Biology subjects

Long, C.

Publications and source records attributed to Long, C..

43 records · Page 3Linked to original sources

bioRxiv2020

Microglial activation results in neuron-type-specific increase in mPFC GABAergic transmission and abnormal behavior in mice

Neuroinflammation and synaptic dysfunction are two early symptoms of most neurological diseases. However, the mechanisms underlying microglia-associated neuroinflammation in the regulation of synaptic activity remain obscure. We report here that acute neuroinflammation induced by a single-dose proinflammatory cytokine inducer, lipopolysaccharide (LPS), results in enhanced inhibitory postsynaptic currents (IPSCs) of glutamatergic neurons, upregulated levels of GABAAR subunits, glutamine synthetase (GS) and vGAT, and downregulated BDNF and pTrkB levels, due to enhanced activation of microglia in the medial prefrontal cortex (mPFC). Blockage of microglial activation by minocycline ameliorated LPS-induced aberrant mIPSCs and associated aberrant protein expression and behavior. Exogenous application of BDNF prior to LPS challenge also ameliorated LPS-induced abnormal mIPSCs. Thus, this study elucidates a critical role for microglia in the neurobiology of GABAergic synaptic dysfunction induced by neuroinflammation, revealing a novel GABAergic signaling pathway that might be targeted therapeutically to treat neuroinflammation-induced abnormal synaptic activity and associated aberrant behavior.

neuroscience↗

bioRxiv2020

Laboratory evolution of multiple E. coli strains reveals unifying principles of adaptation but diversity in driving genotypes

Fitness landscapes are a central concept in evolutionary biology and have been thoroughly detailed in terms of genotypes. However, our understanding of the selected metabolic and gene expression adaptations, and their dependence on genetic background, remains limited. Here, we reveal multi-scale adaptation principles in the E. coli species by taking multi-omics measurements of six different strains throughout their adaptive evolution to glucose minimal media. Statistics and matrix factorization is applied to yield four key results. First, analysis of the metabolic and physiological data shows evolutionary convergence in growth rate, glucose uptake rate, glycolytic ATP and NADH production but divergence in NADPH production strategies. Second, factorization-based analysis of the transcriptome revealed six conserved transcriptomic adaptations describing increased expression of ribosome and amino acid biosynthetic genes and decreased expression of stress response and structural genes. Third, correlation analysis identifies five tradeoffs underlying the transcriptomic profiles. Fourth, statistical tests leveraging ALE design identify four mutation-flux correlates and eight mutation-transcriptomic correlates that link mutations to systems level adaptation principles. Our total results reveal the dominant metabolic and regulatory constraints governing E. coli growth adaptation that either distinguish strains or are conserved principles.

systems biology↗

bioRxiv2020

Plasmodium falciparum-specific IgM B cells dominate in children, expand with malaria and produce parasite inhibitory IgM

IgG antibodies are known to play a central role in naturally acquired immunity to blood-stage malaria in humans, but little is known about the IgM response to blood-stage malaria, the mechanisms by which IgM may protect, or the underlying biology of Plasmodium falciparum (Pf)-specific IgM B cells. In a Mali cohort spanning infants to adults we conducted a longitudinal analysis of B cells specific for the Pf blood-stage antigens AMA1 and MSP1, as well as the comparator antigen influenza hemagglutinin (HA). At the uninfected baseline, before the malaria season, Pf-specific memory B cells (MBCs) in children are disproportionally IgM+ and only gradually shift to IgG+ with age, in contrast to HA-specific MBCs that are predominantly IgG+ from infancy to adulthood. In response to acute febrile malaria, Pf-specific IgM B cells increase in frequency and upregulate activation and co-stimulatory markers. B cell receptor (BCR) analysis showed that Pf-specific IgM B cells are somatically hypermutated at levels comparable to HA-specific IgG B cells. Finally, IgM antibodies from the plasma of malaria-exposed individuals were comparable to IgG in inhibiting Pf blood-stage growth in vitro, and significantly better at enhancing phagocytosis of Pf merozoites, suggesting that IgM may protect through both direct neutralization and opsonization. Thus, somatically hypermutated Pf-specific IgM MBCs dominate in early life, are activated and expand during acute malaria and are associated with plasma IgM that inhibits parasite growth in vitro.

immunology↗

bioRxiv2020

Dppa2/4 promotes zygotic genome activation by binding to GC-rich region of proximal promoter in signaling pathways

Developmental pluripotency associated 2 (Dppa2) and Dppa4 as positive drivers were helpful for transcriptional regulation of ZGA. Here, we systematically assessed the cooperative interplay between Dppa2 and Dppa4 in regulating cell pluripotency of three cell types and found that simultaneous overexpression of Dppa2/4 can make induced pluripotent stem cells closer to embryonic stem cells. Compared with other pluripotency transcription factors (TFs), Dppa2/4 tends to bind on GC-rich region of proximal promoter (0-500bp). Moreover, there was more potent effect of Dppa2/4 regulation on signaling pathways than other TFs, in which 75% and 85% signaling pathways were significantly activated by Dppa2 and Dppa4, respectively. Notably, Dppa2/4 also can dramatically trigger the decisive signaling pathways for facilitating ZGA, including Hippo, MAPK and TGF-beta signaling pathways and so on. At last, we found that Alkaline phosphatase placental-like 2 (Alppl2) was significantly activated at the 2-cell stage in mouse embryos and 4-8 cell stage in human embryos, further predicted that Alppl2 was directly regulated by Dppa2/4 as a candidate driver of ZGA to regulate pre-embryonic development.

bioinformatics↗

bioRxiv2019

Temporal regulation of nicotinic acetylcholine receptor subunits supports central cholinergic synapse development

Construction and maturation of the postsynaptic apparatus are crucial for synapse and dendrite development. The fundamental mechanisms underlying these processes are most often studied in glutamatergic central synapses in vertebrates. Whether the same principles apply to excitatory cholinergic synapses in the insect central nervous system (CNS) is not known. To address this question, we investigated Drosophila ventral lateral neurons (LNvs) and identified nAchR1 (D1) and nAchR6 (D6) as the main functional nicotinic acetylcholine receptor (nAchR) subunits in these cells. With morphological and calcium imaging studies, we demonstrated their distinct roles in supporting dendrite morphogenesis and synaptic transmission. Furthermore, our analyses revealed a transcriptional upregulation of D1 and downregulation of D6 during larval development, indicating a close association between the temporal regulation of nAchR subunits and synapse maturation. Together, our findings show transcriptional regulation of nAchR composition is a core element of developmental and activity-dependent regulation of central cholinergic synapses.

neuroscience↗

bioRxiv2019

Iron-deficiency and estrogen are associated with ischemic stroke by up-regulating transferrin to induce hypercoagulability

In the accompanying manuscript, transferrin has been demonstrated to maintain coagulation balance by interacting with clotting factors, suggesting that elevated transferrin causes thromboembolic diseases and factors up-regulating transferrin is associated with thrombosis. Here we show that transferrin and transferrin-thrombin/FXIIa complexes are elevated in plasma and cerebrospinal fluid of ischemic stroke (IS) patients with iron-deficiency anemia (IDA) history, IDA patients and venous thromboembolism patients using combined oral contraceptives (CC) as well as ID mice, suggesting an association of transferrin up-regulation with ID and CC. ID and estrogen up-regulated transferrin through hypoxia and estrogen response elements located at transferrin gene enhancer and promoter region, respectively. ID, exogenous transferrin/estrogen administration or transferrin over-expression promoted hypercoagulability and aggravated IS, while anti-transferrin antibody, transferrin knockdown or designed peptide inhibitors interfering transferrin-thrombin/FXIIa interaction exerted anti-IS effects in vivo. Collectively, the results reveal that factors (i.e., ID and CC) up-regulating transferrin are risk factors of thromboembolic diseases.

biochemistry↗

bioRxiv2019

Microbial biogeography and ecology of the mouth and implications for periodontal diseases

Human-associated microbial communities differ in composition among body sites and between habitats within a site. Patterns of variation in the distribution of organisms across time and space is referred to as biogeography. The human oral cavity is a critical observatory for exploring microbial biogeography because it is spatially structured, easily accessible, and its microbiota has been linked to the promotion of both health and disease. The biogeographic features of microbial communities residing in spatially distinct but ecologically similar environments on the human body, including the subgingival crevice, have not yet been adequately explored. The purpose of this paper is twofold. First, we seek to provide the dental community with a primer on biogeographic theory, highlighting its relevance to the study of the human oral cavity. For this reason, we summarize what is known about the biogeographic variation of dental caries and periodontitis and postulate as to how this may be driven by spatial patterning in oral microbial community composition and structure. Second, we present a number of methods that investigators can use to test specific hypotheses using biogeographic theory. To anchor our discussion, we apply each method to a case study and examine the spatial variation of the human subgingival microbiota of 2 individuals. Our case study suggests that subgingival communities in the aggregate may conform to an anterior-to-posterior gradient in community composition. The gradient appears to be structured both by deterministic and non-deterministic processes, though additional work is needed to test and confirm specific hypotheses. A better understanding of biogeographic patterns and processes will advance our understanding of ways to optimize the efficacy of dental interventions targeting the oral microbiota.

ecology↗