fecal samples of 22 AS patients, with clinical and radiographic assessments, and 16 healthy controls (HCs) were collected to systematically characterize the gut microbiota and mycobiota in AS patients by 16S rDNA and ITS2-based DNA sequencing. The relationships between therapeutic regimens, disease activity, radiographic damage of AS and gut micro/mycobiome were investigated. Our results showed a distinct mycobiota pattern in AS in addition to microbiota dysbiosis. The gut mycobiome of AS patients was characterized by higher taxonomic levels of Ascomycota, especially the class of Dothideomycetes, and decreased abundance of Basidiomycota, which was mainly contributed by the decease of Agaricales. Compared to HCs, changing of the ITS2/16S biodiversity ratio, and bacteria-fungi interkingdom network were observed in AS patients. Alteration of gut mycobiota was associated with different therapeutic regimens, disease activity, as well as different degrees of radiographic damage. Moreover, we unraveled a disease-specific interkingdom network alteration in AS. Finally, we also identified some trends suggesting that different therapeutic regimens may induce changing of both bacterial and fungal microbiota in AS.\n\nIMPORTANCEHuman gut is colonized by diverse fungi (mycobiome), and they have long been suspected in the pathogenesis of Spondyloarthritis (SpA). Our study unraveled a disease-specific interkingdom network alteration in AS, suggesting that fungi, or the interkingdom interactions between bacteria and fungi, may play an essential role in AS development. However, limited by sample size and indeep mechanism studies, further large scale investigations on the characterization of gut mycobiome in AS patients are needed to form a foundation for research into the relationship between mycobiota dysbiosis and AS development.

microbiology↗

bioRxiv2018

Distracting linguistic information impairs neural entrainment to attended speech

Listening to speech is difficult in noisy environments, and is even harder when the interfering noise consists of intelligible speech as compared to unintelligible sounds. This suggests that the competing linguistic information interferes with the neural processing of target speech. Interference could either arise from a degradation of the neural representation of the target speech, or from increased representation of distracting speech that enters in competition with the target speech. We tested these alternative hypotheses using magnetoencephalography (MEG) while participants listened to a target clear speech in the presence of distracting noise-vocoded speech. Crucially, the distractors were initially unintelligible but became more intelligible after a short training session. Results showed that the comprehension of the target speech was poorer after training than before training. The neural tracking of target speech in the delta range (1-4 Hz) reduced in strength in the presence of a more intelligible distractor. In contrast, the neural tracking of distracting signals was not significantly modulated by intelligibility. These results suggest that the presence of distracting speech signals degrades the linguistic representation of target speech carried by delta oscillations.

neuroscience↗