Biology subjects

Xue, G.

Publications and source records attributed to Xue, G..

32 records · Page 2Linked to original sources

bioRxiv2023

Maintenance and transformation of representational formats during working memory prioritization

Visual working memory depends on both material-specific brain areas in the ventral visual stream (VVS) that support the maintenance of stimulus representations and on regions in prefrontal cortex (PFC) that control these representations. Recent studies identified stimulus-specific working memory contents via representational similarity analysis (RSA) and analyzed their representational format using deep neural networks (DNNs) as models of the multi-layered hierarchy of information processing. How executive control prioritizes relevant working memory contents and whether this affects their representational formats remains an open question, however. Here, we addressed this issue using a multi-item working memory task involving a retro-cue that prompted participants to maintain one particular item. We exploited the excellent spatiotemporal resolution of intracranial EEG (iEEG) recordings in epilepsy patients and analyzed activity at electrodes in VVS (n=28 patients) and PFC (n=16 patients). During encoding, we identified category-specific information in both VVS and PFC. During maintenance, this information re-occurred in VVS but not in the PFC - suggesting a transformation of PFC representations from encoding to maintenance which putatively reflects the prioritization process. We thus applied RSA in combination with different DNN architectures to investigate the representational format of prioritized working memory contents. Representations during the maintenance period matched representations in deep layers of recurrent but not feedforward DNNs, in both VVS and PFC. While recurrent DNN representations matched PFC representations in the beta band following the retro-cue, they corresponded to VVS representations in a lower theta-alpha frequency range (3-14Hz) towards the end of the maintenance period. Findings could be replicated in recurrent DNNs with two different architectures and using two different training sets. Together, these results demonstrate that VWM relies on representational transformations in VVS and PFC that give rise to distinct coding schemes of prioritized contents.

neuroscience↗

bioRxiv2022

DeepCCI: a deep learning framework for identifying cell-cell interactions from single-cell RNA sequencing data

With the rapid development of high throughput single-cell RNA sequencing (scRNA-seq) technologies, it is of high importance to identify Cell-cell interactions (CCIs) from the ever-increasing scRNA-seq data. However, limited by the algorithmic constraints, current computational methods based on statistical strategies ignore some key latent information contained in scRNA-seq data with high sparsity and heterogeneity. To address the issue, here, we developed a deep learning framework named DeepCCI to identify meaningful CCIs from scRNA-seq data. Applications of DeepCCI to a wide range of publicly available datasets from diverse technologies and platforms demonstrate its ability to predict significant CCIs accurately and effectively.

bioinformatics↗

bioRxiv2022

Modulation of RNA binding properties of the RNA helicase UPF1 by its activator UPF2

The NMD helicase UPF1 is a prototype of the superfamily 1 (SF1) of RNA helicases that bind RNA with high affinity and translocate on it in an ATP-dependent manner. Previous studies showed that UPF1 has a low basal catalytic activity that is greatly enhanced upon binding of its interaction partner, UPF2. Activation of UPF1 by UPF2 entails a large conformational change that switches the helicase from an RNA-clamping mode to an RNA-unwinding mode. The ability of UPF1 to bind RNA was expected to be unaffected by this activation mechanism. Here we show, using a combination of biochemical and biophysical methods, that binding of UPF2 to UPF1 drastically reduces the affinity of UPF1 for RNA, leading to a release of the bound RNA. Although UPF2 is capable of binding RNA in vitro, our results suggest that dissociation of the UPF1-RNA complex is not a consequence of direct competition in RNA binding but rather an allosteric effect that is likely mediated by the conformational change induced by binding of the helicase to its activator. We discuss these results in light of transient interactions forged during mRNP assembly, particularly in the UPF1-dependent mRNA decay pathways.

biochemistry↗

bioRxiv2021

The HIV-1 capsid core is an opportunistic nuclear import receptor

The movement of viruses and other large macromolecular cargo through nuclear pore complexes (NPCs) is poorly understood. The human immunodeficiency virus type 1 (HIV-1) provides an attractive model to interrogate this process due to the genetic and cell biological assays to score virus nuclear entry in living cells. Although initial studies of HIV-1 infection of nondividing cells focused on karyophilic virion proteins, subsequent work revealed the viral capsid (CA), the chief structural component of the pre-integration complex (PIC), to be a critical determinant in nuclear transport1. In support of this model, HIV-1 interactions with NPCs can be altered through CA mutation2, which makes direct contact with nucleoporins (Nups)3-5. Here we identify Nup35, Nup153, and POM121 to coordinately support HIV-1 nuclear entry. For Nup35 and POM121, this dependence was strongly dependent cyclophilin A (CypA) interaction with CA. Mutation of CA or removal of soluble host factors changed the interaction with the NPC. Collectively, these findings implicate the HIV-1 CA hexameric lattice that encapsulates the viral genome as a macromolecular nuclear transport receptor (NTR) that exploits soluble host factors to modulate NPC requirements during nuclear invasion.

cell biology↗

bioRxiv2020

Poly(ADP-ribose) potentiates ZAP antiviral activity

Zinc-finger antiviral protein (ZAP), also known as poly(ADP-ribose) polymerase 13 (PARP13), is an antiviral factor that selectively targets viral RNA for degradation. ZAP is active against both DNA and RNA viruses, including important human pathogens such as hepatitis B virus and type 1 human immunodeficiency virus (HIV-1). ZAP selectively binds CpG dinucleotides through its N-terminal RNA-binding domain, which consists of four zinc fingers. ZAP also contains a central region that consists of a fifth zinc finger and two WWE domains. Through structural and biochemical studies, we found that the fifth zinc finger and tandem WWEs of ZAP combine into a single integrated domain that binds to poly(ADP-ribose) (PAR), a cellular polynucleotide. PAR binding is mediated by the second WWE module of ZAP and likely involves specific recognition of iso(ADP-ribose), a repeating structural unit of PAR. Mutation of the putative iso(ADP-ribose) binding site in ZAP abrogates the interaction in vitro and diminishes ZAP activity against a CpG-rich HIV-1 reporter virus. In cells, PAR facilitates formation of non-membranous sub-cellular compartments such as DNA repair foci, spindle poles and cytosolic RNA stress granules. Our results suggest that ZAP-mediated viral mRNA degradation is facilitated by PAR, and provides a biophysical rationale for the reported association of ZAP with RNA stress granules.

microbiology↗

bioRxiv2020

N439K variant in spike protein may alter the infection efficiency and antigenicity of SARS-CoV-2 based on molecular dynamics simulation

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing an outbreak of coronavirus disease 2019 (COVID-19), has been undergoing various mutations. The analysis of the structural and energetic effects of mutations on protein-protein interactions between the receptor binding domain (RBD) of SARS-CoV-2 and angiotensin converting enzyme 2 (ACE2) or neutralizing monoclonal antibodies will be beneficial for epidemic surveillance, diagnosis, and optimization of neutralizing agents. According to the molecular dynamics simulation, a key mutation N439K in the SARS-CoV-2 RBD region created a new salt bridge which resulted in greater electrostatic complementarity. Furthermore, the N439K-mutated RBD bound hACE2 with a higher affinity than wild-type, which may lead to more infectious. In addition, the N439K-mutated RBD was markedly resistant to the SARS-CoV-2 neutralizing antibody REGN10987, which may lead to the failure of neutralization. These findings would offer guidance on the development of neutralizing antibodies and the prevention of COVID-19.

bioinformatics↗

bioRxiv2020

Interpreting the dynamic pathogenesis of Parkinson's disease by longitudinal blood transcriptome analysis

Achieving an improved understanding of the temporal sequence of factors involved in Parkinsons disease (PD) pathogenesis may accelerate drug discovery. In this study, we performed a longitudinal transcriptome analysis to identify associated genes underlying the pathogenesis of PD at three temporal phases. We firstly found that multiple initiator genes, which are related to processes of olfactory transduction and stem cell pluripotency, indicate PD risk to those subjects at the prodromal phase. And many facilitator genes involved in calcium signaling and stem cell pluripotency contribute to PD onset. We next identified 325 aggravator genes whose expression could lead to disease progression through damage to dopaminergic synapses and ferroptosis via an integrative analysis with DNA methylation. Last, we made a systematic comparison of gene expression patterns across PD development and accordingly provided candidate drugs at different phases in an attempt to prevent the neurodegeneration process.

bioinformatics↗

bioRxiv2020

mRNA translation control by Dhx36 binding to 5' UTR G-quadruplex structures is essential for skeletal muscle stem cell regenerative functions

Skeletal muscle has a remarkable ability to regenerate owing to its resident stem cells, also called satellite cells (SCs), that are normally quiescent. When stimulated by damage, SCs activate and expand to form new fibers. The mechanisms underlying SC proliferative progression remain poorly understood. Here we show that Dhx36, a helicase that unwinds RNA quadruplex (rG4) structures, is essential for muscle regeneration by regulating SC expansion. We find that Dhx36 (initially named RHAU) is barely expressed at quiescence and is highly induced during SC activation and proliferation. Inducible deletion of Dhx36 in adult SCs causes defective proliferation and muscle regeneration after damage. System-wide mapping in proliferating SCs revealed Dhx36 binding predominantly to rG4 structures at various regions of mRNAs, while integrated polysome profiling showed that Dhx36 promotes mRNA translation via 5UTR rG4 binding. Furthermore, we demonstrate that Dhx36 specifically regulates the translation of Gnai2 mRNA by unwinding its 5UTR rG4 structures and identify Gnai2 as a downstream effector of Dhx36 for SC expansion. Altogether our findings uncover Dhx36 as an indispensable post-transcriptional regulator of SC function and muscle regeneration through binding and unwinding rG4 structures at 5UTR of target mRNAs.

cell biology↗

bioRxiv2019

Quantifiable In Vivo Imaging Biomarkers of Retinal Regeneration by Photoreceptor Cell Transplantation

PurposeShort-term improvements in retinal anatomy are known to occur in preclinical models of photoreceptor transplantation. However, correlative changes over the long term are poorly understood. We aimed to develop a quantifiable imaging biomarker grading scheme, using non-invasive multimodal confocal scanning laser ophthalmoscopy (cSLO) imaging, to enable serial evaluation of photoreceptor transplantation over the long term. MethodsYellow-green fluorescent microspheres were transplanted into the vitreous cavity and/or subretinal space of C57/BL6J mice. Photoreceptor cell suspensions or sheets from rhodopsin-green fluorescent protein mice were transplanted subretinally, into either NOD.CB17-Prkdcscid/J or C3H/HeJ-Pde6brd1 mice. Multimodal cSLO imaging was performed serially for up to three months after transplantation. Imaging biomarkers were scored, and a grade was defined for each eye by integrating the scores. Image grades were correlated with immunohistochemistry (IHC) data. ResultsMultimodal imaging enabled the extraction of quantitative imaging biomarkers including graft size, GFP intensity, graft length, on-target graft placement, intra-graft lamination, hemorrhage, retinal atrophy, and peri-retinal proliferation. Migration of transplanted material was observed. Changes in biomarker scores and grades were detected in 13/16 and 7/16 eyes, respectively. A high correlation was found between image grades and IHC parameters. ConclusionsSerial evaluation of multiple imaging biomarkers, when integrated into a per-eye grading scheme, enabled comprehensive tracking of longitudinal changes in photoreceptor cell grafts over time. The application of systematic multimodal in vivo imaging could be useful in increasing the efficiency of preclinical retinal cell transplantation studies in rodents and other animal models.

neuroscience↗

bioRxiv2019

Dynamic Predictions: Oscillatory Mechanisms Underlying Multisensory Sequence Processing

Neural oscillations have been proposed to be involved in predictive processing, however less addressed in the multisensory context. In the present study, we recorded cortical activity using magnetoencephalography during an audiovisual serial prediction task in which participants had to acquire stimulus sequences and to monitor whether subsequent probe items complied with the sequence. In a given trial, either visual or auditory features of the bimodal stimuli were task-relevant. Task-related changes of power and coupling of neural oscillations were analyzed using a data-driven clustering approach. We observed prediction-related theta-band (5-7 Hz) coupling in a network involving the cingulate, premotor, prefrontal, and superior temporal regions. The behavioral performance of participants varied as a function of the phase delay of the coupling between different regions in this network. . Two additional spectro-temporal clusters were detected in which beta power (11-16 Hz and 16-22 Hz, respectively) was stronger if the previous or the following stimuli were the same as the current one in the sequence. These clusters spatially overlapped with the theta-band prediction cluster, and interacted with it through cross-frequency coupling. Our results offer novel insights into the multi-timescale neural dynamics underlying multisensory predictions, suggesting that oscillations in multiple frequency ranges, as well as coupling within and across frequencies, may be critical for multisensory sequence processing.

neuroscience↗

bioRxiv2019

Reduced frontal white matter microstructure in healthy older adults with low tactile recognition performance

Aging leads to a reduction of connectivity in large-scale structural brain networks. Sensory processing and other cognitive processes rely on information flow between distant brain areas. However, data linking age-related structural brain alterations to cognitive functioning, especially sensory processing, is sparse.\n\nAiming to determine group differences in sensory processing between older and younger participants, we implemented a complex tactile recognition task and investigated to what extent changes in microstructural white matter integrity of large-scale brain networks might reflect success in task performance. Structural brain integrity was accessed by means of diffusion-weighted imaging and fractional anisotrophy.\n\nThe data revealed that poor performance in complex tactile recognition in older, neurologically healthy individuals is related to decreased structural integrity pronounced in the anterior corpus callosum. This region was strongly connected to the prefrontal cortex. Our data suggests decreased fractional anisotrophy in the anterior corpus callosum as a surrogate marker for progressed brain aging, leading to disturbances in networks relevant for higher-order cognitive processing. Complex tactile recognition might be a sensitive marker for identifying these starting cognitive impairments in older adults.

neuroscience↗

bioRxiv2019

Congruency effects can compensate for deficits of healthy older adults in crossmodal integration

One of the pivotal challenges of aging is to maintain independence in the activities of daily life. In order to adapt to changes in the environment, it is crucial to continuously process and accurately combine simultaneous input from different sensory systems, i.e., crossmodal integration.\n\nWith aging, performance decreases in multiple cognitive domains. The processing of sensory stimuli constitutes one of the key features of this deterioration. Age-related sensory impairments affect all modalities, substantiated by decreased acuity in visual, auditory or tactile detection tasks.\n\nHowever, whether this decline of sensory processing leads to impairments in crossmodal integration remains an unresolved question. While some researchers propose that crossmodal integration degrades with age, others suggest that it is conserved or even gains compensatory importance.\n\nTo address this question, we compared behavioral performance of older and young participants in a well-established crossmodal matching task, requiring the evaluation of congruency in simultaneously presented visual and tactile patterns. Older participants performed significantly worse than young controls in the crossmodal task when being stimulated at their individual unimodal visual and tactile perception thresholds. Performance increased with adjustment of stimulus intensities. This improvement was driven by better detection of congruent stimulus pairs (p<0.01), while detection of incongruent pairs was not significantly enhanced (p=0.12).\n\nThese results indicate that age-related impairments lead to poor performance in complex crossmodal scenarios and demanding cognitive tasks. Performance is enhanced when inputs to the visual and tactile systems are congruent. Congruency effects might therefore be used to develop strategies for cognitive training and neurological rehabilitation.

neuroscience↗

bioRxiv2019

Comparison of different orders of Legendre polynomials in random regression model for estimation of genetic parameters and breeding values of milk yield in the Chinese Holstein population

Random regression test-day model has become the most commonly adopted model for routine genetic evaluations for different dairy populations, which allows accurately accounting for genetic and environmental effects at different periods during lactation. The objective of this study was to explore appropriate random regression test-day model for genetic evaluation of milk yield in Chinese Holstein population. Data included 419,567 test-day records from 54,417 cows in the first lactation. Variance components and breeding values were estimated using random regression test-day model with different order (first order to fifth order) of Legendre polynomials, and accounted for homogeneous or heterogeneous residual variance across the lactation. The goodness of fit of the models was evaluated by total residual variance (TRV) and - 2logL. Further, the predictive ability of the models was assessed by Spearmans rank correlation between estimated breeding values for 305d milk yield (EBV305) from the full data set and reduced data set in which the records from the last calving year were masked. The results showed that random regression models using third order Legendre polynomials (LP3) with heterogeneous residual variance achieved the lower TRV and - 2logL value and the highest correlation for EBV305 between full data and reduced data. Heritability estimated by this model was 0.250 for 305d milk yield and ranged from 0.163 to 0.304 for test-day milk yield. We suggest random regression model with Legendre polynomial of order 3 and accounting for heterogeneous residual variances could be an appropriate model to be used for genetic evaluation of milk yield for Chinese Holstein population.

genetics↗

bioRxiv2018

Single-Cell Modeling of CD8+ T Cell Exhaustion Predicts Response to Cancer Immunotherapy

Accurate prediction of response to immune checkpoint blockade (ICB) and simultaneous development of new efficacious ICB strategy are unmet needs for cancer immunotherapy1-5. Despite the advance of existing clinical or computational biomarkers6-10, it is very limited in explicating phenotypic variability of tumor-infiltrating CD8+ T lymphocytes (TILs) at the single-cell level, including tumor-specificity11,12 and distinct exhaustion profiles13-16, that are crucial for the responsiveness to ICB. Here we show that a quantitative criterion, D value, for evaluating tumor-specific TIL exhaustion, identified by our new high-dimensional single-cell-based computational method, called HD-scMed, accurately predicts response to the ICB, i.e., PD-1, CTLA-4, and PD-1+CTLA-4, with the performance of AUC=100% in human tumors. D-value is the Euclidean distance from a subset of exhausted CD8+ TILs, identified as Pareto Front (PF)18-21 by HD-scMed within the high-dimensional expression space of a variety of exhaustion markers, to the baseline TILs excluded by the PF. We phenotypically distinguished two types of TIL \"exhaustion\" by the D value, namely \"D Extremely-high\" in non-responders, associating with high tumor-specificity imprinted with enhanced exhaustion and inactivated effector and cytotoxic signatures; and \"D low\" specific to responders, alternatively enriched with T cell activation and cytolytic effector T cell signatures. We also observed a large portion of \"D negative\" bystander T cells irrelevant to response. Notably, D-low TILs in clinical responders display very low LAG3 expression. To reverse the functionality of the LAG3-high TILs after receiving PD-1+CTLA-4, we combined LAG3 with PD-1+CTLA-4 in treating a murine tumor model. Remarkably, LAG3+PD-1+CTLA-4 displays extraordinary antitumor efficacy to eradicate advanced tumors, which is associated with burst GZMBhi TIL populations; whereas PD-1+CTLA-4 or PD-1+CTLA-4 plus other ICBs as control only induce moderate tumor growth inhibition. Our study has important implications for cancer immunotherapy as providing both accurate predictions of ICB response and alternative strategy to reverse ICB resistance.

bioinformatics↗