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Biology subjects

Wan, Q.

Publications and source records attributed to Wan, Q..

At least 19 recordsLinked to original sources

The development of navigation and attentional abilities shapes how children explore naturalistic environments

Exploration is fundamental to how children learn about the world. To explore a new environment comprehensively, a child must navigate without getting lost while simultaneously attending to salient information along the way. Both abilities improve across childhood, yet most studies examine them in isolation, often in constrained spaces with limited sensory complexity. Here, we asked 7- to 14-year-old children (N=42) and young adults (18-22; N=42) to freely explore a large furniture store in immersive virtual reality, which contained many objects and attention-capturing multisensory events. Surprisingly, despite traveling comparable distances, children explored less - they covered less spatial area and examined fewer unique objects than adults. Fine-grained analyses of their behaviors showed that the reduction in exploration was due to children spending more time backtracking and children taking longer to adapt to salient multisensory objects, which were uncorrelated across individuals after controlling for age and independently predicted exploration. However, only backtracking duration predicted success in a subsequent search task, demonstrating a link between navigational success during exploration and the quality of learned spatial representations for later use. Together, the results demonstrate that children explore less comprehensively than adults in large-scale spaces because they are susceptible to getting lost and perseverating on salient events nested within a large environment, but that these behaviors change with age. This suggests that while children are widely considered to be curious explorers within local environments, their ability to do so within larger environments is shaped by the maturation of cognitive systems that integrate experiences over complex contexts.

animal behavior and cognition↗

Self-guided search in immersive VR reveals active hierarchical planning

Despite the ubiquitous nature of visual search in our daily lives, our knowledge of the underlying mechanisms is almost entirely derived from studies using simple, synthetic stimuli briefly flashed on a computer monitor. In real life, however, visual search occurs in three-dimensional environments over much longer timescales and involves the dynamic coordination of attention, memory, and action planning, generating novel predictions that cannot be tested with traditional approaches. Here, we examined how self-guided visual search unfolds under naturalistic conditions that extend over space and time. We asked participants (N=80) to find specific objects (e.g., a green lamp, an orange shelf) in an immersive, visually rich virtual reality environment using range-limited teleportation (2 m steps). Consistent with our hypotheses, we found that self-guided search engaged a hierarchical information-seeking policy characterized at each stage by recurring plan-and-execute cycles paired with subgoal-specific attentional priorities. Subgoal priorities progressed from wayfinding to identification of clusters of target-similar objects, and then to specific target features. These search priorities progressively narrowed the search space through coordinated eye, head, and body movements that recurred throughout the task. We conclude that naturalistic search is hierarchical, built from sequential subgoals with shifting attentional priorities that single-level tasks cannot capture. Moreover, immersive VR with eye-head-body tracking dissociates motor planning from execution moments and reveals how looking content shifts with each task subgoal while the person moves through space, something desktop tasks cannot capture.

animal behavior and cognition↗

IgG Propels Atherosclerosis by Noncanonically Activating Macrophages

Despite being a central component of adaptive immunity and a highly abundant serum protein, the contribution of IgG to the milieu of atherosclerosis remains unappreciated. Here, we identify a pro-atherogenic role for IgG as it activates an innate immune cascade, independent of its classical antigen-neutralizing function. Analyses of human coronary artery plaques reveal a positive correlation between IgG and cardiovascular and cerebrovascular disease severity. Integrated single-cell plaque analyses localize IgG, coinciding with its recycling receptor FcRn, to pro-inflammatory and foamy macrophages. Genetic ablation of FcRn in myeloid cells prevents IgG from accumulating in mouse atherosclerotic lesions, diminishing plaque size and inflammation. Mechanistically, IgG acts as an endogenous ligand for TLR4, triggering NF-{kappa}B-NLRP3 inflammasome signaling without requiring its antigen-binding domain. Additionally, IgG accelerates macrophage foam cell formation through upregulation of downstream effector LCN2. Our work uncovers a role for previously overlooked adaptive immune molecules in the pathogenesis of atherosclerosis through a noncanonical mechanism linked with innate immunity.

immunology↗

Small molecule inhibitor of PPARγ acetylation promotes insulin sensitization and browning of white adipose tissue with improved safety

The nuclear receptor PPAR{gamma} is a primary therapeutic target for insulin resistance and type 2 diabetes (T2D); however, its thiazolidinedione (TZD) class of PPAR{gamma} agonists have substantial safety concerns in clinical utilization. Genetic inhibition of PPAR{gamma} acetylation at K268 and K293 dissociates the major adverse effects of TZDs from insulin sensitization and other metabolic improvements. We therefore posit that chemical inhibition of PPAR{gamma} acetylation would elicit insulin sensitization with improved safety. Here we describe the identification of a synthetic thiopyrimidine derivative (TPMD) that acts as a small molecule inhibitor of PPAR{gamma} acetylation. TPMD improves insulin sensitivity, promotes brown remodeling of white adipose tissue (WAT), increases energy expenditure, and decreases adiposity in dietary and genetic mouse models of T2D. Importantly, TPMD is deprived of the major side effects of TZDs, including weight gain, fluid retention, cardiac hypertrophy, bone marrow adiposity, and bone loss. X-ray crystallography at 2.0 [A] resolution reveals a unique binding mode of TPMD molecules to the PPAR{gamma} ligand-binding domain and provides structural and molecular basis for the acetylation inhibitory activity of TPMD together with site-directed mutagenesis studies. These findings identify TPMD as a first-in-class compound that specifically targets PPAR{gamma} acetylation and possesses the potential of developing into a safe insulin sensitizer to treat and prevent T2D and obesity.

cell biology↗

Post-transcriptional Regulation Coordinating Transcription and Translation During Circadian Oscillation and Stress Recovery in Plants

Circadian rhythms orchestrate gene expression to align plant growth and development with daily environmental cycles. However, the post-transcriptional mechanisms that coordinate transcriptional and translational rhythmicity remain incompletely understood. To address this, we analyzed time-series transcriptome and translatome profiles in Arabidopsis seedlings, identifying 5,185 genes with rhythmicity at both levels. These genes were classified into four distinct groups based on phase and amplitude differences between transcription and translation. Circadian mRNAs with high oscillation amplitudes tended to undergo co-translational RNA decay (CTRD), whereas intronless genes displayed the lowest amplitudes, likely due to their mRNA instability and short half-lives. While CTRD and NAD capping modulate amplitude differences, intronless and circadian translational efficiency (TE) influence both phase and amplitude variations. Additionally, CTRD, NAD+ capping and circadian TE facilitate fast recovery of heat-induced genes to normal hemostasias. Collectively, our findings demonstrate that these post-transcriptional regulation shapes both synchronized and decoupled transcription and translation during plants response to diel and environmental dynamics.

genetics↗

Methylation variability and LINE-1 activation in multiple myeloma

Multiple myeloma (MM) is a type of hematological cancer that arises from uncontrolled proliferation of plasma cells. In addition to frequent genetic mutations, malignant plasma cells are characterized by alterations to the epigenome. Myeloma cells display a genome-wide loss of DNA methylation and a corresponding increase in active chromatin modifications. The dramatic epigenetic remodeling that occurs in cancer genomes is associated with loss of silencing at transposable elements, which can impact genome regulation. Through paired epigenome and transcriptome profiling of patient derived MM samples, we have found that loss of DNA methylation in MM genomes results in the formation of partially methylated domains that are variable across patients. This loss of DNA methylation coincides with the expression of hundreds of transcripts driven by LINE-1 (L1) retrotransposons that are epigenetically silenced in normal cells. MM samples can be stratified based on L1 activity with distinct gene expression signatures. The high L1 samples are characterized by a more proliferative, less differentiated state as well as inhibition of interferon and genome defense pathways. Several L1 promoters generate chimeric transcripts with adjacent oncogenes. We further find that KRAB-zinc finger proteins (KZFPs) that are responsible for the epigenetic silencing of L1s have abnormally low abundance in MM samples with high L1 activity. These results indicate that cell proliferation in MM is associated with a loss of KZFP expression and activation of L1 elements. SignificanceEpigenome and transcriptional profiling of patient-derived multiple myeloma samples reveals heterogeneous loss of DNA methylation, reduction of KZFP expression and LINE-1 activation as a clinical indicator of progression.

cancer biology↗

Fever induces long-term synaptic enhancement and protects learning in an accelerated aging model

Physiological impact of fever in the brain remains poorly understood. Here, we demonstrate that induction of fever by yeast injection in rats (N=9) and by whole-body hyperthermia in mice (N=7) triggers structural synaptic enhancement in the prefrontal cortex involving AMPA-type glutamate receptor signalling and protein translation (N=6). Repeated fever induction in juvenile rats (N=9) results in synaptic strengthening that persists into adulthood, mitigating learning deficits and synaptic loss in a D-galactose model of accelerated aging (N=11). Our results show how common environmental conditions may shape brain function in the long-term via synaptic plasticity, warranting further exploration of thermal treatment for cognitive protection in aging.

neuroscience↗

Rapid long-range synaptic remodeling in hyperacute ischemic stroke

Physiological mechanisms of the key hyperacute (0-24 hours) stage of stroke remain incompletely understood, hampering development of new stroke therapies. Synaptic plasticity has been strongly implicated in early stages of neurodegenerative and neurodevelopmental disorders. Here, we describe rapid region-specific patterns of synaptic remodeling in stroke, arising within 4 hours of onset. While the ischemic core exhibits profound structural and functional synaptic decline, synapses in the mildly ischemic penumbra largely retain their structure, decreasing synaptic function. Conversely, synapses in the contralateral cortex across the brain show widespread structural and functional increase. Mechanistically, hyperacute stroke triggers synaptic recruitment of NMDA receptors in the ischemic core and penumbra, while NMDA receptor blockade exacerbates structural synaptic decline in the penumbra and abolishes contralateral synaptic enhancement. Proteomic analysis confirms cross-brain synaptic strengthening and reveals emergence of metabolic rearrangement in the penumbra, while RNAseq indicates broad downregulation of synaptic gene expression in the penumbra. These findings identify brain-wide homeostatic synaptic rebalancing as a potential mechanism for rapid-response functional compensation in early stroke, highlighting the extent of brain resilience to acute perturbation. HighlightsO_LIStroke induces rapid long-range synaptic enhancement in the contralateral hemisphere C_LIO_LINMDAR signaling orchestrates short and long-range synaptic remodeling in stroke C_LIO_LIProteomics and RNAseq reveal details of region-specific synaptic remodeling C_LI eTOC blurbWhat happens to synaptic communication across the brain during the first hours of stroke is unclear. We find that while synapses at the center of the stroke quickly fall apart, those in the surrounding area are protected and those in the opposite hemisphere are rapidly strengthened by the activity of NMDA-type glutamate receptors.

neuroscience↗

Temperature-induced membrane trafficking drives antibody delivery to the brain

Despite quotidian occurrence of fever and hyperthermia, cell biological mechanisms underlying their effects remain unclear. Neurological complications of severe (>40{degrees}C) fever have been associated with increased blood-brain barrier (BBB) permeability due to structural disruption, while little is known about brain physiology of moderate fever. Here, we show that a temperature increase to 39-40{degrees}C increased fluid-phase uptake in PC12 cells and primary neurons. Uptake of selective cargoes showed that clathrin-mediated endocytosis and macropinocytosis were induced in a translation-dependent manner, consistent with a role for heat shock response. Exocytic recycling was also increased by hyperthermia, suggesting a comprehensive boost of membrane trafficking. Mild (<39{degrees}C) whole-body hyperthermia in vivo triggered fluid-phase uptake in various organs, notably enabling brain accumulation of an intravenously injected antibody that was blocked by dynamin inhibition. Taken together, our findings show that fever systemically regulates membrane trafficking, reveal dynamin-dependent endocytosis as a cell biological mechanism for temperature control of BBB permeability, and demonstrate a clinical potential of mild hyperthermia for facilitating brain delivery of biologic drugs. HighlightsO_LITemperature increase of 2-3{degrees}C upregulates endocytosis and exocytosis C_LIO_LITemperature-induced upregulation of membrane trafficking requires protein translation and dynamin function C_LIO_LIMild whole-body hyperthermia enhances fluid-phase endocytosis across the body C_LIO_LIMild hyperthermia enables delivery of an exogenous antibody from the bloodstream into the brain through a dynamin-dependent pathway C_LI

cell biology↗

Representing context and priority in working memory

The ability to prioritize among contents in working memory (WM) is critical for successful control of thought and behavior. Recent work has demonstrated that prioritization in WM can be implemented by representing different states of priority in different representational formats. Here, we explored the mechanisms underlying WM prioritization by simulating the double serial retrocuing (DSR) task with recurrent neural networks (RNNs). Visualization of stimulus representational dynamics using principal component analysis (PCA) revealed that the network represented trial context (order of presentation) and priority via different mechanisms. Ordinal context, a stable property lasting the duration of the trial, was accomplished by segregating representations into orthogonal subspaces. Priority, which changed multiple times during a trial, was accomplished by separating representations into different manifolds within each subspace. We assessed the generality of these mechanism by applying dimensionality reduction and multiclass decoding to fMRI and EEG datasets and found that priority and context are represented differently along the dorsal visual stream, and that behavioral performance is sensitive to trial-by-trial efficacy of priority coding, but not context coding.

neuroscience↗

Hyperglycosylation of prosaposin in tumor DCs promotes immune escape in cancer

Tumors develop strategies to evade immunity by suppressing antigen presentation. Here, we show that prosaposin drives CD8 T cell-mediated tumor immunity and that its hyperglycosylation in tumor DCs leads to cancer immune escape. We found that lysosomal prosaposin and its single saposin cognates mediated disintegration of tumor cell-derived apoptotic bodies to facilitate presentation of membrane-associated antigen and T cell activation. In the tumor microenvironment, TGF-{beta} induced hyperglycosylation of prosaposin and its subsequent secretion, which ultimately caused depletion of lysosomal saposins. In melanoma patients, we found similar prosaposin hyperglycosylation in tumor-associated DCs, and reconstitution with prosaposin rescued activation of tumor-infiltrating T cells. Targeting tumor DCs with recombinant prosaposin triggered cancer protection and enhanced immune checkpoint therapy. Our studies demonstrate a critical function of prosaposin in tumor immunity and escape and introduce a novel principle of prosaposin-based cancer immunotherapy. One Sentence SummaryProsaposin facilitates antigen cross-presentation and tumor immunity and its hyperglycosylation leads to immune evasion.

immunology↗

Widespread PRC barrel proteins play critical roles in archaeal cell division

Cell division is fundamental to all cellular life. Most of the archaea employ one of two alternative division machineries, one centered around the prokaryotic tubulin homolog FtsZ and the other around the endosomal sorting complex required for transport (ESCRT). However, neither of these mechanisms has been thoroughly characterized in archaea. Here, we show that three of the four PRC (Photosynthetic Reaction Center) barrel domain proteins of Haloferax volcanii (renamed Cell division proteins B1/2/3 (CdpB1/2/3)), play important roles in division. CdpB1 interacts directly with the FtsZ membrane anchor SepF and is essential for division, whereas deletion of cdpB2 and cdpB3 causes a major and a minor division defect, respectively. Orthologs of CdpB proteins are also involved in cell division in other haloarchaea. Phylogenetic analysis shows that PRC barrel proteins are widely distributed among archaea, including the highly conserved CdvA protein of the crenarchaeal ESCRT-based division system. Thus, diverse PRC barrel proteins appear to be central to cell division in most if not all archaea. Further study of these proteins is expected to elucidate the division mechanisms in archaea and their evolution.

microbiology↗

Direct N-Me Aziridination Reaction Enables Pinpointing C=C Bonds in Lipids with Mass Spectrometry

The biological functions of lipids largely depend on their chemical structures. The position of C=C bonds is an essential attribute that determines the structures of unsaturated lipids. Here, we developed a new type of chemical derivatization method for C=C bond using aziridination reaction. This new cyclization method for the C=C bonds in lipids based on the direct N-Me aziridination reaction of olefins using N-methyl-O-tosylhydroxylamine (TsONHCH3) as the aminating reagent. When combined with the tandem MS analysis, this novel activation approach for C=C bonds enables the accurate identification their positions in different kinds of unsaturated lipids. Furthermore, an integrated workflow has been established for comprehensively identifying the C=C bond positional isomers of lipids in complicated biological sample. This work provided a new chemical approach for the structural lipidomics.

biochemistry↗

Dual-Resolving of Lipid Positional and Geometric Isomers of C=C Bonds via Bifunctional Photocycloaddition-Photoisomerization Reaction System and Mass Spectrometry

The biological functions of lipids largely depend on their chemical structures. The position and configuration of C=C bonds are two of the essential attributes that determine the structures of unsaturated lipids. However, simultaneous identification of both attributes remains challenging. Here, we developed a bifunctional visible-light-activated photocycloaddition-photoisomerization reaction system, which enabled the dual-resolving of the positional and geometric isomerism of C=C bonds in lipids when combined with liquid chromatographic mass spectrometry. The dual-pathway reaction mechanism was demonstrated by experiments and density functional theory calculations. Based on this bifunctional reaction system, a workflow of deep structural lipidomics was established, and allowed the revealing of unique patterns of cis-trans-isomers in bacteria, as well as the tracking of C=C positional isomers changes in mouse brain ischemia. This study not only offers a powerful tool for deep lipid structural biology, but also provides a new paradigm for developing the multifunctional visible-light-induced reaction.

biochemistry↗

A novel high-throughput assay using mixed genomic DNA for fast screening germline pathogenic variants in breast cancer susceptibility genes

The demand for genetic testing for breast cancer susceptibility genes is increasing for both breast cancer patients and healthy individuals. Here we established a novel high-throughput assay to detect germline pathogenic variants in breast cancer susceptibility genes. In general, up 10 to 50 individual genomic DNA samples were mixed together to create a mixed DNA sample and the mixed DNA sample was subjected to a next-generation multigene panel. Germline pathogenic variants in breast cancer susceptibility genes could be found in the mixed DNA sample; next, site-specific Sanger sequencing was performed to identify individuals who carried he pathogenic variant in the mixed samples. We found that the recall and precision rates were 89.9% and 92.9% when twenty individual genomic samples were mixed. Therefore, our new assay can increase an approximately 20-fold of efficacy to identify the pathogenic variants in breast cancer susceptibility genes in individuals when compared with current assay.

genetics↗

Rotational remapping between differently prioritized representations in visual working memory

How does the brain prioritize among the contents of working memory (WM) to appropriately guide behavior? Using inverted encoding modeling (IEM), previous work (Wan et al., 2020) showed that unprioritized memory items (UMI) are actively represented in the brain but in a "flipped", or opposite, format compared to prioritized memory items (PMI). To gain insight into the mechanisms underlying the UMI-to-PMI representational transformation, we trained recurrent neural networks (RNNs) with an LSTM (long short-term memory) architecture to perform a 2-back working memory task. Although visualization of LSTM hidden layer activity using Principal Component Analysis (PCA) suggested that stimulus representations undergo a smooth rotational transformation across the trial, demixed (d)PCA of the same data decomposed this pattern into a cascade of multiple trajectories, each with a different time course, unfolding within UMI and PMI subspaces. The application of the same analyses to the EEG dataset of Wan et al. (2020) indicated that an items trajectory through the UMI subspace closely mirrored that of the RNN, but that its trajectory through the PMI subspace differed markedly from the RNN. It may be a general principle that, at the level of the representational code, information held in WM undergoes priority-based transformations that allow for its retention while preventing it from interfering with concurrent behavior. Implementational details of this process may vary across model systems. Author SummaryHow is information held in working memory (WM) but outside the current focus of attention? Motivated by previous neuroimaging studies, we trained recurrent neural networks (RNNs) to perform a 2-back WM task that entails shifts of an items priority status. Dimensionality reduction of the resultant activity in the hidden layer of the RNN allowed us to characterize how a stimulus items representation follows a transformational trajectory through high-dimensional representational space as its priority status changes from memory probe to unprioritized to prioritized. This work illustrates the value of artificial neural networks for assessing and refining hypotheses about mechanisms for information processing in the brain.

neuroscience↗

A precise and general FRET-based method for monitoring structural transitions in protein self-organization

Proteins assemble into a tremendous variety of dynamic and functional structures. Sensitive measurements directly in cells with a high spatiotemporal resolution are needed to distinguish these different assemblies. Here, we demonstrate precise and continuous monitoring of cytoplasmic protein self-assemblies and their structural transitions. Intermolecular FRET with both the donor and acceptor protein at the same target protein provides high sensitivity while retaining the advantage of straightforward ratiometric imaging. We measure different assembly structures, transient intermediate states kinetics, and assembly formation resolved in space and time. Specifically, the method recapitulates that i) the mutant Huntingtin exon1 (mHttex1) protein first forms low-FRET and presumably less ordered assemblies in yeast and human cells, which develop into high-FRET aggregates, ii) the chaperone DNAJB6b prevents low-FRET mHttex1 assemblies, yet coassembles with mHttex1 aggregates, and iii) FUS condensates have mutation-dependent nanoscopic structures. FACS measurements allow assembly measurement in a high-throughput manner crucial for screening efforts, while fluorescence microscopy provides spatiotemporally-resolved measurements on the single-condensate level during a cells lifetime to assess the biological consequences. Implementation in other native or non-native proteins could provide insight into many studies involving protein condensation or aggregation.

biophysics↗

Incidence and Characteristics of Co-infection and Secondary Infection in Patients with COVID-19

ObjectiveThe etiology and epidemiology of co-infection and secondary infection in COVID-19 patients remain unknown. The study aims to investigate the occurrence and characteristics of co-infection and secondary infection in COVID-19 patients, mainly focusing on Streptococcus pneumoniae co-infections. MethodsThis study was a prospective, observational cohort study of the inpatients diagnosed with COVID-19 in two designated hospitals in south China enrolled between Jan 11 and Feb 22, 2020. The urine specimen was collected on admission and applied for pneumococcal urinary antigen tests (PUATs). Demographic, clinical and microbiological data of patients were recorded simultaneously. ResultA total of 146 patients with a confirm diagnosis of COVID-19 at the median age of 50.0 years (IQR 36.0-61.0) were enrolled, in which, 16 (11.0%) were classified as severe cases and 130 (89.0%) as non-severe cases. Of the enrolled patients, only 3 (2.1%) were considered to present the co-infection, in which 1 was co-infected with S.pneumoniae, 1 with B. Ovatus infection and the other one with Influenza A virus infection. Secondary infection occurred in 16 patients, with S. maltophilia as the most commonly isolated pathogen (43.8%), followed by P. aeruginosa (25.0%), E. aerogenes (25.0%), C. parapsilosis (25.0%) and A. fumigates (18.8%). ConclusionPatients with confirmed COVID-19 were rarely co-infected with Streptococcus pneumoniae or other pathogens, indicating that the application of antibiotics against CAP on admission may not be necessary in the treatment of COVID-19 cases.

microbiology↗