Biology subjects

Xie, H.

Publications and source records attributed to Xie, H..

At least 145 records · Page 8Linked to original sources

bioRxiv2020

Mapping the Antibody Repertoires in Ferrets with Repeated Influenza A/H3 Infections: Is Original Antigenic Sin Really "Sinful"?

The influenza-specific antibody repertoire is continuously reshaped by infection and vaccination. The host immune response to contemporary viruses can be redirected to preferentially boost antibodies specific for viruses encountered early in life, a phenomenon called original antigenic sin (OAS) that is suggested to be responsible for diminished vaccine effectiveness after repeated vaccination. In this study, we used a new computational tool called Neutralization Map to determine the hemagglutination inhibition profiles of individual antibodies within ferret antisera elicited by repeated influenza A/H3 infections. Our results suggest that repeated infections continuously reshape the ferret antibody repertoire, but that a broadly neutralizing antibody signature can nevertheless be induced irrespective of OAS. Overall, our study offers a new way to visualize how immune history shapes individual antibodies within a repertoire, which may help inform future vaccine design.

immunology↗

bioRxiv2020

Multidimensional face representation in deep convolutional neural network reveals the mechanism underlying AI racism

The increasingly popular application of AI runs the risks of amplifying social bias, such as classifying non-white faces to animals. Recent research has attributed the bias largely to data for training. However, the underlying mechanism is little known, and therefore strategies to rectify the bias are unresolved. Here we examined a typical deep convolutional neural network (DCNN), VGG-Face, which was trained with a face dataset consisting of more white faces than black and Asian faces. The transfer learning result showed significantly better performance in identifying white faces, just like the well-known social bias in human, the other-race effect (ORE). To test whether the effect resulted from the imbalance of face images, we retrained the VGG-Face with a dataset containing more Asian faces, and found a reverse ORE that the newly-trained VGG-Face preferred Asian faces over white faces in identification accuracy. In addition, when the number of Asian faces and white faces were matched in the dataset, the DCNN did not show any bias. To further examine how imbalanced image input led to the ORE, we performed the representational similarity analysis on VGG-Faces activation. We found that when the dataset contained more white faces, the representation of white faces was more distinct, indexed by smaller ingroup similarity and larger representational Euclidean distance. That is, white faces were scattered more sparsely in the representational face space of the VGG-Face than the other faces. Importantly, the distinctiveness of faces was positively correlated with the identification accuracy, which explained the ORE observed in the VGG-Face. In sum, our study revealed the mechanism underlying the ORE in DCNNs, which provides a novel approach of study AI ethics. In addition, the face multidimensional representation theory discovered in human was found also applicable to DCNNs, advocating future studies to apply more cognitive theories to understand DCNNs behavior.

neuroscience↗

bioRxiv2020

SARS-CoV-2 ORF6 disrupts nucleocytoplasmic transport through interactions with Rae1 and Nup98

RNA viruses that replicate in the cytoplasm often disrupt nucleocytoplasmic transport to preferentially translate their own transcripts and prevent host antiviral responses. The Sarbecovirus accessory protein ORF6 has previously been shown to be the major inhibitor of interferon production in both SARS-CoV and SARS-CoV-2. SARS-CoV-2 ORF6 was recently shown to co-purify with the host mRNA export factors Rae1 and Nup98. Here, we demonstrate SARS-CoV-2 ORF6 strongly represses protein expression of co-transfected reporter constructs and imprisons host mRNA in the nucleus, which is associated with its ability to co-purify with Rae1 and Nup98. These protein-protein interactions map to the C-terminus of ORF6 and can be abolished by a single amino acid mutation in Met58. Overexpression of Rae1 restores reporter expression in the presence of SARS-CoV-2 ORF6. We further identify an ORF6 mutant containing a 9-amino acid deletion, ORF6 {Delta}22-30, in multiple SARS-CoV-2 clinical isolates that can still downregulate the expression of a co-transfected reporter and interact with Rae1 and Nup98. SARS-CoV ORF6 also interacts with Rae1 and Nup98. However, SARS-CoV-2 ORF6 more strongly co-purifies with Rae1 and Nup98 and results in significantly reduced expression of reporter proteins compared to SARS-CoV ORF6, a potential mechanism for the delayed symptom onset and pre-symptomatic transmission uniquely associated with the SARS-CoV-2 pandemic. ImportanceSARS-CoV-2, the causative agent of COVID-19, is an RNA virus with a large genome that encodes accessory proteins. While these accessory proteins are not required for growth in vitro, they can contribute to the pathogenicity of the virus. One of SARS-CoV-2s accessory proteins, ORF6, was recently shown to co-purify with two host proteins, Rae1 and Nup98, involved in mRNA nuclear export. We demonstrate SARS-CoV-2 ORF6 interaction with these proteins is associated with reduced expression of a reporter protein and accumulation of poly-A mRNA within the nucleus. SARS-CoV ORF6 also shows the same interactions with Rae1 and Nup98. However, SARS-CoV-2 ORF6 more strongly represses reporter expression and co-purifies with Rae1 and Nup98 compared to SARS-CoV ORF6. The ability of SARS-CoV-2 ORF6 to more strongly disrupt nucleocytoplasmic transport than SARS-CoV ORF6 may partially explain critical differences in clinical presentation between the two viruses.

microbiology↗

bioRxiv2020

A single-cell transcriptome atlas of the aging human and macaque retina

The human retina is a complex neural tissue that detects light and sends visual information to the brain. However, the molecular and cellular processes that underlie aging primate retina remain unclear. Here, we provide a comprehensive transcriptomic atlas based on 119,520 single cells of the foveal and peripheral retina of humans and macaques covering different ages. The molecular features of retinal cells differed between the two species, suggesting the distinct regional and species specializations of the human and macaque retinae. In addition, human retinal aging occurred in a region- and cell-type- specific manner. Aging of human retina exhibited a foveal to peripheral gradient. MYO9A- rods and a horizontal cell subtype were greatly reduced in aging retina, indicating their vulnerability to aging. Moreover, we generated a dataset showing the cell-type- and region- specific gene expression associated with 55 types of human retinal disease, which provides a foundation to understand the molecular and cellular mechanisms underlying human retinal diseases. Together, these datasets are valuable for understanding the molecular characteristics of primate retina, as well as the molecular regulation of aging progression and related diseases.

neuroscience↗

bioRxiv2020

Unravel the Mystery of NIC1-locus on Nicotine Biosynthesis Regulation in Tobacco

ABSTRACTBackground Nicotine biosynthesis is mainly regulated by jasmonate (JA) signaling cascade in Nicotiana tabacum. As an allotetraploid species, the regulation of nicotine biosynthesis has been genetically verified via two unlinked NIC loci (named as NIC1 and NIC2) which are possibly originated from its two ancestral diploids. Previously, a N. tomentosiformis originated ethylene response factor (ERF) gene cluster was identified as the NIC2-locus which has been demonstrated positively regulates nicotine accumulation in N. tabacum.Results Here, we describe the genetic mapping of NIC1-locus, the major nicotine regulatory locus, by using a NIC1-locus segregating population through bulked segregant analysis. We identified two linkage marker TM23004 and TM22038 were delimited the NIC1-locus within a ~34.3-Mb genomic region at pseudochromosome 07 of tobacco genome. Genomic scan within this region revealed a NIC2-like locus ERF gene cluster exist in. To verify this ERF gene cluster is the genetically called “NIC1-locus”, different functional experiments based on most of the ERFs in regulating nicotine biosynthesis and their influences on alkaloid accumulations have been carried out. Collinearity analysis showed that NIC1-locus ERF genes are originated from N. sylvestris and exclusively expressed in root tissues. In addition, transcriptomic results indicate that NIC1-locus ERF genes are coexpressed with the NIC2-locus ERF genes and other nicotine biosynthetic genes and regulators after JA induction. Furthermore, the suppressed expression of four ERFs of the NIC1-locus genes corresponding with decreased NtPMT and NtQPT expression in NtMYC2-RNAi lines indicates the selected NIC1-locus ERFs function in downstream of NtMYC2 in the JA signaling cascades. In the meanwhile, the alkaloid levels are also determined by the amplitude of the four ERF gene expressions in both wild type and LA mutant. Additionally, in vitro binding assays, transient activation assays, and ectopic expression in transgenic plants demonstrate that these ERF genes are able to bind the GCC-box elements residing in the step-limiting gene promoters (such as NtPMT2, NtQPT2) and functional redundant but quantitatively transactivate nicotine biosynthetic gene expression. For nic1-locus mutation, two different sizes of deletions (nic1-S and nic1-B) were identified which occurred at the surrounding regions of the NIC1-locus gene cluster, which might disrupt, to some extent, chromosomal microenvironment and change gene expression around the deletion regions (including NIC1-locus ERFs), resulting in the decreased expression levels of NIC1-locus ERFs (such as NtERF199) and reduced alkaloid accumulation in the nic1-locus mutant.Conclusions Our findings not only provide insight in to the mechanism of the NIC1-locus ERFs in the regulatory network of nicotine biosynthesis, but also unraveled the theoretical basis of the nic1-locus mutation in low nicotine mutant. These functional verified NIC1-locus ERF genes can be further used as potential target(s) for ethyl methanesulfonate-based mutagenesis to manipulate nicotine level in tobacco variety in tobacco breeding program.Competing Interest StatementThe authors have declared no competing interest.AbbreviationsA622a PIP family oxidoredutase for nicotine precursors condensationODCornithine decarboxylaseADCarginine decarboxylasePMTputrescine N-methyltransferaseMPON-methylputrescine oxidaseAOaspartate oxidaseQSquinolinic acid synthaseQPTqunolinic acid phosphoribosyl transferaseSPDSspermidine synthaseSAMSS-adenosylmethionine synthaseSAMDCS-adenosylmethione decarboxylasePCRPolymerase chain reactionRNA-seqRNA SequencingRPKMReads Per Kilobase per Million mapped readsSSRsimple sequence repeatqRT-PCRQuantitative real-time PCRCRchromosome rearrangementCNVcopy number variantView Full Text

plant biology↗

bioRxiv2020

In vivo antiviral host response to SARS-CoV-2 by viral load, sex, and age

Despite limited genomic diversity, SARS-CoV-2 has shown a wide range of clinical manifestations in different patient populations. The mechanisms behind these host differences are still unclear. Here, we examined host response gene expression across infection status, viral load, age, and sex among shotgun RNA-sequencing profiles of nasopharyngeal swabs from 430 individuals with PCR-confirmed SARS-CoV-2 and 54 negative controls. SARS-CoV-2 induced a strong antiviral response with upregulation of antiviral factors such as OAS1-3 and IFIT1-3, and Th1 chemokines CXCL9/10/11, as well as a reduction in transcription of ribosomal proteins. SARS-CoV-2 culture in human airway epithelial cultures replicated the in vivo antiviral host response. Patient-matched longitudinal specimens (mean elapsed time = 6.3 days) demonstrated reduction in interferon-induced transcription, recovery of transcription of ribosomal proteins, and initiation of wound healing and humoral immune responses. Expression of interferon-responsive genes, including ACE2, increased as a function of viral load, while transcripts for B cell-specific proteins and neutrophil chemokines were elevated in patients with lower viral load. Older individuals had reduced expression of Th1 chemokines CXCL9/10/11 and their cognate receptor, CXCR3, as well as CD8A and granzyme B, suggesting deficiencies in trafficking and/or function of cytotoxic T cells and natural killer (NK) cells. Relative to females, males had reduced B and NK cell-specific transcripts and an increase in inhibitors of NF-{kappa}B signaling, possibly inappropriately throttling antiviral responses. Collectively, our data demonstrate that host responses to SARS-CoV-2 are dependent on viral load and infection time course, with observed differences due to age and sex that may contribute to disease severity.

microbiology↗

bioRxiv2020

Parabrachial neuron types categorically encode thermoregulation variables during heat defense

Heat defense is crucial for survival and fitness, and its dysregulation may result in deaths due to poor management. Transmission of thermosensory signals into hypothalamic thermoregulation centers represent a key layer of regulation in heat defense. However, the mechanism by which these signals are transmitted into the hypothalamus remains poorly understood. Here, we reveal that glutamatergic prodynorphin and cholecystokinin neuron populations in the lateral parabrachial (LPB) are progressively recruited to defend elevated body temperature. These two nonoverlapping neuron types form circuitries with downstream preoptic hypothalamic neurons to inhibit BAT thermogenesis and activate tail vasodilation, respectively. Both circuitries are selectively activated by warm temperatures and are required for fever limiting. The prodynorphin circuitry is further required for regulation of energy expenditure and weight homeostasis. Thus, these findings establish that the genetic and functional specificity of heat defense neurons occurs as early as in the LPB and uncover categorical neuron types for encoding two heat defense variables, which may provide targets for treating thermoregulation disorders.

neuroscience↗

bioRxiv2020

Zika virus-based immunotherapy enhances long-term survival of rodents with brain tumors through upregulation of memory T-cells

Zika virus (ZIKV) exhibits a tropism for brain tumor cells and has been used as an oncolytic virus to target brain tumors in mice with modest effects on extending median survival. Recent studies have highlighted the potential for combining virotherapy and immunotherapy to target cancer. We postulated that ZIKV could be used as an adjuvant to enhance the long-term survival of mice with malignant glioblastoma and generate memory T-cells capable of providing long-term immunity against cancer remission. To test this hypothesis mice bearing malignant intracranial GL261 tumors were subcutaneously vaccinated with irradiated GL261 cells previously infected with the ZIKV. Mice also received intracranial injections of live ZIKV, irradiated ZIKV, or irradiated GL261 cells previously infected with ZIKV. Long-term survivors were rechallenged with a second intracranial tumor to examine their immune response and look for the establishment of protective memory T-cells. Mice with subcutaneous vaccination plus intracranial irradiated ZIKV or intracranial irradiated GL261 cells previously infected with ZIKV exhibited the greatest extensions to overall survival. Flow cytometry analysis of immune cells within the brains of long-term surviving mice after tumor rechallenge revealed an upregulation in the levels of T-cells, including CD4+ and tissue-resident memory CD4+ T-cells, in comparison to long-term survivors that were mock-rechallenged, and in comparison to naive untreated mice challenged with intracranial gliomas. These results suggest that ZIKV can serve as an adjuvant to subcutaneous tumor vaccines that enhance long-term survival and generate protective tissue-resident memory CD4+ T-cells.

cancer biology↗

bioRxiv2020

Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro

Human infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause coronavirus disease 19 (COVID-19) and there is currently no cure. The 3C-like protease (3CLpro), a highly conserved protease indispensable for replication of coronaviruses, is a promising target for development of broad-spectrum antiviral drugs. To advance the speed of drug discovery and development, we investigated the inhibition of SARS-CoV-2 3CLpro by natural products derived from Chinese traditional medicines. Baicalin and baicalein were identified as the first non-covalent, non-peptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography is distinctly different from those of known inhibitors. Baicalein is perfectly ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a "shield" in front of the catalytic dyad to prevent the peptide substrate approaching the active site. The simple chemical structure, unique mode of action, and potent antiviral activities in vitro, coupled with the favorable safety data from clinical trials, emphasize that baicalein provides a great opportunity for the development of critically needed anti-coronaviral drugs.

molecular biology↗

bioRxiv2020

3D printing of Microgel-loaded Modular LEGO-like Cages as Instructive Scaffolds for Tissue Engineering

Biomaterial scaffolds have served as the foundation of tissue engineering and regenerative medicine. However, scaffold systems are often difficult to scale in size or shape in order to fit defect-specific dimensions, and thus provide only limited spatiotemporal control of therapeutic delivery and host tissue responses. Here, a lithography-based three-dimensional (3D) printing strategy is used to fabricate a novel miniaturized modular LEGO-like cage scaffold system, which can be assembled and scaled manually with ease. Scalability is based on an intuitive concept of stacking modules, like conventional LEGO blocks, allowing for literally thousands of potential geometric configurations, and without the need for specialized equipment. Moreover, the modular hollow-cage design allows each unit to be loaded with biologic cargo of different compositions, thus enabling controllable and easy patterning of therapeutics within the material in 3D. In summary, the concept of miniaturized cage designs with such straight-forward assembly and scalability, as well as controllable loading properties, is a flexible platform that can be extended to a wide range of materials for improved biological performance. TOC3D printed LEGO-like hollow microcages can be easily assembled, adjoined, and stacked-up to suit the complexity of defect tissues; aid spatial loading of cells and biomolecules; instruct cells migration three-dimensionally; and facilitate cell invasion and neovascularization in-vivo, thus accelerating the process of tissue healing and new tissue formation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/974204v1_ufig1.gif" ALT="Figure 1"> View larger version (88K): org.highwire.dtl.DTLVardef@1a97a72org.highwire.dtl.DTLVardef@1a60fbeorg.highwire.dtl.DTLVardef@1538f13org.highwire.dtl.DTLVardef@d6345b_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2020

Herpes Simplex Virus Mistyping due to HSV-1 x HSV-2 Interspecies Recombination in Viral Gene Encoding Glycoprotein B

Human herpes simplex viruses (HSV) 1 and 2 are most often typed via molecular assays. Here we describe the first known case of HSV mistyping due to a previously undescribed HSV-1 x HSV-2 recombination event in UL27, the gene that encodes glycoprotein B. This is the first reported HSV interspecies recombination event impacting this gene, which is frequently used as a target for diagnostics and experimental therapeutics.

genomics↗

bioRxiv2020

Estimation of Full-Length TprK Diversity in Treponema pallidum subspecies pallidum

Immune evasion and disease progression of Treponema pallidum subspecies pallidum are associated with sequence diversity in the hypervariable, putative outer membrane protein TprK. Previous attempts to study variation within TprK have sequenced at depths insufficient to fully appreciate the hypervariable nature of the protein, failed to establish linkage between the proteins 7 variable regions, or were conducted on strains passed through rabbits. As a consequence, a complete profiling of tprK during infection in the human host is still lacking. Furthermore, prior studies examining how T. pallidum uses its repertoire of genomic donor sites to generate diversity within the V regions of the tprK also yielded a partial understanding of this process, due to the limited number of tprK alleles examined. In this study, we used short- and long-read deep sequencing to directly characterize full-length tprK alleles from T. pallidum collected from early lesions of patients attending two STD clinics in Italy. Our data, combined with recent data available on Chinese T. pallidum strains, show the near complete absence of overlap in TprK sequences among the 41 strains profiled to date. Moreover, our data allowed us to redefine the boundaries of tprK V regions, identify 55 donor sites, and estimate the total number of TprK variants that T. pallidum can potentially generate. Altogether, our results support how T. pallidum TprK antigenic variation system is an unsurmountable obstacle for the human immune system to naturally achieve infection eradication, and reiterate the importance of this mechanism for pathogen persistence in the host. ImportanceSyphilis continues to be a significant public health issue in both low- and high-income nations, including the United States, where the number of infectious syphilis cases has increased dramatically over the past five years. T. pallidum, the causative agent of syphilis, encodes an outer membrane protein TprK that undergoes segmental gene conversion to constantly create new sequences. We performed deep TprK profiling to understand full-length TprK diversity in T. pallidum-positive clinical specimens and compared these to all samples for which TprK deep sequencing is available. We found almost no overlap in TprK sequences between different patients. We further estimate that the total baseline junctional diversity of full-length TprK rivals that of current estimates of the human adaptive immune system. These data underscore the immunoevasive ability of TprK that allows T. pallidum to establish lifelong infection.

microbiology↗

bioRxiv2019

Unsupervised content-preserving transformation for optical microscopy

The development of deep learning and the open access to a substantial collection of imaging data provide a potential solution to computational image transformation, which is gradually changing the landscape of optical imaging and biomedical research. However, current implementations of deep learning usually operate in a supervised manner and the reliance on a laborious and error-prone data annotation procedure remains a barrier towards more general applicability. Here, we propose an unsupervised image transformation to facilitate the utilization of deep learning for optical microscopy, even in some cases where supervised models cannot apply. By introducing a saliency constraint, the unsupervised model, dubbed as Unsupervised content-preserving Transformation for Optical Microscopy (UTOM), can learn the mapping between two image domains without requiring paired training data and avoid the distortion of the image content. UTOM shows promising performances in a wide range of biomedical image transformation tasks, including in silico histological staining, fluorescence image restoration, and virtual fluorescence labeling. Quantitative evaluations elucidate that UTOM achieves stable and high-fidelity image transformations across different imaging conditions and modalities. We anticipate that our framework will encourage a paradigm shift in training neural networks and enable more applications of artificial intelligence in biomedical imaging.

bioinformatics↗

bioRxiv2019

Comparative Genomics and Full-Length TprK Profiling of Treponema pallidum subsp. pallidum Reinfection

Developing a vaccine against Treponema pallidum subspecies pallidum, the causative agent of syphilis, remains a public health priority. Syphilis vaccine design efforts have been complicated by lack of an in vitro T. pallidum culture system, prolific antigenic variation in outer membrane protein TprK, and lack of functional annotation for nearly half of the genes. Understanding the genetic basis of T. pallidum reinfection can provide insights into variation among strains that escape cross-protective immunity. Here, we present comparative genomic sequencing and deep, full-length tprK profiling of two T. pallidum isolates from blood from the same patient that were collected six years apart. Notably, this patient was diagnosed with syphilis four times, with two of these episodes meeting the definition of neurosyphilis, during this interval. Outside of the highly variable tprK gene, we identified 14 coding changes in 13 genes. Nine of these genes putatively localized to the periplasmic or outer membrane spaces, consistent with a potential role in serological immunoevasion. Using a newly developed full-length tprK deep sequencing protocol, we profiled the diversity of this gene that far outpaces the rest of the genome. Intriguingly, we found that the reinfecting isolate demonstrated less diversity across each tprK variable region compared to the isolate from the first infection. Notably, the two isolates did not share any full-length TprK sequences. Our results are consistent with an immunodominant-evasion model in which the diversity of TprK explains the ability of T. pallidum to successfully reinfect individuals, even when they have been infected with the organism multiple times. Author SummaryThe causative agent of syphilis, Treponema pallidum subspecies pallidum, is capable of repeat infections in people, suggesting that the human immune response does not develop sufficiently broad or long-lasting immunity to cover treponemal diversity. Here, we examined the genomes from two blood-derived isolates of T. pallidum derived 6 years apart from a patient who had syphilis four times during the same period to understand the genetic basis of reinfection. We found a paucity of coding changes across the genome outside of the highly variable tprK gene. Using deep profiling of the full-length tprK gene, we found surprisingly that the two isolates did not share any full-length TprK sequences.

microbiology↗

bioRxiv2019

Low-disturbance farming regenerates healthy critical zone towards sustainable agriculture

Intensive conventional farming has degraded farmland topsoil and seriously threaten food and environment security globally. Although low-disturbance practices have been widely adapted to restore soil health, whether this measure in a long run can potentially recover the critical deep soil to meet sustainable intensification of crop production are still unclear. Here we compared soil microbiome, physicochemical parameters along 3-m deep soil profiles, and crop yield in Northeast China subjected to ten years of farming practices at 3 levels of disturbance, including conventional tillage (CT), no-tillage without stover mulching (NTNS), and no-tillage with stover mulching (NTSM). We found that low-disturbance practices (NTNS and NTSM) promoted the ability of the deep soil to retain water, nitrogen and salt-extractable organic, regenerated whole-soil microbial diversity and metabolic function, improved topsoil organic carbon stock and corn yield in the drought year, showed the potential to reduce energy consumption and greenhouse gas emissions, thus regenerating highly efficient, sustainable agriculture.

ecology↗

bioRxiv2019

TET1-mediated Oligodendrocyte Homeostasis Regulates Myelination and Synaptic Functions

Ten-eleven translocation (TET) proteins, the dioxygenase for DNA hydroxymethylation, are important players in nervous system development and diseases. However, their role in myelination and remyelination after injury remains elusive. Here, we identify a genome-wide and locus-specific DNA hydroxymethylation landscape shift during differentiation of oligodendrocyte-progenitor cells (OPC). Ablation of Tet1 results in stage-dependent defects in oligodendrocyte (OL) development and myelination in the mouse brain. The mice lacking Tet1 in the oligodendrocyte lineage develop behavioral deficiency. We also show that TET1 is required for remyelination in adulthood. Transcriptomic, genomic occupancy, and DNA hydroxymethylation profiling reveal a critical TET1-regulated epigenetic program for oligodendrocyte differentiation that includes genes associated with myelination, cell division, and calcium transport. Tet1-deficient OPCs exhibit reduced calcium activity, increasing calcium activity rescues the differentiation defects in vitro. Deletion of a TET1-5hmC target gene, Itpr2 impairs the onset of OPC differentiation. Together, our results suggest that stage-specific TET1-mediated epigenetic programming and intracellular signaling are important for proper myelination and remyelination in mice.

neuroscience↗

bioRxiv2019

HPV-positive head and neck cancer derived exosomal miR-9 induces M1 macrophage polarization and increases tumor radiosensitivity

Human papillomavirus (HPV) is an etiological risk factor for a subset of head and neck squamous cell carcinoma (HNSCC). HPV+ HNSCC is significant more radiosensitive than HPV-HNSCC, but the underlying mechanism is still unknown. Tumor microenvironment can affect tumor response to radiation therapy. Cancer secreted exosomes are emerging as crosstalk mediators between tumor cells and the tumor microenvironment. The main objectives of this study were to determine the role of HPV+ HNSCC-derived exosomes in increased radiation sensitivity. Here, we found that exosomes derived from HPV+ HNSCC cells activate macrophages into the M1 phenotype, which then increases the radiosensitivity of HNSCC cells. miR-9 was enriched in exosomes released from HPV+ HNSCC cells and it could be transported to macrophages, leading to altered cellular functions. Overexpression of miR-9 in macrophages induced polarization into the M1 phenotype via downregulation of PPAR{delta}. Increased radiosensitivity was observed for HNSCC cells co-cultured with macrophages in which miR-9 was upregulated or treated with M1 macrophages. These observations suggest that HPV+ HNSCC cells secrete miR-9-rich exosomes, which then polarize macrophages into M1 phenotype and lead to increased radiosensitivity of HNSCC cells. Hence, miR-9 may be a potential treatment strategy for HNSCC.\n\nStatement of significanceHPV+ HNSCC through the release of miR-9-rich exosomes polarize macrophages into M1 phenotype and lead to increased radiosensitivity of HNSCC.

cancer biology↗

bioRxiv2019

Finding the neural correlates of collaboration using a three-person fMRI hyperscanning paradigm

Humans have an extraordinary ability to interact and cooperate with others, which plays a pivotal role in societies at large. Despite its potential social and evolutionary significance, research on finding the neural correlates of collaboration has been limited partly due to restrictions on simultaneous neuroimaging of more than one participant (a.k.a. hyperscanning). A series of works now exists that used dyadic fMRI hyperscanning to examine the interaction between two participants. However, to our knowledge, no study to date has aimed at revealing the neural correlates of social interactions using a 3-person (or triadic) fMRI hyperscanning paradigm. Here, for the first time, we simultaneously measured the blood-oxygenation-level-dependent (BOLD) signal of triads (m=12 triads; n=36 participants), while they engaged in a joint drawing task based on the social game of Pictionary(R). General linear model (GLM) analysis revealed increased activation in the brain regions previously linked with the theory of mind (ToM) during the collaborative phase compared to the independent phase of the task. Furthermore, using intersubject brain synchronization (IBS) analysis, we revealed increased synchrony of the right temporo-parietal junction (R TPJ) during the collaborative phase. The increased synchrony in the R TPJ was observed to be positively associated with the overall team performance on the task. In sum, our novel paradigm revealed a vital role of the R TPJ among other ToM regions during a triadic collaborative drawing task.

neuroscience↗