Biology subjects

Gao, F.

Publications and source records attributed to Gao, F..

At least 127 records · Page 7Linked to original sources

bioRxiv2021

Word structure tunes electrophysiological and hemodynamic responses in the frontal cortex

To date, it is still unclear how word structure might impact lexical processing in the brain for morphological impoverished language like Chinese. In this study, concurrent EEG and fNIRS recordings were performed to inspect the temporal and spatial brain activity that are related to the morphological priming effect (compound/derivation constitute priming vs. non-morphological priming) and word structure (compound vs. derivation) modulation. Interestingly, it was discovered that the morphological priming effect was mainly detected by the behavioral performance and spatial brain activation in the left prefrontal cortex, while word structure effect was revealed by the behavioral data as well as the temporal and spatial brain activation patterns. In addition, Chinese derivations exhibited significantly enhanced brain activation in the frontal cortex and involved more brain networks as compared to lexicalized compounds. The results were interpreted by the differing connection patterns between constitute morphemes within a given word structure from spreading activation perspective. More importantly, we demonstrated that Chinese word structure effect showed a distinct brain activation pattern as compared to that from the dual-route mechanism in alphabetic languages. Therefore, this pilot work paves a new avenue for comprehensively understanding the underlying cognitive neural mechanism associated with Chinese derivations and coordinate compounds.

neuroscience↗

bioRxiv2021

Dysconnectivity between auditory-cognitive network associated with auditory GABA and glutamate levels in presbycusis patients

Accumulating studies suggest an interaction between presbycusis (PC) and cognitive impairment, which may be explained by the cognitive-ear link to a large extent. However, the neurophysiological mechanisms underlying this link are largely unknown. Here, 51 PC patients and 51 well-matched healthy controls were recruited. We combined resting-state functional MRI and edited magnetic resonance spectroscopy to investigate changes of intra- and inter-network functional connectivity and their relationships with auditory gamma-aminobutyric acid (GABA) and glutamate (Glu) levels and cognitive impairment in PC. Our study confirmed the plastic model of cognitive-ear link at the level of the large-scale brain network, including the dysconnectivity within high-order cognitive networks and between the auditory-cognitive network and overactivation between cognitive networks dependent on hearing loss, which was closely related to the cognitive impairment of PC patients. Moreover, GABA and Glu levels in the central auditory processing were abnormal in patients with PC. Importantly, reduction of GABA-mediated inhibition plays a crucial role in a dysconnectivity between the auditory-cognitive network, which may be neurochemical underpinnings of functional remodeling of cognitive-ear link in PC. Modulation of GABA neurotransmission may enable the development of new therapeutic strategies for the cognitive impairment of PC patients.

neuroscience↗

bioRxiv2021

CircSry regulates spermatogenesis by enhancing γH2AX expression via sponging miR-138-5p

Sry on the Y chromosome is the master switch in sex determination in mammals. It has been well established that Sry encodes a transcription factor that is transiently expressed in somatic cells of male gonad, inducing a series of events that lead to the formation of testes. In the testis of adult mice, Sry is expressed as a circular RNA (circRNA) transcript, a type of noncoding RNA that forms a covalently linked continuous loop. However, the physiological function of this Sry circRNA (circSry) remains unknown since its discovery in 1993. Here we show that circSry is mainly expressed in the spermatocytes, but not in mature sperms and Sertoli cells. Loss of circSry led to the reduction of sperm number and the defect of germ cell development. The expression of {gamma}H2AX was decreased and failure of XY body formation was noted in circSry KO germ cells. Further study demonstrates that circSry regulates H2AX mRNA indirectly in pachytene spermatocytes through sponging miR-138-5p. Our study demonstrates that, in addition to its well-known sex-determination function, Sry also plays important role in spermatogenesis as a circRNA.

developmental biology↗

bioRxiv2021

Tissue-wide coordination of calcium signaling regulates the epithelial stem cell pool during homeostasis

Skin epidermal homeostasis is maintained via constant regeneration by stem cells, which must communicate to balance their self-renewal and differentiation. A key molecular pathway, Ca2+ signaling has been implicated as a signal integrator in developing and wounded epithelial tissues[1, 2, 3, 4]. Yet how stem cells carry out this signaling across a regenerative tissue remains unknown due to significant challenges in studying signaling dynamics in live mice, limiting our understanding of the mechanisms of stem cell communication during homeostasis. To interpret high dimensional signals that have complex spatial and temporal patterns, we combined optimized imaging of Ca2+ signaling in thousands of epidermal stem cells in living mice with a new machine learning tool, Geometric Scattering Trajectory Homology (GSTH). Using a combination of signal processing, data geometry, and topology, GSTH captures patterns of signaling at multiple scales, either between direct or distant stem cell neighbors. Here we show that epidermal stem cells display dynamic intercellular Ca2+ signaling among neighborhoods of up to 10 cells that is surprisingly coordinated and directed through time across a pool of thousands of stem cells. We find that this collective coordination is an emergent property of the stem cell compartment, distinct from excitatory quiescent neuronal tissues. We demonstrate that cycling stem cells, specifically G2 cells, govern homeostatic patterns of Ca2+ signaling. Stem cells in different cell cycle stages dynamically regulate localization of the gap junction component Connexin43 (Cx43). Lastly, we uncouple global from local communication and identify Cx43 as the molecular mediator necessary for connectivity between local signaling neighborhoods. This work provides resolution in how stem cells at different stages of the cell cycle communicate and how that diversity of phases is essential for tissue wide communication and signaling flow during epidermal regeneration. Our approach provides a framework to investigate stem cell populations and their signaling dynamics, previously not possible.

cell biology↗

bioRxiv2021

Generation of a molecular interactome of the glioblastoma perivascular niche reveals Integrin Binding Sialoprotein as a key mediator of tumor cell migration

Glioblastoma (GBM) is characterized by extensive microvascular hyperproliferation. In addition to supplying blood to the tumor, GBM vessels also provide trophic support to glioma cells and serve as conduits for migration into the surrounding brain promoting recurrence. Here, we enriched CD31-expressing glioma vascular cells (GVC) and A2B5-expressing glioma tumor cells (GTC) from primary GBM and utilized RNA sequencing to create a comprehensive interaction map of the secreted and extracellular factors elaborated by GVC that can interact with receptors and membrane molecules on GTC. To validate our findings, we utilized functional assays, including a novel hydrogel-based migration assay and in vivo mouse models to demonstrate that one identified factor, the little-studied integrin binding sialoprotein (IBSP) enhances tumor growth and promotes the migration of GTC along the vasculature. This perivascular niche interactome will serve a resource to the research community in defining the potential functions of the GBM vasculature.

cancer biology↗

bioRxiv2021

Single-cell perturbation dissects transcription factor control of progression speed and trajectory choice in early T-cell development

In early T-cell development, single cells dynamically shift expression of multiple transcription factors (TFs) during transition from multipotentiality to T-lineage commitment, but the functional roles of many TFs have been obscure. Here, synchronized in vitro differentiation systems, scRNA-seq with batch indexing, and controlled gene-disruption strategies have unraveled single-cell impacts of perturbing individual TFs at two stages in early T-cell development. Single-cell CRISPR perturbation revealed that early-acting TFs Bcl11a, Erg, Spi1 (PU.1), Gata3, and Tcf7 (TCF1) each play individualized roles promoting or retarding T-lineage progression and suppressing alternative trajectories, collectively determining population dynamics and path topologies. Later, during T-lineage commitment, cells prevented from expressing TF Bcl11b realized this abnormality not with a developmental block, but by shifting into a divergent path via bZIP and Sox TF activation as well as E protein antagonism, finally exiting the T-lineage trajectory. These TFs thus exert a network of impacts to control progression kinetics, trajectories, and differentiation outcomes of early pro-T cells.

immunology↗

bioRxiv2021

Deep Bayesian networks for uncertainty estimation and adversarial resistance of white matter hyperintensity segmentation

White matter hyperintensities (WMH) are frequently observed on structural neuroimaging of elderly populations and are associated with cognitive decline and increased risk of dementia. Many existing WMH segmentation algorithms produce suboptimal results in populations with vascular lesions or brain atrophy, or require parameter tuning and are computationally expensive. Additionally, most algorithms do not generate a confidence estimate of segmentation quality, limiting their interpretation. MRI-based segmentation methods are often sensitive to acquisition protocols, scanners, noise-level, and image contrast, failing to generalize to other populations and out-of-distribution datasets. Given these concerns, we propose a novel Bayesian 3D Convolutional Neural Network (CNN) with a U-Net architecture that automatically segments WMH, provides uncertainty estimates of the segmentation output for quality control and is robust to changes in acquisition protocols. We also provide a second model to differentiate deep and periventricular WMH. 432 subjects were recruited to train the CNNs from four multi-site imaging studies. A separate test set of 158 subjects was used for evaluation, including an unseen multi-site study. We compared our model to two established state-of-the-art techniques (BIANCA and DeepMedic), highlighting its accuracy and efficiency. Our Bayesian 3D U-Net achieved the highest Dice similarity coefficient of 0.89 {+/-} 0.08 and the lowest modified Hausdorff distance of 2.98 {+/-} 4.40 mm. We further validated our models highlighting their robustness on clinical adversarial cases simulating data with low signal-to-noise ratio, low resolution, and different contrast (stemming from MRI sequences with different parameters). Our pipeline and models are available at: https://hypermapp3r.readthedocs.io

neuroscience↗

bioRxiv2021

Lupus Gut Microbiota Transplants Cause Autoimmunity and Inflammation

BackgroundThe etiology of systemic lupus erythematosus (SLE) is multifactorial. Recently, growing evidence suggests that the microbiota plays a role in SLE, yet whether gut microbiota participates in the development of SLE remains largely unknown. To investigate this issue, we carried out 16s rDNA sequencing analyses in a cohort of 18 female un-treated active SLE patients and 7 female healthy controls, and performed fecal microbiota transplantation from patients and healthy controls to germ-free mice. ResultsCompared to the healthy controls, we found no significant different microbial diversity but some significantly different species in SLE patients including Turicibacter genus and other 5 species. Fecal transfer from SLE patients to germ free (GF) C57BL/6 mice caused GF mice to develop a series of lupus-like phenotyptic features, which including an increased serum autoimmune antibodies, and imbalanced cytokines, altered distribution of immune cells in mucosal and peripheral immune response, and upregulated expression of genes related to SLE in recipient mice that received SLE fecal microbiota transplantation (FMT). Moreover, the metabolism of histidine was significantly altered in GF mice treated with SLE patient feces, as compared to those which received healthy fecal transplants. ConclusionsOverall, our results describe a causal role of aberrant gut microbiota in contributing to the pathogenesis of SLE. The interplay of gut microbial and histidine metabolism may be one of the mechanisms intertwined with autoimmune activation in SLE.

immunology↗

bioRxiv2021

Augmenting Neutralization breadth against Diverse HIV-1 by increasing the Ab-Ag interface on V2

Understanding maturation pathways of broadly neutralizing antibodies (bnAbs) against HIV-1 in non-human primates can be highly informative for HIV-1 vaccine development. We now obtained a lineage of J038 from Chinese rhesus macaques after 7-years of SHIV infection. J038 has short complementary determining loops and neutralizes 54% of global circulating HIV-1 strains. Its binding induces a unique "up" conformation for one of the V2 loops in the trimeric envelope glycoprotein (Env) and is heavily dependent on glycan, which provides nearly half of the binding surface. The unmutated common ancestor of the J038 lineage antibodies binds monomeric gp120 and neutralizes the autologous virus. Continuous maturation enhances neutralization potency and breadth of J038 lineage antibodies via expanding antibody-Env contact areas surrounding the core region contacted by germline-encoded residues. Developmental details and recognition features of J038 lineage antibodies revealed here provide a new pathway for maturation elicitation of V2-targeting bnAbs. Highlights* Long-term infected NHPs develop antibodies neutralizing up to 54% of HIV-1 strains * Antibody J038 binds one V2 loop on HIV-1 Env trimer in a unique "up" position * UCA of the J038 lineage effectively neutralizes the autologous virus * J038 lineage antibodies mature through gradually increased contact to glycans

immunology↗

bioRxiv2021

Investigating the Contribution of White Matter Hyperintensities and Cortical Thickness to Empathy in Neurodegenerative and Cerebrovascular Diseases

Introduction: Change in empathy is an increasingly recognised symptom of neurodegenerative diseases and contributes to caregiver burden and patient distress. Empathy impairment has been associated with brain atrophy but its relationship to white matter hyperintensities (WMH) is unknown. We aimed to investigate the relationships amongst WMH, brain atrophy, and empathy deficits in neurodegenerative and cerebrovascular diseases. Methods: 513 participants with Alzheimers Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia (FTD), Parkinsons Disease, or Cerebrovascular Disease (CVD) were included. Empathy was assessed using the Interpersonal Reactivity Index. WMH were measured using a semi-automatic segmentation and FreeSurfer was used to measure cortical thickness. Results: A heterogeneous pattern of cortical thinning was found between groups, with FTD showing thinning in frontotemporal regions and CVD in left superior parietal, left insula, and left postcentral. Results from both univariate and multivariate analyses revealed that several variables were associated with empathy, particularly cortical thickness in the fronto-insulo-temporal and cingulate regions, sex(female), global cognition, and right parietal and occipital WMH. Conclusions: Our results suggest that cortical atrophy and WMH may be associated with empathy deficits in neurodegenerative and cerebrovascular diseases. Future work should consider investigating the longitudinal effects of WMH and atrophy on empathy deficits in neurodegenerative and cerebrovascular diseases.

neuroscience↗

bioRxiv2021

Atp13a5 Marker Reveals Pericytes of The Central Nervous System in Mice

Perivascular mural cells including vascular smooth cells (VSMCs) and pericytes are integral components of the vascular system. In the central nervous system (CNS), pericytes are also known as the guardian of the blood-brain barrier, blood-spinal cord barrier and blood-retinal barrier, and play key roles in maintaining cerebrovascular and neuronal functions. However, the functional difference between CNS and peripheral pericytes has not been resolved at the genetic and molecular levels. Hence, the generation of reliable CNS pericyte-specific models and genetic tools remains very challenging. Here, we report a new CNS pericyte marker in mice. This cation-transporting ATPase 13A5 (Atp13a5) marker is highly specific to the pericytes in brain, spinal cord and retina. We generated a transgenic model with a knock-in tdTomato reporter and Cre recombinase. The tdTomato reporter reliably labels the CNS pericytes, but not found in any other CNS cell types including closely related VSMCs, or in peripheral organs. More importantly, Atp13a5 is turned on at embryonic day E15, suggesting brain pericytes are shaped by the developing neural environment. We hope that the new tools will allow us to further explore the heterogeneity of pericytes and achieve a better understanding of CNS pericytes in health and diseases.

neuroscience↗

bioRxiv2021

SAFA facilitates chromatin opening of immune genes through interacting with nascent antiviral RNAs

Regulation of chromatin accessibility determines the transcription activities of genes, which endow the host with function-specific gene expression patterns. It remains unclear how chromatin accessibility is specifically directed, particularly, during host defense against viral infection. We previously reported that the nuclear matrix protein SAFA surveils viral RNA and regulates antiviral immune genes expression. However, how SAFA regulates the expression and what determines the specificity of antiviral immune genes remains unknown. Here, we identified that the depletion of SAFA specifically decreased the chromatin accessibility, activation and expression of virus induced genes in a genome-wide scale after VSV infection. SAFA exclusively bound with antiviral related RNAs, which mediated the specific opening of the according chromatin and robust transcription of these genes. Knockdown of these associated RNAs dampened the accessibility of corresponding genes in an extranuclear signaling pathway dependent manner. Moreover, VSV infection cleaved SAFA protein at the C-terminus which deprived its RNA binding ability for immune evasion. Thus, our results demonstrated that SAFA and the interacting RNA products during viral infection collaborate and remodel chromatin accessibility to facilitate antiviral innate immune response.

immunology↗

bioRxiv2021

Constraints and Opportunities for Detecting Land Surface Phenology in Drylands

Land surface phenology (LSP) enables global scale tracking of ecosystem processes, but its utility is limited in drylands due to low vegetation cover and resulting low annual amplitudes of vegetation indices (VIs). Due to the importance of drylands for biodiversity, food security, and the carbon cycle it is necessary to understand limitations in measuring dryland dynamics. Here, using simulated data and multi-temporal unmanned aerial vehicle (UAV) imagery of a desert shrubland, we explore the feasibility of detecting LSP with respect to fractional vegetation cover, plant functional types, VI uncertainty, and two different detection algorithms. Using simulated data we found that plants with distinct VI signals, such as deciduous shrubs, can require up to 60% fractional cover to consistently detect LSP. Evergreen plants, with lower seasonal VI amplitude, require considerably higher cover and can have undetectable phenology even with 100% vegetation cover. Our evaluation of two algorithms showed that neither performed the best in all cases. Even with adequate cover, biases in phenological metrics can still exceed 20 days, and can never be 100% accurate due to VI uncertainty from shadows, sensor view angle, and atmospheric interference. We showed how high-resolution UAV imagery enables LSP studies in drylands, and highlighted important scale effects driven by within canopy VI variation. With high-resolution imagery the open canopies of drylands are beneficial as they allow for straightforward identification of individual plants, enabling the tracking of phenology at the individual level. Drylands thus have the potential to become an exemplary environment for future LSP research.

ecology↗

bioRxiv2021

The role of Cyp19a1 in female pathway of a freshwater turtle (Mauremys reevesii) with temperature-dependent sex determination

The molecular mechanism of temperature-dependent sex determination (TSD) in reptiles has been drawn great interest from biologists for several decades. However, which genetic factors are essential for TSD remain elusive, especially for the female sex determination process. Cyp19a1, encodes an enzyme of aromatase catalyzing the conversion of testosterone to estrogen, has been confirmed to modulate steroid hormones involved in the sexual differentiation of many species, but whether it has a critical role in determining the gonadal sexual fate in TSD is still to be elucidated. Here, we identified that Cyp19a1 expression exhibited a temperature-dependent, sexually dimorphic expression pattern, preceding gonadal sex differentiation in a TSD turtle Mauremys reevesii. Cyp19a1 expression in gonads increased dramatically when embryos developed at high female-producing temperatures (FPT), but were extremely low throughout embryogenesis at low male-producing temperatures (MPT). Cyp19a1 expression increased rapidly in response to the temperature shift from MPT to FPT in developing gonads. The sexual phenotype of turtles was successfully reversed by aromatase inhibitor treatment at FPT, and by estrogen treatment at MPT, accompanied with the rapid upregulation of Cyp19a1. These results demonstrate that Cyp19a1 is essential for the female sex determination process in M. reevesii, indicating its vital role in the female pathway of TSD.

developmental biology↗

bioRxiv2021

SARS-CoV-2 receptor ACE2 identifies immuno-hot tumors in breast cancer

Angiotensin-converting enzyme 2 (ACE2) is known as a host cell receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which is identified to be dysregulated in multiple tumors. Although the characterization of abnormal ACE2 expression in malignancies has been preliminarily explored, in-depth analysis of ACE2 in breast cancer (BRCA) has not been elucidated. A systematic pan-cancer analysis was conducted to assess the expression pattern and immunological role of ACE2 based on RNA-sequencing (RNA-seq) data downloaded from The Cancer Genome Atlas (TCGA). Next, correlations between ACE2 expression immunological characteristics in the BRCA tumor microenvironment (TME) were evaluated. Also, the role of ACE2 in predicting the clinical features and the response to therapeutic options in BRCA was estimated. These findings were subsequently validated in another public transcriptomic cohort as well as a recruited cohort. ACE2 was lowly expressed in most cancers compared with adjacent tissues. ACE2 was positively correlated with immunomodulators, tumor-infiltrating immune cells (TIICs), cancer immunity cycles, immune checkpoints, and tumor mutation burden (TMB). Besides, high ACE2 levels indicated the triple-negative breast cancer (TNBC) subtype of BRCA, lower response to endocrine therapy and higher response to chemotherapy, anti-ERBB therapy, antiangiogenic therapy and immunotherapy. To sum up, ACE2 correlates with an inflamed TME and identifies immuno-hot tumors, which may be used as an auxiliary biomarker for the identification of immunological characteristics in BRCA.

immunology↗

bioRxiv2021

Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression ofPAK3 via miRNA regulation

Over 85% of lung cancer patients harbor overt or subclinical metastases at diagnosis, and therefore most patients die of progressive metastatic disease despite aggressive local and systemic therapies. Somatic mutations in the Smad4 gene have been found in non-small-cell lung cancer, but the underlying mechanism by which Smad4 loss-of-function (LOF) accelerates lung cancer metastasis is yet to be elucidated. Here, we generated a highly aggressive lung cancer mouse model bearing conditional KrasG12D, p53fl/fl LOF and/or Smad4 fl/fl LOF mutations. The Smad4fl/fl; p53 fl/fl; KrasG12D (SPK) mutant mice manifested a much higher incidence of tumor metastases than the p53 fl/fl; KrasG12D (PK) mice. Molecularly, PAK3 was identified as a novel downstream effector of Smad4, mediating metastatic signal transduction via the PAK3-JNK-Jun pathway. Upregulation of PAK3 by Smad4 LOF in SPK mice was achieved by attenuating Smad4-dependent transcription of miR-495 and miR-543. These microRNAs (miRNAs) directly bind to the PAK3 3UTR for blockade of PAK3 production, ultimately regulating lung cancer metastasis. An inverse correlation between Smad4 and PAK3 pathway components suggests clinical use of Smad4 LOF as a potential marker for prognosis in human lung cancer. Our study highlights the Smad4-PAK3 regulation as a point of potential therapy in metastatic lung cancer.

cancer biology↗

bioRxiv2021

Ultrapotent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus displayed remarkable efficacy against authentic B.1.351 virus. Each of these 3 mAbs in combination with one neutralizing Ab recognizing non-competing epitope exhibited synergistic effect against authentic SARS-CoV-2 virus. Surprisingly, structural analysis revealed that 58G6 and 13G9, encoded by the IGHV1-58 and the IGKV3-20 germline genes, both recognized the steric region S470-495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly bound to another region S450-458 in the RBD. Significantly, 58G6 and 510A5 both demonstrated prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. These 2 ultrapotent neutralizing Abs can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.

immunology↗

bioRxiv2021

PRMT5 regulates ovarian follicle development by facilitating Wt1 translation

Protein arginine methyltransferase 5 (Prmt5) is the major type II enzyme responsible for symmetric dimethylation of arginine. Here, we found PRMT5 was expressed at high level in ovarian granulosa cells of growing follicles. Inactivation of Prmt5 in granulosa cells resulted in aberrant follicle development and female infertility. In Prmt5-knockout mice, follicle development was arrested with disorganized granulosa cells in which WT1 expression was dramatically reduced and the expression of steroidogenesis-related genes was significantly increased. The premature differentiated granulosa cells were detached from oocytes and follicle structure was disrupted. Mechanism studies revealed that Wt1 expression was regulated by PRMT5 at the protein level. PRMT5 facilitated IRES-dependent translation of Wt1 mRNA by methylating HnRNPA1. Moreover, the upregulation of steroidogenic genes in Prmt5-deficient granulosa cells was repressed by Wt1 overexpression. These results demonstrate PRMT5 participates in granulosa cell lineage maintenance by inducing Wt1 expression. Our study uncovers a new role of post-translational arginine methylation in granulosa cell differentiation and follicle development.

developmental biology↗