Biology subjects

Fu, Z.

Publications and source records attributed to Fu, Z..

At least 163 records · Page 9Linked to original sources

bioRxiv2020

Ultra-high-order ICA: fine overlapping functional parcellations and spatiotemporal reconfiguration

Our recent findings show that functional organizations evolve spatially over time, highlighting the importance of considering within-subject spatial variations and dynamic functional parcellations in brain functional analyses. Meanwhile, a considerable level of multi-functionality suggests the need for overlapping brain parcellations. In this work, we used ultra-high-order ICA to identify fine overlapping functional dynamic parcellations of the brain. The preliminary result of this work was presented at the organization for human brain mapping workshop (OHBM 2019)1.

neuroscience↗

bioRxiv2020

FMR1 loss results in early changes to intrinsic membrane excitability in human cellular models

Fragile X mental retardation 1 (FMR1) encodes the RNA binding protein FMRP. Loss of FMRP drives Fragile X syndrome (FXS), the leading inherited cause of intellectual disability and a leading monogenic cause of autism. Cortical hyperexcitability is a hallmark of FXS, however, the underlying mechanisms reported, including alterations in synaptic transmission and ion channel expression and properties, are heterogeneous and at times contradictory. Here, we generated isogenic FMR1y/+ and FMR1y/- human pluripotent stem cell (hPSC) lines using CRISPR-Cas9, differentiated these stem cell tools into excitatory cortical neurons and systematically assessed the impact of FMRP loss on intrinsic membrane and synaptic properties over the course of in vitro differentiation. Using whole-cell patch clamp analyses at five separate time-points, we observed significant changes in multiple metrics following FMRP loss, including decreased membrane resistance, increased capacitance, decreased action potential half-width and higher maximum frequency, consistent with FMR1y/- neurons overall showing an increased intrinsic membrane excitability compared with age-matched FMR1y/+ controls. Surprisingly, a majority of these changes emerged early during in vitro differentiation and some were not stable over time. Although we detected significant differences in intrinsic properties, no discernable alterations were observed in synaptic transmission. Collectively, this study provides a new isogenic hPSC model to study the mechanisms of FMR1 gene function, identifies electrophysiological impacts of FMRP loss on human excitatory cortical neurons over time in vitro, and underscores that early developmental changes to intrinsic membrane properties may be a critical cellular pathology contributing to cortical hyperexcitability in FXS.

neuroscience↗

bioRxiv2019

Structural brain architectures match intrinsic functional networks and vary across domains: A study from 15000+ individuals

Brain structural networks have been shown to consistently organize in functionally meaningful architectures covering the entire brain. However, to what extent brain structural architectures match the intrinsic functional networks in different functional domains remains under explored. In this study, based on independent component analysis, we revealed 45 pairs of structural-functional (S-F) component maps, distributing across 9 functional domains, in both a discovery cohort (n=6005) and a replication cohort (UK Biobank, n=9214), providing a well-match multimodal spatial map template for public use. Further network module analysis suggested that unimodal cortical areas (e.g. somatomotor and visual networks) indicate higher S-F coherence, while heteromodal association cortices, especially the frontoparietal network (FPN), exhibit more S-F divergence. Collectively, these results suggest that the expanding and maturing brain association cortex demonstrates a higher degree of changes compared to unimodal cortex, which may lead to higher inter-individual variability and lower S-F coherence.

neuroscience↗

bioRxiv2019

Delineating the Organization of Projection Neuron Subsets with Multi-fluorescent Rabies Virus Tracing Tool

The elegant functions of the brain are facilitated by sophisticated connections between neurons, the architecture of which is frequently characterized by one nucleus connecting to multiple targets via projection neurons. Delineating the sub-nucleus fine architecture of projection neurons in a certain nucleus could greatly facilitate its circuit, computational, and functional resolution. Here, we developed multi-fluorescent rabies virus to delineate the fine organization of corticothalamic projection neuron subsets in the primary visual cortex (V1). By simultaneously labeling multiple distinct subsets of corticothalamic projection neurons in V1 from their target nuclei in thalamus (dLGN, LP, LD), we observed that V1-dLGN corticothalamic neurons were densely concentrated in layer VI, except for several sparsely scattered neurons in layer V, while V1-LP and V1-LD corticothalamic neurons were localized to both layers V and VI. Meanwhile, we observed a fraction of V1 corticothalamic neurons targeting multiple thalamic nuclei, which was further confirmed by fMOST whole-brain imaging. We further conceptually proposed an upgraded sub-nucleus tracing system with higher throughput (21 subsets) for more complex architectural tracing. The multi-fluorescent RV tracing tool can be extensively applied to resolve architecture of projection neuron subsets, with a strong potential to delineate the computational and functional organization of these nuclei.

neuroscience↗

bioRxiv2019

Distinct architecture and composition of mouse axonemal radial spoke head revealed by cryo-EM

The radial spoke (RS) transmits mechanochemical signals from the central pair apparatus (CP) to axonemal dynein arms to coordinate ciliary motility. The RS head, directly contacting with CP, differs dramatically in morphology between protozoan and mammal. Here we show the murine RS head is compositionally distinct from the Chlamydomonas one. Our reconstituted murine RS head core complex consists of Rsph1, Rsph3b, Rsph4a, and Rsph9, lacking Rsph6a whose orthologue exists in the Chlamydomonas RS head. We present the unprecedented cryo-EM structure of RS head core complex at 4.5-[A] resolution and identified the subunit location and their interaction network. In this complex, Rsph3b, Rsph4a, and Rsph9 forms a compact body with Rsph4a serving possibly as an assembly scaffold and Rsph3b in a location that might link the head with stalk. Interestingly, two Rsph1 subunits constitute the two stretching-arms possibly for optimized RS-CP interaction. We also propose a sawtooth model for the RS-CP interaction. Our study suggests that the RS head experiences profound remodeling to probably comply with both structural and functional alterations of the axoneme during evolution.

cell biology↗

bioRxiv2019

Viral manipulation of functionally distinct neurons from mice to humans

Recent success in identifying gene regulatory elements in the context of recombinant adeno-associated virus vectors have enabled cell type-restricted gene expression. However, within the cerebral cortex these tools are presently limited to broad classes of neurons. To overcome this limitation, we developed a strategy that led to the identification of multiple novel enhancers to target functionally distinct neuronal subtypes. By investigating the regulatory landscape of the disease gene Scn1a, we identified enhancers that target the breadth of its expression, including two that are selective for parvalbumin and vasoactive intestinal peptide cortical interneurons. Demonstrating the functional utility of these elements, we found that the PV-specific enhancer allowed for the selective targeting and manipulation of these neurons across species, from mice to humans. Finally, we demonstrate that our selection method is generalizable to other genes and characterize four additional PV-specific enhancers with exquisite specificity for distinct regions of the brain. Altogether, these viral tools can be used for cell-type specific circuit manipulation and hold considerable promise for use in therapeutic interventions.

neuroscience↗

bioRxiv2019

Age-related Structural and Functional Variations in 5967 Individuals across the Adult Lifespan

Exploring brain changes across the human lifespan is becoming an important topic in neuroscience. Though there are multiple studies which investigated the relationship between age and brain imaging data, the results are heterogeneous due to small sample sizes and relatively narrow age ranges. Here, based on year-wise estimation of 5967 subjects from 13 to 72 years old, we aimed to provide a more precise description of adult lifespan variation trajectories of gray matter volume (GMV), structural network correlation (SNC) and functional network connectivity (FNC) using independent component analysis and multivariate linear regression model. Our results revealed the following relationships: 1)GMV linearly declined with age in most regions, while parahippocampus showed an inverted U-shape quadratic relationship with age; SNC presented a U-shape quadratic relationship with age within cerebellum, and inverted U-shape relationship primarily in the default mode network (DMN) and frontoparietal (FP) related correlation. 2) FNC tended to linearly decrease within resting-state networks (RSNs), especially in visual network and DMN. Early increase was revealed between RSNs, primarily in FP and DMN, which experienced decrease at older ages. U-shape relationship was also revealed to compensate for the cognition deficit in attention and subcortical related connectivity at late years. 3) The link between middle occipital gyrus and insula, as well as precuneus and cerebellum, exhibited similar changing trends between SNC and FNC across the adult lifespan. Collectively, these results highlight the benefit of lifespan study and provide a precise description of age-related regional variation and SNC/FNC changes based on a large dataset.

neuroscience↗

bioRxiv2019

Interferon stimulated genes mark pathogenic cells of the emergency myelopoietic response to sterile tissue injury in mice and humans

Sterile tissue injury locally activates innate immune responses via interactions with damage associated molecular patterns (DAMPs). Here, by analyzing [~]120K single cell transcriptomes after myocardial infarction (MI) in mice and humans, we show neutrophil and monocyte subsets induce type I interferon (IFN) stimulated genes (ISGs) in myeloid progenitors of the bone marrow, far from the site of injury. In patients with acute MI, peripheral blood neutrophils and monocytes express ISGs at levels far beyond healthy individuals and comparable to patients with lupus. In the bone marrow of Tet2-/- mice, ISGs are spontaneously induced in myeloid progenitors and their progeny. In the heart, IFN responses are negatively regulated by Ccr2- resident macrophages in a Nrf2-dependent fashion. Our results show post-MI IFN signaling begins in the bone marrow, implicate multiple transcription factors in its regulation (Tet2, Irf3, Nrf2), and provide a clinical biomarker (ISG score) for studying post-MI IFN signaling in patients.

immunology↗

bioRxiv2019

Age-dependent sexual dimorphism in the adult human gut microbiota

A decade of studies has established the importance of the gut microbiome in human health. In spite of sex differences in the physiology, lifespan, and prevalence of many age-associated diseases, sex and age disparities in the gut microbiota have been little studied. Here we show age-related sex differences in the adult gut microbial composition and functionality in two community-based cohorts from Northern China and the Netherlands. Consistently, women harbour a more diverse and stable microbial community across broad age ranges, whereas men exhibit a more variable gut microbiota strongly correlated with age. Reflecting the sex-biased age-gut microbiota interaction patterns, sex differences observed in younger adults are considerably reduced in the elderly population. Our findings highlight the age- and sex-biased differences in the adult gut microbiota across two ethnic population and emphasize the need for considering age and sex in studies of the human gut microbiota.

genomics↗

bioRxiv2019

Population imaging of neural activity in awake behaving mice in multiple brain regions

A longstanding goal in neuroscience has been to image membrane voltage, with high temporal precision and sensitivity, in awake behaving mammals. Here, we report a genetically encoded voltage indicator, SomArchon, which exhibits millisecond response times and compatibility with optogenetic control, and which increases the sensitivity, signal-to-noise ratio, and number of neurons observable, by manyfold over previous reagents. SomArchon only requires conventional one-photon microscopy to achieve these high performance characteristics. These improvements enable population analysis of neural activity, both at the subthreshold and spiking levels, in multiple brain regions - cortex, hippocampus, and striatum - of awake behaving mice. Using SomArchon, we detect both positive and negative responses of striatal neurons during movement, highlighting the power of voltage imaging to reveal bidirectional modulation. We also examine how the intracellular subthreshold theta oscillations of hippocampal neurons govern spike output, finding that nearby cells can exhibit highly correlated subthreshold activities, even as they generate highly divergent spiking patterns.

neuroscience↗

bioRxiv2019

Parallel Group ICA + ICA: Joint Estimation of Linked Functional Network Variability and Structural Covariation with Application to Schizophrenia

There is growing evidence that rather than using a single brain imaging modality to study its association with physiological or symptomatic features, the field is paying more attention to fusion of multimodal information. However, most current multimodal fusion approaches that incorporate functional magnetic resonance imaging (fMRI) are restricted to second-level 3D features, rather than the original 4D fMRI data. This trade-off is that the valuable temporal information is not utilized during the fusion step. Here we are motivated to propose a novel approach called \"parallel group ICA+ICA\" that incorporates temporal fMRI information from GICA into a parallel ICA framework, aiming to enable direct fusion of first-level fMRI features with other modalities (e.g. structural MRI), which thus can detect linked functional network variability and structural covariations. Simulation results show that the proposed method yields accurate inter-modality linkage detection regardless of whether it is strong or weak. When applied to real data, we identified one pair of significantly associated fMRI-sMRI components that show group difference between schizophrenia and controls in both modalities. Finally, multiple cognitive domain scores can be predicted by the features identified in the linked component pair by our proposed method. We also show these multimodal brain features can predict multiple cognitive scores in an independent cohort. Overall, results demonstrate the ability of parallel GICA+ICA to estimate joint information from 4D and 3D data without discarding much of the available information up front, and the potential for using this approach to identify imaging biomarkers to study brain disorders.

bioinformatics↗

bioRxiv2018

The structural basis for release factor activation during translation termination revealed by time-resolved cryogenic electron microscopy

When the mRNA translating ribosome encounters a stop codon in its aminoacyl site (A site), it recruits a class-1 release factor (RF) to induce hydrolysis of the ester bond between peptide chain and peptidyl-site (P-site) tRNA. This process, called termination of translation, is under strong selection pressure for high speed and accuracy. Class-1 RFs (RF1, RF2 in bacteria, eRF1 in eukarya and aRF1 in archaea), have structural motifs that recognize stop codons in the decoding center (DC) and a universal GGQ motif for induction of ester bond hydrolysis in the peptidyl transfer center (PTC) 70 [A] away from the DC. The finding that free RF2 is compact with only 20 [A] between its codon reading and GGQ motifs came therefore as a surprise1. Cryo-electron microscopy (cryo-EM) then showed that ribosome-bound RF1 and RF2 have extended structures2,3, suggesting that bacterial RFs are compact when entering the ribosome and switch to the extended form in a stop signal-dependent manner3. FRET4, cryo-EM5,6 and X-ray crystallography7, along with a rapid kinetics study suggesting a pre-termination conformational change on the millisecond time-scale of ribosome-bound RF1 and RF28, have lent indirect support to this proposal. However, direct experimental evidence for such a short-lived compact conformation on the native pathway to RF-dependent termination is missing due to its transient nature. Here we use time-resolved cryo-EM9,10,11,12,13 to visualize compact and extended forms of RF1 and RF2 at 3.5 and 4 [A] resolution, respectively, in the codon-recognizing complex on the pathway to termination. About 25% of ribosomal complexes have RFs in the compact state at 24 ms reaction time after mixing RF and ribosomes, and within 60 ms virtually all ribosome-bound RFs are transformed to their extended forms.

biophysics↗

bioRxiv2018

Group ICA for Identifying Biomarkers in Schizophrenia: ‘Adaptive’ Networks via Spatially Constrained ICA Show More Sensitivity to Group Differences than Spatio-temporal Regression

Brain functional networks identified from fMRI data can provide potential biomarkers for brain disorders. Group independent component analysis (GICA) is popular for extracting brain functional networks from multiple subjects. In GICA, different strategies exist for reconstructing subject-specific networks from the group-level networks. However, it is unknown whether these strategies have different sensitivities to group differences and abilities in distinguishing patients. Among GICA, spatio-temporal regression (STR) and spatially constrained ICA approaches such as group information guided ICA (GIG-ICA) can be used to propagate components (indicating networks) to a new subject that is not included in the original subjects. In this study, based on the same a priori network maps, we reconstructed subject-specific networks using these two methods separately from resting-state fMRI data of 151 schizophrenia patients (SZs) and 163 healthy controls (HCs). We investigated group differences in the estimated functional networks and the functional network connectivity (FNC) obtained by each method. The networks were also used as features in a cross-validated support vector machine (SVM) for classifying SZs and HCs. We selected features using different strategies to provide a comprehensive comparison between the two methods. GIG-ICA generally showed greater sensitivity in statistical analysis and better classification performance (accuracy 76.45{+/-}8.9%, sensitivity 0.74{+/-}0.11, specificity 0.79{+/-}0.11) than STR (accuracy 67.45{+/-}8.13%, sensitivity 0.65{+/-}0.11, specificity 0.71{+/-}0.11). Importantly, results were also consistent when applied to an independent dataset including 82 HCs and 82 SZs. Our work suggests that the functional networks estimated by GIG-ICA are more sensitive to group differences, and GIG-ICA is promising for identifying image-derived biomarkers of brain disease.

neuroscience↗

bioRxiv2018

Real-time structural dynamics of late steps in bacterial translation initiation visualized using time-resolved cryogenic electron microscopy

Bacterial translation initiation entails the tightly regulated joining of the 50S ribosomal subunit to an initiator transfer RNA (fMet-tRNAfMet)-containing 30S ribosomal initiation complex (IC) to form a 70S IC that subsequently matures into a 70S elongation-competent complex (70S EC). Rapid and accurate 70S IC formation is promoted by 30S IC-bound initiation factor (IF) 1 and the guanosine triphosphatase (GTPase) IF2, both of which must ultimately dissociate from the 70S IC before the resulting 70S EC can begin translation elongation1. Although comparison of 30S2-6 and 70S5,7-9 IC structures have revealed that the ribosome, IFs, and fMet-tRNAfMet can acquire different conformations in these complexes, the timing of conformational changes during 70S IC formation, structures of any intermediates formed during these rearrangements, and contributions that these dynamics might make to the mechanism and regulation of initiation remain unknown. Moreover, lack of an authentic 70S EC structure has precluded an understanding of ribosome, IF, and fMet-tRNAfMet rearrangements that occur upon maturation of a 70S IC into a 70S EC. Using time-resolved cryogenic electron microscopy (TR cryo-EM)10 we report the first, near-atomic-resolution view of how a time-ordered series of conformational changes drive and regulate subunit joining, IF dissociation, and fMet-tRNAfMet positioning during 70S EC formation. We have found that, within ~20-80 ms, rearrangements of the 30S subunit and IF2, uniquely captured in its GDP*Pi-bound state, stabilize fMet-tRNAfMet in its intermediate, 70S P/I, configuration7 and trigger dissociation of IF1 from the 70S IC. Within the next several hundreds of ms, dissociation of IF2 from the 70S IC is coupled to further remodeling of the ribosome that positions fMet-tRNAfMet into its final, P/P, configuration within the 70S EC. Our results demonstrate the power of TR cryo-EM to determine how a time-ordered series of conformational changes contribute to the mechanism and regulation of one of the most fundamental processes in biology.

molecular biology↗

bioRxiv2018

Maize EHD1 is Required for Kernel Development and Vegetative Growth through Regulating Auxin Homeostasis

The roles of EHDs in clathrin-mediated endocytosis (CME) in plants are poorly understood. Here, we isolated a maize mutant, designated as ehd1, which showed defects in kernel development and vegetative growth. Positional cloning and transgenic analysis revealed that ehd1 encodes an EHD protein. Internalization of the endocytic tracer FM4-64 was significantly reduced in ehd1 mutant and ZmEHD1 knock-out mutants. We further demonstrated that ZmEHD1 and ZmAP2 {sigma} subunit physically interact in the plasma membranes. Cellular IAA levels were significantly lower in ehd1 mutant than in wild-type maize. Auxin distribution and ZmPIN1a-YFP localization were altered in ehd1 mutant. Exogenous application of 1-NAA but not GA3 rescued the seed germination and seedling emergency phenotypic defects of ehd1 mutants. Taken together, these results indicate that ZmEHD1 regulates auxin homeostasis by mediating CME through its interaction with the ZmAP2 {sigma} subunit, which is crucial for kernel development and vegetative growth of maize.

plant biology↗

bioRxiv2018

Spatial dynamics of brain functional domains: A new avenue to study time-varying brain function

The analysis of time-varying activity and connectivity patterns (i.e., the chronnectome) using resting-state magnetic resonance imaging has become an important part of ongoing neuroscience discussions. The majority of previous work has focused on variations of temporal coupling among fixed spatial nodes or transition of the dominant activity/connectivity pattern over time. Here, we introduce an approach to capture spatial dynamics within functional domains (FD), as well as temporal dynamics within and between FD. The approach models the brain as a hierarchical functional architecture with different levels of granularity, where lower levels have higher functional homogeneity and less dynamic behavior and higher levels have less homogeneity and more dynamic behavior. First, a high-order spatial independent component analysis is used to approximate functional units. A functional unit is a pattern of regions with very similar functional activity over time. Next, functional units are used to construct FDs. Finally, functional modules (FMs) are calculated from FDs, providing an overall view of brain dynamics. Results highlight the spatial fluidity within FDs, including a broad spectrum of changes in regional associations from strong coupling to complete decoupling. Moreover, FMs capture the dynamic interplay between FDs. Patients with schizophrenia show transient reductions in functional activity and state connectivity across several FDs, particularly the subcortical domain. Activity and connectivity differences convey unique information in many cases (e.g. the default mode) highlighting their complementarity information. The proposed hierarchical model to capture FD spatiotemporal variation provides new insight into the macroscale chronnectome and identifies changes hidden from existing approaches.

neuroscience↗

bioRxiv2018

Overexpressed microRNA-141-3p enhance proliferation via targeting PLAG1 in non-diabetic macrosomia

Several studies have shown microRNAs (miRNAs) could regulate the placental development, yet the role and mechanism of miRNAs in the development of non-diabetic macrosomia (NDFMS) remains unclear. The key miRNA that abnormal expressed in NDFMS placentas was screened out by miRNA microarray and verified using qRT-PCR in 91 subjects. The effects of the key miRNA were verified by proliferation assay and invasion assay in HTR-8/SVneo cell, and also in pregnant C57BL/6J mice. miR-141-3p was determined as the key miRNA with the most significant difference, which could promote the proliferation and invasion by regulating the expression of target gene PLAG1. Overexpression of PLAG1 could reverse the effect of cell proliferation and invasion ability caused by miR-141-3p overexpression. Significant difference in fetal birth weight was observed between the control group and treated group with miR-141-3p agomir in late pregnancy, but not in early pregnancy. This study revealed miR-141-3p could increase the proliferation of placenta to participate in the occurrence and development of NDFMS through regulating PLAG1 expression.

developmental biology↗

bioRxiv2017

Proteomic Architecture of Human Coronary and Aortic Atherosclerosis

The inability to detect premature atherosclerosis significantly hinders implementation of personalized therapy to prevent coronary heart disease. A comprehensive understanding of arterial protein networks and how they change in early atherosclerosis could identify new biomarkers for disease detection and improved therapeutic targets. Here we describe the human arterial proteome and the proteomic features strongly associated with early atherosclerosis based on mass-spectrometry analysis of coronary artery and aortic specimens from 100 autopsied young adults (200 arterial specimens). Convex analysis of mixtures, differential dependent network modeling and bioinformatic analyses defined the composition, network re-wiring and likely regulatory features of the protein networks associated with early atherosclerosis. Among other things the results reveal major differences in mitochondrial protein mass between the coronary artery and distal aorta in both normal and atherosclerotic samples - highlighting the importance of anatomic specificity and dynamic network structures in in the study of arterial proteomics. The publicly available data resource and the description of the analysis pipeline establish a new foundation for understanding the proteomic architecture of atherosclerosis and provide a template for similar investigations of other chronic diseases characterized by multi-cellular tissue phenotypes.\n\nHighlightsO_LILC MS/MS analysis performed on 200 human aortic or coronary artery samples\nC_LIO_LINumerous proteins, networks, and regulatory pathways associated with early atherosclerosis\nC_LIO_LIMitochondrial proteins mass and selected metabolic regulatory pathways vary dramatically by disease status and anatomic location\nC_LIO_LIPublically available data resource and analytic pipeline are provided or described in detail\nC_LI

molecular biology↗