Biology subjects

Tian, Y.

Publications and source records attributed to Tian, Y..

At least 217 records · Page 12Linked to original sources

bioRxiv2021

T helper 2 transcriptional profile predicts single-cell HIV envelope-specific polyfunctional CD4+ T cells correlated with reduced risk of infection in RV144 trial

Despite the critical role antigen-specific T cells play in responding to viral infections, their aggregate frequencies in peripheral blood have not correlated with clinical protection during HIV infection. However, a subset of HIV-specific CD4+ T cells, termed polyfunctional T cells, can produce multiple effector cytokines simultaneously. In the RV144 HIV vaccine trial, polyfunctional T cells correlated with reduced risk of HIV infection. Little is known about what differentiates polyfunctional T cells from other vaccine-elicited T cells. Therefore, we developed a novel live-cell multiplexed cytokine capture assay, to identify and transcriptionally profile vaccine-specific polyfunctional CD4+ T cells. We applied these methods to samples from the HVTN 097 clinical trial of the same vaccine regimen as RV144. We discovered two surface receptors that were enriched among polyfunctional CD4+ T cells and a Th2-biased signature (IL-4, IL-5, and IL-13) that specifically predicted the envelope-specific polyfunctional CD4+ T cells that were correlated with reduced risk of HIV infection in RV144. By linking single-cell transcriptional and functional profiles, we may be able to further define the role of vaccine-elicited polyfunctional T cells in contributing to effective immunity. Key PointsO_LINovel ex vivo multiplexed cytokine capture assay to enumerate and single-cell sort polyfunctional T cells for downstream analyses C_LIO_LIPolyfunctional T cells were specifically detected among the HIV envelope-stimulated CD4+ T cells C_LIO_LISingle-cell RNA sequencing identified novel surface markers enriched among vaccine-specific polyfunctional CD4+ T cells C_LIO_LITh2 transcriptional signature predicted polyfunctional CD4+ T cell profile that had correlated with reduced risk of HIV infection in the RV144 HIV efficacy trial C_LI

immunology↗

bioRxiv2021

Machine learning prediction of cognition from functional connectivity: Are feature weights reliable?

Cognitive performance can be predicted from an individuals functional brain connectivity with modest accuracy using machine learning approaches. As yet, however, predictive models have arguably yielded limited insight into the neurobiological processes supporting cognition. To do so, feature selection and feature weight estimation need to be reliable to ensure that important connections and circuits with high predictive utility can be reliably identified. We comprehensively investigate feature weight test-retest reliability for various predictive models of cognitive performance built from resting-state functional connectivity networks in healthy young adults (n=400). Despite achieving modest prediction accuracies (r=0.2-0.4), we find that feature weight reliability is generally poor for all predictive models (ICC<0.3), and significantly poorer than predictive models for overt biological attributes such as sex (ICC {approx} 0.5). Larger sample sizes (n=800), the Haufe transformation, non-sparse feature selection/regularization and smaller feature spaces marginally improve reliability (ICC<0.4). We elucidate a tradeoff between feature weight reliability and prediction accuracy and find that univariate statistics are marginally more reliable than feature weights from predictive models. Finally, we show that measuring agreement in feature weights between cross-validation folds provides inflated estimates of feature weight reliability. We thus recommend for reliability to be estimated out-of-sample, if possible. We argue that rebalancing focus from prediction accuracy to model reliability may facilitate mechanistic understanding of cognition with machine learning approaches.

neuroscience↗

bioRxiv2021

Effect of water temperature on the behavior of Neptunea cumingii and the histology, immune enzyme activity, and transcriptome of its gills and kidneys

The behavior of the marine snail Neptunea cumingii cultured at different temperatures (0, 4, 8, 12, 16 (control), 20, 24, and 28{degrees}C) and the histology, immune enzyme activity, and transcriptome of its gills and kidneys were studied using ecological and molecular methods. At 0{degrees}C, most of the snails shrank in size and did not eat during the first 6 h. At 28{degrees}C, snails also did not eat, death began to occur at 24 h. when the temperature was 8 {degrees}C and 12 {degrees}C, there was no significant difference in the mean feed intake of N. cumingii (P>0.05). And it was higher than the average conch intake under other temperature conditions. However, the histology of the gills and kidneys differed among test temperatures. At 0{degrees}C, the morphology of the gill pieces was difficult to judge. At 24{degrees}C, edema was present in the small gills, and at 28{degrees}C the small gills were severely deformed, the distance between the gill capillaries and the surrounding area was enlarged, and the gill tissue was severely damaged. Temperature increase or decrease from 16{degrees}C caused the columnar cells of the kidney to become shorter and more numerous. The total antioxidant capacity (T-AOC), catalase (CAT) and superoxide dismutase activities (SOD) of the gill and kidney differed significantly among the temperature conditions (p < 0.05). Transcriptome results showed that temperature change resulted in up-regulation of 2339 genes and down-regulation of 2058 genes in the gills, and in up-regulation of 2300 genes and down-regulation of 2060 genes in the kidneys of N. cumingii. Furthermore, the DEGs were subject to GO and KEGG enrichment analysis, and which showed that most of the DEGs in gill were involved in protein folding, defolding, translation, ribosome, and most of the DEGs in kidney were involved in DNA recombination, nuclear euchromatin, RNA-directed DNA polymerase activity. Finally, the results from this study show that N. cumingii prefers the temperature range was 8 to 16, temperature increase or decrease from that range, many aspects of N. cumingii biology could be significantly affected.

physiology↗

bioRxiv2021

Superscan: Supervised Single-Cell Annotation

Automated cell type annotation of single-cell RNA-seq data has the potential to significantly improve and streamline single cell data analysis, facilitating comparisons and meta-analyses. However, many of the current state-of-the-art techniques suffer from limitations, such as reliance on a single reference dataset or marker gene set, or excessive run times for large datasets. Acquiring high-quality labeled data to use as a reference can be challenging. With CITE-seq, surface protein expression of cells can be directly measured in addition to the RNA expression, facilitating cell type annotation. Here, we compiled and annotated a collection of 16 publicly available CITE-seq datasets. This data was then used as training data to develop Superscan, a supervised machine learning-based prediction model. Using our 16 reference datasets, we benchmarked Superscan and showed that it performs better in terms of both accuracy and speed when compared to other state-of-the-art cell annotation methods. Superscan is pre-trained on a collection of primarily PBMC immune datasets; however, additional data and cell types can be easily added to the training data for further improvement. Finally, we used Superscan to reanalyze a previously published dataset, demonstrating its applicability even when the dataset includes cell types that are missing from the training set.

bioinformatics↗

bioRxiv2021

Virus-Targeted Transcriptomic Analyses Implicate Ranaviral Interaction with Host Interferon Response in Frog Virus 3-infected Frog Tissues

Frog Virus 3 (FV3) is a large dsDNA virus that cause global infections in amphibians, fish and reptiles, and contribute to amphibian declines. FV3s genome contains near 100 putative open reading frames (ORFs). Previous studies have classified these coding genes into temporal classes as immediate early, delayed early and late viral transcripts based on their sequential expression during FV3 infection. To genome-wide characterize ranaviral gene expression, we performed a whole transcriptomic analysis (RNA-Seq) using total RNA samples containing both viral and cellular transcripts from FV3-infected Xenopus laevis adult tissues using two FV3 strains, a wild type (FV3-WT) and an ORF64R-deleted recombinant (FV3-{Delta}64R). In samples from the infected intestine, liver, spleen, lung and especially kidney, a FV3-targeted transcriptomic analysis mapped reads spanning the full-genome coverage at [~]10x depth on both positive and negative strands. By contrast, reads were only mapped to partial genomic regions in samples from the infected thymus, skin and muscle. Extensive analyses validated the expression of almost all annotated 98 ORFs and profiled their differential expression in a tissue-, virus-, and temporal class-dependent manners. Further studies identified several putative ORFs that encode hypothetical proteins containing viral mimicking conserved domains found in host interferon (IFN) regulatory factors (IRFs) and IFN receptors. This study provides the first comprehensive genome-wide viral transcriptome profiling during infection and across multiple amphibian host tissues that will serve as instrumental reference. It also presents evidence implying that ranaviruses like FV3 have acquired previously unknown molecular mimics interfering with host IFN signaling during evolution. ImportanceFrog Virus 3 (FV3), are large dsDNA viruses that cause devastating infections globally in amphibians, fish and reptiles, and contribute to catastrophic amphibian declines. FV3s large genome encodes near 100 coding genes, of which most have been functionally uncharacterized in the viral pathogenesis. Using a whole transcriptomic analysis (RNA-Seq) in FV3-infected amphibian samples, we determined a genome-wide virus transcriptome and profiled their differential expression in a tissue-, virus-, and temporal class-dependent manners. Further studies identified several putative ORFs that encode hypothetical proteins containing viral mimicking conserved domains found in host interferon (IFN) regulatory factors (IRFs) and IFN receptors. This study provides the first comprehensive genome-wide viral transcriptome profiling during infection and across multiple amphibian host tissues that will serve as instrumental reference. It also presents evidence implying that ranaviruses like FV3 have acquired previously unknown molecular mimics interfering with host IFN signaling during evolution.

microbiology↗

bioRxiv2021

scTenifoldKnk: a machine learning workflow performing virtual knockout experiments on single-cell gene regulatory networks

Bigger PictureO_LIGene knockout (KO) experiments, using genetically altered animals, are a proven powerful approach to elucidate the role of a gene in a biological process. However, systematic KO experiments targeting many genes are usually prohibitive due to limited experimental and animal resources. Here, we present scTenifoldKnk, an efficient virtual KO tool that allows the systematic deletion of many genes individually. scTenifoldKnk uses single-cell RNA sequencing (scRNAseq) data from wild-type (WT) samples to predict gene function in a cell type-specific manner. We show that predictions made by scTenifoldKnk recapitulate findings from real-animal KO experiments. scTenifoldKnk has proven to be a powerful and effective approach for elucidating gene function, prioritizing KO targets, predicting experimental outcomes before real-animal KO experiments are conducted. C_LI HighlightsO_LIscTenifoldKnk performs virtual KO experiments using scRNAseq data. C_LIO_LIscTenifoldKnk only requires data from WT samples; no data is needed from KO samples. C_LIO_LIPredictions made by scTenifoldKnk recapitulate findings from real-animal KO experiments. C_LI Data Science Maturity Level O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=14 SRC="FIGDIR/small/436484v2_ufig1.gif" ALT="Figure 1"> View larger version (8K): org.highwire.dtl.DTLVardef@157126aorg.highwire.dtl.DTLVardef@17a2e76org.highwire.dtl.DTLVardef@805c4dorg.highwire.dtl.DTLVardef@12bdc1b_HPS_FORMAT_FIGEXP M_FIG C_FIG eTOC blurbscTenifoldKnk is a machine learning workflow performing virtual KO experiments to predict gene function. It constructs gene regulatory networks using single-cell RNA sequencing data from wild-type samples and then computationally deletes target genes. Real-data applications demonstrate that scTenifoldKnk recapitulates findings of real-animal KO experiments and accurately predicts gene function in analyzed cells. SummaryGene knockout (KO) experiments are a proven, powerful approach for studying gene function. However, systematic KO experiments targeting a large number of genes are usually prohibitive due to the limit of experimental and animal resources. Here, we present scTenifoldKnk, an efficient virtual KO tool that enables systematic KO investigation of gene function using data from single-cell RNA sequencing (scRNAseq). In scTenifoldKnk analysis, a gene regulatory network (GRN) is first constructed from scRNAseq data of wild-type samples, and a target gene is then virtually deleted from the constructed GRN. Manifold alignment is used to align the resulting reduced GRN to the original GRN to identify differentially regulated genes, which are used to infer target gene functions in analyzed cells. We demonstrate that the scTenifoldKnk-based virtual KO analysis recapitulates the main findings of real-animal KO experiments and recovers the expected functions of genes in relevant cell types.

bioinformatics↗

bioRxiv2021

GdDO3NI allows imaging of hypoxia after brain injury

PurposeIn this study, we use the hypoxia targeting agent (GdDO3NI, a nitroimidazole-based T1 MRI contrast agent) for imaging hypoxia in the injured brain after experimental traumatic brain injury (TBI) using magnetic resonance imaging (MRI), and validate the results with immunohistochemistry (IHC) using pimonidazole. MethodsTBI induced mice (controlled cortical impact model) were imaged at 7T using a T2 weighted fast spin-echo sequence to estimate the extent of the injury. The mice were then were intravenously injected with either conventional T1 agent (gadoteridol) or GdDO3NI at 0.3 mmol/kg dose (n=5 for each cohort) along with pimonidazole (60 mg/kg). Mice were imaged pre- and post-contrast using a T1-weighted spin-echo sequence for three hours. Regions of interests were drawn on the brain injury region, the contralateral brain as well as on the cheek muscle region for comparison of contrast kinetics. Brains were harvested immediately post imaging for immunohistochemical analysis. ResultsGdDO3NI is retained in the injury region for up to 3 hours post-injection (p< 0.05 compared to gadoteridol) while it rapidly clears out of the muscle region. On the other hand, conventional MRI contrast agent gadoteridol clears out of both the injury region and muscle rapidly, although with a relatively more delayed wash out in the injury region. Minimal contrast enhancement was seen for both agents in the contralateral hemisphere. Pimonidazole staining confirms the presence of hypoxia in both gadoteridol and GdDO3NI cohorts, and the later cohort shows good agreement with MRI contrast enhancement. ConclusionGdDO3NI was successfully shown to visualize hypoxia in the brain post-TBI using T1-wt MRI.

bioengineering↗

bioRxiv2021

Considerations for MESF-bead based assignment of absolute fluorescence values to nanoparticles and extracellular vesicles by flow cytometry

Flow cytometry is commonly used to characterize nanoparticles (NPs) and extracellular vesicles (EVs) but results are often expressed in arbitrary units to indicate fluorescence intensity. This hampers interlaboratory and inter-platform comparisons. We investigated the use of molecules of equivalent soluble fluorophores (MESF)-beads for assignment of fluorescence values to NPs and EVs by comparing two FITC-MESF bead sets as calibrators on different flow cytometry platforms (BD Influx, CytoFLEX LX and SORP BD FACSCelesta). Next, fluorescence signals of NPs and EVs were calibrated using different sets of FITC and PE-MESF beads. Fluorescence calibration using beads designed for cellular flow cytometry allowed inter-platform comparison. However, the intrinsic uncertainty in the fluorescence assignment to these MESF beads impacts the reliable assignment of MESF values to NPs and EVs based on extrapolation into the dim fluorescence range. Our findings demonstrate that the use of the same set of calibration materials (vendor and lot number) and the same number of calibration points, greatly improves robust interlaboratory and inter-platform comparison of fluorescent submicron sized particles.

biophysics↗

bioRxiv2021

Regulation of large-conductance Ca2+- and voltage-gated K+ channels by electrostatic interactions with auxiliary β subunits.

Large-conductance Ca2+- and voltage-gated K+ (BK KCa1.1) channel complexes include pore-forming Slo1 subunits and often auxiliary {beta} subunits, latter of which noticeably modify the channels pharmacological and gating characteristics. In the absence of intracellular Ca2+, {beta}1 and {beta}4 modestly shift the overall voltage dependence of the channel to the positive direction by decreasing the probability that the ion conduction gate is open without any allosteric influence from the channels voltage or Ca2+ sensors. This intrinsic open probability is also critically regulated by the intracellular-facing 329RKK331 segment of human Slo1 (hSlo1) downstream of the transmembrane segment S6 in association with two negatively charged residues in S6 (E321 and E324) (Tian et al., Proc Natl Acad Sci USA, 116, 8591-8596, 2019). This study examined how {beta}1/{beta}4 and the RKK segment function together to control the channel gate. With select mutations in the RKK segment, inclusions of {beta}1 or {beta}4 can dramatically increase the intrinsic gate opening probability and shift the overall voltage dependence of the channel to the negative direction by up to 200 mV without Ca2+. This remarkable shift is mediated at least in part by electrostatic interactions between the Slo1 RKK and {beta} N-terminal segments as suggested by the results of double-mutant cycle analysis, ionic strength experiments, and molecular modelling. With or without auxiliary {beta} subunits, the Slo1 RKK and E321/E324 segments are thus critical determinants of the intrinsic open probability of the ion conduction gate and changes in the electrostatic environment near the RKK-EE segments are a potential mechanism of pharmacological gating modifiers.

physiology↗

bioRxiv2021

Epstein-Barr virus long non-coding RNA RPMS1 full-length spliceome in transformed epithelial tissue

Epstein-Barr virus is associated with two types of epithelial neoplasms, nasopharyngeal carcinoma and gastric adenocarcinoma. The viral long non-coding RNA RPMS1 is the most abundantly expressed poly-adenylated viral RNA in these malignant tissues. The RPMS1 gene is known to contain two cassette exons, exon Ia and Ib, and several alternative splicing variants have been described in low-throughput studies. To characterize the entire RPMS1 spliceome we combined long-read sequencing data from the nasopharyngeal cell line C666-1 and a primary gastric adenocarcinoma, with complementary short-read sequencing datasets. We developed FLAME, a Python-based bioinformatics package that can generate complete high resolution characterization of RNA splicing at full-length. Using FLAME, we identified 32 novel exons in the RPMS1 gene, primarily within the large constitutive exons III, V and VII. Two of the novel exons contained retention of the intron between exon III and exon IV, and a novel cassette exon was identified between VI and exon VII. All previously described transcript variants of RPMS1 containing putative ORFs were identified at various levels. Similarly, native transcripts with the potential to form previously reported circular RNA elements were detected. Our work illuminates the multifaceted nature of viral transcriptional repertoires. FLAME provides a comprehensive overview of the relative abundance of alternative splice variants and allows for a wealth of previously unknown splicing events to be unveiled.

bioinformatics↗

bioRxiv2021

Identification of Nocardia species using Autof MS 1000 and Bruker MALDI-TOF MS systems: A comparison

Nocardia is an important cause of clinically invasive disease, but for most clinical laboratories, identification of these isolates to the species level is challenging. Recently, matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been widely used for identification of most bacterial and fungal isolates. In this multicenter study, we evaluated the identification of Nocardia isolates using Autof MS1000 and Bruker Biotyper. A total of 86 non-duplicate Nocardia isolates from 7 hospital laboratories were evaluated. Further, we carried out sequence analysis of 16S rRNA, gyrB, secA1, hsp65, and rpoB genes as a reference method for Nocardia species identification. The 86 isolates were directly spotted on the target plate and plate protein extraction was performed. Data were analyzed by SPSS 19.0. In total, 72 (83.7%) strains (score [≥] 9.0) and 70 (81.4%) strains (score [≥] 2.0) were correctly identified by the Autof MS1000 and Bruker Biotyper systems, respectively, at the species level. There was no significant difference (P > 0.05) between the two systems using the same protein extraction method. In conclusion, the Autof MS 1000 and Bruker MALDI-TOF systems showed no difference in identification of Nocardia spp. to the species level and could meet the most important clinical requirement for species identification.

microbiology↗

bioRxiv2020

SARS-CoV-2 infecting the inner ear results in potential hearing damage at the early stage or prognosis of COVID-19 in rodents

ObjectivesIn order to find out the association between the sensorineural hearing loss and COVID-19, we detected the expression ACE2 and TMPRSS2 in the mouse the hamster. DesignUsing the public data from NCBI and GISAID, we assessed the expression of ACE2 and TMPRSS2 at the transcriptomic, DNA, and protein levels of ACE2 in the brain, inner ear, and muscle from the golden Syrian hamster (Mesocricetus auratus) and mouse (Mus musculus). ResultsWe identified ACE2 and TMPRSS2 expressed at different level in the inner ear and brain at DNA and transcriptomic levels of both mouse and the hamster. The protein expression shows a similar pattern of the brain and inner ear, while the expression of ACE2 from the inner ear was relatively higher than it from the muscle. ConclusionSARS-CoV-2 could infect the hearing system potentially and SSNHL could be a characteristic to detect asymptomatic patients of COVID-19.

bioinformatics↗

bioRxiv2020

Spike Protein of SARS-CoV-2 Activates Macrophages and Contributes to Induction of Acute Lung Inflammations in Mice

BackgroundCoronavirus disease 2019 (COVID-19) patients exhibit multiple organ malfunctions with a primary manifestation of acute and diffuse lung injuries. The Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial to mediate viral entry into host cells; however, whether it can be cellularly pathogenic and contribute to pulmonary hyper-inflammations in COVID-19 is not well known. Methods and FindingsIn this study, we developed a Spike protein-pseudotyped (Spp) lentivirus with the proper tropism of SARS-CoV-2 Spike protein on the surface and tracked down the fate of Spp in wild type C57BL/6J mice receiving intravenous injection of the virus. A lentivirus with vesicular stomatitis virus glycoprotein (VSV-G) was used as the control. Two hours post-infection (hpi), Spp showed more than 27-75 times more viral burden in the lungs than other organs; it also exhibited about 3-5 times more viral burden than VSV-G lentivirus in the lungs, liver, kidney and spleen. Acute pneumonia was evident in animals 24 hpi. Spp lentivirus was mainly found in LDLR+ macrophages and pneumocytes in the lungs, but not in MARC1+ macrophages. IL6, IL10, CD80 and PPAR-{gamma} were quickly upregulated in response to infection of Spp lentivirus in the lungs in vivo as well as in macrophage-like RAW264.7 cells in vitro. We further confirmed that forced expression of the Spike protein in RAW264.7 cells could significantly increase the mRNA levels of the same panel of inflammatory factors. ConclusionsOur results demonstrate that the Spike protein of SARS-CoV-2 alone can induce cellular pathology, e.g. activating macrophages and contributing to induction of acute inflammatory responses.

pathology↗

bioRxiv2020

The vascular niche controls Drosophila hematopoiesis via Fibroblast Growth Factor signaling

In adult mammals, hematopoiesis, the production of blood cells from hematopoietic stem and progenitor cells (HSPCs), is tightly regulated by extrinsic signals from the microenvironment called "niche". Bone marrow HSPCs are heterogeneous and controlled by both endosteal and vascular niches. The Drosophila hematopoietic lymph gland is located along the cardiac tube which corresponds to the vascular system. In the lymph gland, the niche called Posterior Signaling Center controls only a subset of the heterogeneous hematopoietic progenitor population indicating that additional signals are necessary. Here we report that the vascular system acts as a second niche to control lymph gland homeostasis. The FGF ligand Branchless produced by vascular cells activates the FGF pathway in hematopoietic progenitors. By regulating intracellular calcium levels, FGF signaling maintains progenitor pools and prevents blood cell differentiation. This study reveals that two niches contribute to the control of Drosophila blood cell homeostasis through their differential regulation of progenitors.

developmental biology↗

bioRxiv2020

Chemoproteomics Maps Glycolytic Targetome in Cancer Cells

Hyperactivated glycolysis, favoring uncontrolled growth and metastasis by producing essential metabolic intermediates engaging bioenergetics and biosynthesis, is a metabolic hallmark of most cancer cells. Although sporadic information has revealed glycolytic metabolites also possess non-metabolic function as signaling molecules, it remains largely elusive how these metabolites interact with and functionally regulate their binding targets. Here we introduce a Target Responsive Accessibility Profiling (TRAP) approach that measures ligand binding-induced steric hindrance in protein targets via global profiling accessibility changes in reactive lysines, and mapped 913 target candidates and 2,487 interactions for 10 major glycolytic metabolites in cancer cells via TRAP. The elucidated targetome uncovers diverse regulatory modalities of glycolytic metabolites involving the direct perturbation of carbohydrate metabolism enzymes, intervention of transcriptional control, modulation of proteome-level acetylation and protein complex assemblies. The advantages gained from glycolysis by cancer cells are expanded by discovering lactate as a ligand for an orphan transcriptional regulator TRIM 28 that promotes p53 degradation, and by identifying pyruvate acting against a cell apoptosis inducer trichostatin A via attenuating protein acetylation. Lastly, the inhibition of glycolytic key enzymes led to identify an intrinsically active glycolytic intermediate glyceraldehyde 3-phosphate that elicits its cytotoxicity by engaging with ENO1 and MTHFD1. Collectively, the glycolytic targetome depicted by TRAP constitutes a fertile resource for understanding how glycolysis finely tunes metabolism and signaling in support of cancer cells, and fostering the exploitation of glycolytic targetome as promising nodes for anti-cancer therapeutics development.

cancer biology↗

bioRxiv2020

The effect of Basal core promoter and pre-core mutations on HBV replication and persistence in mice

The appearance of the BCP or Pre-C mutations, which reduce or abolish HBeAg production, could increase HBV replication. The remove of the HBeAg often lead to a vigorous immune response, which has an important role in HBV related fulminant outcome. In this study, BCP mutations and Pre-C mutations were separately introduced by site-directed mutagenesis in the same genetic background of an HBV infectious clone, to determine the effect of these mutations per se on replication. BCP and Pre-C mutations increased HBV replication both in vitro and in vivo. HBV could persist in mice injected with wild type HBV infectious clone for about 7 weeks. However, HBV could persist about 5 weeks in mice injected with BCP HBV infectious clone, and 3 weeks only in mice injected with Pre-C HBV infectious clone. HBV related CD8+ CTL response in BCP HBV infectious clone injected mice only slightly increased, but significantly increased in Pre-C HBV infectious clone injected mice compared with that in wild type HBV infectious clone injected mice. The population of Tregs significantly increased in liver but not in spleen of mice injected with Pre-C HBV infectious clone. In summary, we demonstrate that HBeAg plays an important role in suppressing the CTL response, which is related with increasing the frequency of Tregs in mouse. Lack of HBeAg expression leads to the partial loss of immune tolerance.

microbiology↗

bioRxiv2020

Information Confusion Reveals an Innate Limit of the Information Processing by Neurons

Information experiences complex transformation processes in the brain, involving various errors. A daunting and critical challenge in neuroscience is to understand the origin of these errors and their effects on neural information processing. While previous efforts have made substantial progresses in studying the information errors in bounded, unreliable and noisy transformation cases, it still remains elusive whether the neural system is inherently error-free under an ideal and noise-free condition. This work brings the controversy to an end with a negative answer. We propose a novel neural information confusion theory, indicating the widespread presence of information confusion phenomenon after the end of transmission process, which originates from innate neuron characteristics rather than external noises. Then, we reformulate the definition of zero-error capacity under the context of neuroscience, presenting an optimal upper bound of the zero-error transformation rates determined by the tuning properties of neurons. By applying this theory to neural coding analysis, we unveil the multi-dimensional impacts of information confusion on neural coding. Although it reduces the variability of neural responses and limits mutual information, it controls the stimulus-irrelevant neural activities and improves the interpretability of neural responses based on stimuli. Together, the present study discovers an inherent and ubiquitous precision limitation of neural information transformation, which shapes the coding process by neural ensembles. These discoveries reveal that the neural system is intrinsically error-prone in information processing even in the most ideal cases. Author summaryOne of the most central challenges in neuroscience is to understand the information processing capacity of the neural system. Decades of efforts have identified various errors in nonideal neural information processing cases, indicating that the neural system is not optimal in information processing because of the widespread presences of external noises and limitations. These incredible progresses, however, can not address the problem about whether the neural system is essentially error-free and optimal under ideal information processing conditions, leading to extensive controversies in neuroscience. Our work brings this well-known controversy to an end with a negative answer. We demonstrate that the neural system is intrinsically error-prone in information processing even in the most ideal cases, challenging the conventional ideas about the superior neural information processing capacity. We further indicate that the neural coding process is shaped by this innate limit, revealing how the characteristics of neural information functions and further cognitive functions are determined by the inherent limitation of the neural system.

neuroscience↗

bioRxiv2020

Brain preparedness: The proactive role of the cortisol awakening response

Upon awakening from nighttime sleep, the stress hormone cortisol exhibits a burst in the morning within 30-minutes in humans. This cortisol awakening response (CAR) is thought to prepare the brain for upcoming challenges. Yet, the neurobiological mechanisms underlying the CAR-mediated preparation function remains unknown. Using blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD-fMRI) with a dedicated prospective design and pharmacological manipulation, we investigated this proactive mechanism in humans across two fMRI studies. In Study 1, we found that a robust CAR was predictive of less hippocampal and prefrontal activity, though enhanced functional coupling between those regions and facilitated working memory performance, during a demanding task later in the afternoon. These results implicate the CAR in proactively promoting brain preparedness based on improved neural efficiency. To address the causality of this proactive effect, we conducted a second study (Study 2) in which we suppressed the CAR with a double blind, placebo controlled, randomized design using Dexamethasone. We found that pharmacological suppression of CAR mirrored the proactive effects from Study 1. Dynamic causal modeling analyses further revealed a reduction of prefrontal top-down modulation over hippocampal activity when performing a cognitively demanding task in the afternoon. These findings establish a causal link between the CAR and its proactive role in optimizing brain functional networks involved in neuroendocrine control and memory.

neuroscience↗