Biology subjects

Zhu, X.

Publications and source records attributed to Zhu, X..

At least 181 records · Page 10Linked to original sources

bioRxiv2023

Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4

Endolysosomal exonucleases PLD3 and PLD4 (phospholipases D3 and D4) are associated with autoinflammatory and autoimmune diseases. We report structures of these enzymes, and the molecular basis of their catalysis. The structures reveal an intra-chain dimer topology forming a basic active site at the interface. Like other PLD superfamily members, PLD3 and PLD4 carry HxKxxxxD/E motifs and participate in phosphodiester-bond cleavage. The enzymes digest ssDNA and ssRNA in a 5'-to-3' manner and are blocked by 5'-phosphorylation. We captured structures in apo, intermediate, and product states and revealed a link-and-release two-step catalysis. We also unexpectedly demonstrated phosphatase activity via a covalent 3- phosphistidine intermediate. PLD4 contains an extra hydrophobic clamp that stabilizes substrate and could affect oligonucleotide substrate preference and product release. Biochemical and structural analysis of disease-associated mutants of PLD3/4 demonstrated reduced enzyme activity or thermostability and the possible basis for disease association. Furthermore, these findings provide insight into therapeutic design.

biochemistry↗

bioRxiv2023

Captivity affects mitochondrial aerobic respiration and carotenoid metabolism in the house finch (Haemorhous mexicanus)

In many species of animals, red carotenoid-based coloration is produced by metabolizing yellow dietary pigments, and this red ornamentation is an honest signal of individual quality. However, the physiological basis for associations between organism function and the metabolism of red ornamental carotenoids from yellow dietary carotenoids remains uncertain. A recent hypothesis posits that carotenoid metabolism depends on mitochondrial performance, with diminished red coloration resulting from altered mitochondrial aerobic respiration. To test for an association between mitochondrial respiration and red carotenoids, we held wild-caught, molting male house finches in either small bird cages or large flight cages to create environmental challenges during the period when red ornamental coloration is produced. We predicted that small cages would present a less favorable environment than large flight cages and that captivity would affect both mitochondrial performance and the abundance of red carotenoids. We found no evidence that living in small versus large cages had significant effects on wild-caught house finches; however, birds in cages of any size circulated fewer red carotenoids, showed increased mitochondrial respiratory rates, and had lower complex II respiratory control ratios--a metric associated with mitochondrial efficiency--compared to free-living birds. Moreover, among captive individuals, the birds that circulated the most red carotenoids had the highest mitochondrial respiratory control ratio for complex II substrates. These data support the hypothesis that the metabolism of red carotenoid pigments is linked to mitochondrial aerobic respiration in the house finch, but the mechanisms for this association remain to be established. SUMMARY STATEMENTHolding wild-caught male house finches in cages exposed a relationship between red carotenoid production and mitochondrial respiratory efficiency.

evolutionary biology↗

bioRxiv2023

Cerebellar a1D-adrenergic receptors mediate stress-induced dystonia in totteringtg/tg mice

Episodic ataxia type 2 (EA2) is an inherited neurological disorder, where patients suffer from chronic ataxia and severe episodes of motor dysfunction exhibited as dystonia. Despite other factors, physical and emotional stress triggers those episodes reliably in both human and mice. We used the well-established EA2 mouse model tottering to explore the cerebellar adrenergic receptor (AR) involvement in stress-induced dystonic attacks. We found that 1-ARs, but not 2-ARs, on cerebellar Purkinje cells (PCs) are activated by norepinephrine (NE) from the locus coeruleus (LC), differentially expressed and required for initiation of dystonia. Moreover, pharmacological blockade and shRNA-induced knock down of cerebellar 1D-ARs was sufficient to effectively prevent stress-induced dystonia in homozygous totteringtg/tg mice but had no impact on ataxia amelioration. In vivo recordings and live calcium (Ca2+) imaging of PCs demonstrated that 1D-AR blockade successfully protects PCs from NE-mediated erratic firing patterns through decreased release of calcium from intracellular stores, thus preventing stress-induced dystonia. Furthermore, chemogenetic inhibition of the LC-NE pathway alleviated the frequency and symptoms of stress-induced dystonia. Together, our data show the modulatory effects of NE on dystonia severity and suggest a predominant role of cerebellar 1D-ARs in the formation of stress-induced dystonia in totteringtg/tg mice and, thereby providing a potential new therapeutic target to treat stress-induced dystonia in EA2.

neuroscience↗

bioRxiv2023

Distinct functions of the kinesin-9 family in mammalian motile cilia

Ciliary beat and intraflagellar transport (IFT) depend on dynein and kinesin motors. Kinesin-9 family members Kif6 and Kif9 are implicated in ciliary motilities across protists and mammals. How they function and whether they act redundantly, however, remain unclear. Here, we show that they play distinct roles in mammals. Kif6 forms puncta that move bidirectionally without or with IFT-B particles along axonemes, whereas Kif9 is immobilized on ciliary central apparatus. Only Kif6 binds to and glides microtubules, and the activities are self-inhibited. Kif6 deficiency in mice impairs directional ciliary beat across ependymal tissues and cerebrospinal fluid flow, resulting in severe hydrocephalus and high mortality, whereas Kif9 deficiency induces mild hydrocephalus without obviously defective ciliary beat and life span. Both Kif6-/- and Kif9-/- males are infertile but show respectively oligozoospermia with poor sperm motility and defective forward motion of sperms. These results suggest Kif6 as a motile cilia-specific IFT motor and Kif9 as a central apparatus regulator.

cell biology↗

bioRxiv2023

Vina-GPU 2.1: towards further optimizing docking speed and precision of AutoDock Vina and its derivatives

AutoDock Vina and its derivatives have established themselves as a prevailing pipeline for virtual screening in contemporary drug discovery. Our Vina-GPU method leverages the parallel computing power of GPUs to accelerate AutoDock Vina, and Vina-GPU 2.0 further enhances the speed of AutoDock Vina and its derivatives. Given the prevalence of large virtual screens in modern drug discovery, the improvement of speed and accuracy in virtual screening has become a longstanding challenge. In this study, we propose Vina-GPU 2.1, aimed at enhancing the docking speed and precision of AutoDock Vina and its derivatives through the integration of novel algorithms to facil-itate improved docking and virtual screening outcomes. Building upon the foundations laid by Vina-GPU 2.0, we introduce a novel algorithm, namely Reduced Iteration and Low Complexity BFGS (RILC-BFGS), designed to expedite the most time-consuming operation. Additionally, we implement grid cache optimization to further enhance the docking speed. Furthermore, we employ optimal strategies to individually optimize the structures of ligands, receptors, and binding pockets, thereby enhancing the docking precision. To assess the performance of Vina-GPU 2.1, we conduct extensive virtual screening experiments on three prominent targets, utilizing two fundamental compound libraries and seven docking tools. Our results demonstrate that Vina-GPU 2.1 achieves an average 4.97-fold acceleration in docking speed and an average 342% improvement in EF1% compared to Vina-GPU 2.0. The source code and tools for Vina-GPU 2.1 are freely available at https://github.com/DeltaGroupNJUPT/Vina-GPU-2.1, accompanied by comprehensive instructions and illustrative examples.

developmental biology↗

bioRxiv2023

Dynamic Regulation of Innate Lymphoid Cell Development During Ontogeny

Innate lymphoid cells (ILCs) are crucial for maintaining tissue homeostasis. The dynamic composition of ILC subsets during ontogeny has been observed for over a decade, yet the underlying mechanisms remain incompletely understood. Here, we combined differentiation assay and scRNA-seq analysis to compare the fetal and adult ILC development, and assessed their contribution to the dynamic change of ILC subsets. We revealed the preference for LTi cell differentiation in fetal hematopoietic progenitors, contrasted with a non-LTi differentiation bias in adult stages. Our analyses elucidated that the two stages shared a conserved differentiation trajectory and regulatory programs but used different controlling logic. Through computational prediction and dose-response experiments, we proposed a model where a transition from fetal ROR{gamma}t-dominant states to adult Notch-GATA3-dominant states orchestrates these changes. This study suggests that ILC development can be modulated to accommodate the varying demands for specific ILC subsets within the body at different developmental stages. HighlightO_LIThe ratio of LTi cells to non-LTi ILCs decreases from fetal to adult stage C_LIO_LIModified fate determination of ILC progenitors contributes to this decrease of LTi cell ratio during ontogeny C_LIO_LIA conserved trajectory exists from early LPs to Innate Lymphoid Cell Precursors (ILCPs) during both fetal and adult ILC development C_LIO_LIEnhanced activity of Notch-GATA3 signaling in ILC precursors accounts for the transition of their differentiation from LTi cells in the fetal to non-LTi ILCs in adults. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/565141v2_ufig1.gif" ALT="Figure 1"> View larger version (85K): org.highwire.dtl.DTLVardef@11a031eorg.highwire.dtl.DTLVardef@c2d652org.highwire.dtl.DTLVardef@184cdfeorg.highwire.dtl.DTLVardef@1efe7ae_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Pulmonary Ventilation Analysis Using 1H Ultra-Short Echo Time (UTE) Lung MRI: A Reproducibility Study

PurposeTo evaluate methods for quantification of pulmonary ventilation with ultrashort echo time (UTE) MRI. MethodsWe performed a reproducibility study, acquiring two free-breathing 1H UTE lung MRIs on the same day for six healthy volunteers. The 1) 3D + t cyclic b-spline and 2) symmetric image normalization (SyN) methods for image registration were applied after respiratory phase-resolved image reconstruction. Ventilation maps were calculated using 1) Jacobian determinant of the deformation fields minus one, termed regional ventilation, and 2) intensity percentage difference between the registered and fixed image, termed specific ventilation. We compared the reproducibility of all four method combinations via statistical analysis. ResultsSplit violin plots and Bland-Altman plots are shown for whole lungs and lung sections. The cyclic b-spline registration and Jacobian determinant regional ventilation quantification provide total ventilation volumes that match the segmentation tidal volume, smooth and uniform ventilation maps. The cyclic b-spline registration and specific ventilation combination yields the smallest standard deviation in the Bland-Altman plot. ConclusionCyclic registration performs better than SyN for respiratory phase-resolved 1H UTE MRI ventilation quantification. Regional ventilation correlates better with segmentation lung volume, while specific ventilation is more reproducible.

bioengineering↗

bioRxiv2023

NeuroMotion: Open-source Simulator with Neuromechanical and Deep Network Models to Generate Surface EMG signals during Voluntary Movement

Neuromechanical studies investigate how the nervous system interacts with the musculoskeletal (MSK) system to generate volitional movements. Such studies have been supported by simulation models that provide insights into variables that cannot be measured experimentally and allow a large number of conditions to be tested before the experimental analysis. However, current simulation models of electromyography (EMG), a core physiological signal in neuromechanical analyses, are mainly limited to static contractions and cannot fully represent the dynamic modulation of EMG signals during volitional movements. Here, we overcome these limitations by presenting NeuroMotion, an open-source simulator that provides a full-spectrum synthesis of EMG signals during voluntary movements. NeuroMotion is comprised of three modules. The first module is an upper-limb MSK model with OpenSim API to estimate the muscle fibre lengths and muscle activations during movements. The second module is BioMime, a deep neural network-based EMG generator that receives nonstationary physiological parameter inputs, such as muscle fibre lengths, and efficiently outputs motor unit action potentials (MUAPs). The third module is a motor unit pool model that transforms the muscle activations into discharge timings of motor units. The discharge timings are convolved with the output of BioMime to simulate EMG signals during the movement. Here we also provide representative applications of NeuroMotion. We first show how simulated MUAP waveforms change during different levels of physiological parameter variations and different movements. We then show that the synthetic EMG signals during two-degree-of-freedom hand and wrist movements can be used to augment experimental data for regression. Ridge regressors trained on the synthetic dataset were directly used to predict joint angles from experimental data. NeuroMotion is the first full-spectrum EMG generative model to simulate human forearm electrophysiology during voluntary hand, wrist, and forearm movements. All intermediate variables are available, which allows the user to study cause-effect relationships in the complex neuromechanical system, fast iterate algorithms before collecting experimental data, and validate algorithms that estimate non-measurable parameters in experiments. We expect this full-spectrum model will complement experimental approaches and facilitate neuromechanical research. Author summaryNeuromechanical studies investigate how the nervous system and musculoskeletal system interact to generate movements. Such studies heavily rely on simulation models, which provide non-measurable variables to complement the experimental analyses. However, the simulation models of surface electromyography (EMG), the core physiological signal widely used in neuromechanical analyses, are limited to static conditions. We bridged this gap by proposing NeuroMotion, the first full-spectrum EMG simulator that can be used to generate EMG signals during voluntary movements. NeuroMotion integrates a musculoskeletal model, a neural network-based EMG generator, and an advanced motoneuron model. With representative applications of this simulator, we show that it can be used to investigate the variabilities of EMG signals during voluntary movement. We also demonstrate that the synthetic signals generated by NeuroMotion can be used to augment experimental data for regressing joint angles. We expect the functionality provided by NeuroMotion, which is provided open-source, will stimulate progress in neuromechanics.

bioengineering↗

bioRxiv2023

Enhancing plant photosynthesis through activating cells deficient in photosynthetic apparatus

Much efforts have been devoted to identify options to improve plant photosynthetic capacity. Most of these engineering focuses more on enhancing photosynthetic capacity of the mesophyll cells. In this study, we specifically expressed CYTOKININRESPONSIVE GATA FACTOR 1 (CGA1) in the vascular bundle and bundle sheath cells (ProGLDPA: CGA1) which generally have low photosynthetic capacity. The introduction of CGA1 resulted in increased numbers and sizes of chloroplasts in both bundle sheath and vascular bundle, without noticeable difference in these properties in mesophylls. Additionally, compared with wild type (WT), transgenic lines showed enhanced development of mitochondria and peroxisomes. Leaf photosynthetic rates in these transgenic lines were higher than those in WT, especially under high light. Furthermore, the amount of RuBisCO, Vcmax, Jmax, and the number of starch granules were also significantly increased in the transgenic lines, which led to about 20% increase in biomass. Remarkably, the CO2 compensation point of ProGLDPA: CGA1 decreased compared with WT, resembling the characteristics of proto-Kranz during C4 evolution. All these results indicated that enhancing photosynthetic properties of vascular bundle and bundle sheath cell is an effective approach to improve leaf photosynthesis, and highlighted that utilization of the cell lacking photosynthetic capacity is a promising way to improve plant photosynthesis for greater capacity.

plant biology↗

bioRxiv2023

Inhibition of SARS-CoV-2 Infection in Human Airway Epithelium with a Xeno-Nucleic Acid Aptamer

BackgroundSARS-CoV-2, the agent responsible for the COVID-19 pandemic, enters cells through viral spike glycoprotein binding to the cellular receptor, angiotensin-converting enzyme 2 (ACE2). Given the lack of effective antivirals targeting SARS-CoV-2, we previously utilized systematic evolution of ligands by exponential enrichment (SELEX) and selected fluoro-arabino nucleic acid (FANA) aptamer R8-9 that was able to block the interaction between the viral receptor-binding domain and ACE2. MethodsHere, we further assessed FANA-R8-9 as an entry inhibitor in contexts that recapitulate infection in vivo. ResultsWe demonstrate that FANA-R8-9 inhibits spike-bearing pseudovirus particle uptake in cell lines. Then, using an in-vitro model of human airway epithelium (HAE) and SARS-CoV-2 virus, we show that FANA-R8-9 significantly reduces viral infection when added either at the time of inoculation, or several hours later. These results were specific to the R8-9 sequence, not the xeno-nucleic acid utilized to make the aptamer. Importantly, we also show that FANA-R8-9 is stable in HAE culture secretions and has no overt cytotoxic effects. ConclusionsTogether, these results suggest that FANA-R8-9 effectively prevents infection by specific SARS-CoV-2 variants and indicate that aptamer technology could be utilized to target other clinically-relevant viruses in the respiratory mucosa.

microbiology↗

bioRxiv2023

Altered hierarchical gradients of intrinsic neural timescales in mild cognitive impairment and Alzheimer's disease

Alzheimers disease (AD) is a devastating neurodegenerative disease that affects millions of older adults in the US and worldwide. Resting-state functional magnetic resonance imaging (rs-fMRI) has become a widely used neuroimaging tool to study neurophysiology in AD and its prodromal condition, mild cognitive impairment (MCI). The intrinsic neural timescale (INT), which can be estimated through the magnitude of the autocorrelation of intrinsic neural signals using rs-fMRI, is thought to quantify the duration that neural information is stored in a local cortical circuit. The heterogeneity of the timescales is considered to be a basis of the functional hierarchy in the brain. In addition, INT captures an aspect of circuit dynamics relevant to excitation/inhibition (E/I) balance, which is thought to be broadly relevant for cognitive functions. Here we examined its relevance to AD. We used rs-fMRI data of 904 individuals from the Alzheimers Disease Neuroimaging Initiative (ADNI) database. The subjects were divided into 4 groups based on their baseline and end-visit clinical status, which were cognitively normal (CN), stable MCI, Converter, and AD groups. Linear mixed effect model and pairwise comparison were implemented to investigate the large-scale hierarchical organization and local differences. We observed high similarities between AD and Converter groups. Specifically, among the eight identified ROIs with distinct INT alterations in AD, three ROIs (inferior temporal, caudate, pallidum areas) exhibit stable and significant alteration in AD converter. In addition, distinct INT related pathological changes in stable MCI and AD/Converter were found. For AD and Converter groups, neural information is stored for a longer time in lower hierarchical order areas, while higher levels of hierarchy seem to be preferentially impaired in stable MCI leading to a less pronounced hierarchical gradient effect. These results inform that the INT holds great potential as an additional measure for AD prediction, a stable biomarker for clinical diagnosis and an important therapeutic target in AD.

neuroscience↗

bioRxiv2023

Dairy practices select for thermostable endolysins in phages

Endolysins are phage lytic enzymes that degrade the bacterial cell wall to release phage progeny. We found that the diversity of endolysins is unsuspectedly low and dominated by a single structural type in distinct phages that infect Streptococcus thermophilus. Through X-ray crystallography, we discovered that this type of endolysin contains a highly conserved calcium-binding motif in its cell wall binding domain. Inactivation of the motif in the purified endolysin or in the phage genome revealed its key role in stabilizing the enzyme under conditions that mimic the cheesemaking process, including at elevated temperatures. Fermented dairy products such as yogurt and cheeses are incubated or cooked at higher temperatures and require the addition of thermophilic lactic acid bacteria such as S. thermophilus to drive milk fermentation. It appears that dairy practices have influenced the genetic signatures of streptococcal phages by selecting for thermostable endolysins, which in turn have limited their diversity.

microbiology↗

bioRxiv2023

Progressive community, biogeochemical and evolutionary remodeling of the soil microbiome underpins long-term desert ecosystem restoration

Ecological restoration of degraded lands is essential to human sustainability. Yet, an in-depth community, functional, and evolutionary microbial perspective of long-term restoration of damaged ecosystems is lacking. Herein, we comprehensively assessed the impact of long-term (up to 17 years) restoration of Tengger Desert, China, by multi-omic profiling of 1,910 topsoil samples. The soil biophysiochemical properties, especially soil hydraulics, microbiome stability, and functional diversity, significantly improved during restoration. The soil microbiome transitioned from an extreme oligotrophic and autotrophic community to a diverse copiotrophic ecosystem. The soil microbiota, including fungi, could mediate the soil physicochemical changes through metabolites. Importantly, the systematic rewiring of nutrient cycles featured the multi-domain preference of an efficient carbon fixation strategy in the extreme desert environment. Finally, the microbiome was evolving via positive selections of genes of biogeochemical cycles, resistance, and motility. In summary, we present a comprehensive community, functional, biogeochemical, and evolutionary landscape of the soil microbiome during the long-term restoration of desert environments. We highlight the crucial microbial role in restoration from soil hydraulic and biogeochemical perspectives, offering promising field applications. HighlightsO_LIThe desert soil microbiome transformed from simple oligotrophic to a diverse, stable, and nutrient-rich ecosystem with expanded functional diversity. C_LIO_LIRestoration led to systematically rewired biogeochemical cycles, which are highly efficient in carbon fixation in the desert environment. C_LIO_LIThe microbiome was evolving via positive selections of genes involved in biogeochemical cycles and environmental adaptations. C_LIO_LIMicrobes and metabolites could facilitate desert restoration from hydraulic and biogeochemical aspects, offering promising field applications. C_LI

microbiology↗

bioRxiv2023

simmr: An open-source tool to perform simulations in Mendelian Randomization

Mendelian Randomization (MR) has become a popular tool for inferring causality of risk factors on disease. There are currently over 45 different methods available to perform MR, reflecting this extremely active research area. It would be desirable to have a standard simulation environment to objectively evaluate the existing and future methods. We present simmr, an open-source software for performing simulations to evaluate the performance of MR methods in a range of scenarios encountered in practice. Researchers can directly modify the simmr source code so that the research community may arrive at a widely accepted frame-work for researchers to evaluate the performance of different MR methods.

bioinformatics↗

bioRxiv2023

Explaining Deep Learning-Based Representations of Resting State Functional Connectivity Data: Focusing on Interpreting Nonlinear Patterns in Autism Spectrum Disorder

BackgroundResting state Functional Magnetic Resonance Imaging fMRI (rs-fMRI) has been used to study brain function in psychiatric disorders, yielding insight into brain organization. However, the high dimensionality of the rs-fMRI data presents challenges, and requires dimensionality reduction before applying machine learning techniques. Neural networks, specifically variational autoencoders (VAEs), have been instrumental in extracting low-dimensional latent representations of resting state functional connectivity patterns, addressing the complex nonlinear structure of rs-fMRI. However, interpreting those latent representations remains a challenge. This paper aims to address this gap by creating explainable VAE models and testing their utility using rs-fMRI data in autism spectrum disorder (ASD). MethodsOne-thousand one hundred and fifty participants (601 HC and 549 patients with ASD) were included in the analysis. We extracted functional connectivity correlation matrices from the preprocessed rs-fMRI data using Power atlas with 264 ROIs. Then VAEs were trained in an unsupervised fashion. Lastly, we introduce our latent contribution scores to explain the relationship between estimated representations and the original rs-fMRI brain measures. ResultsWe quantified the latent contribution scores for the ASD and control groups at the network level. We found that both ASD and control groups share the top network connectivity that contribute to all estimated latent components. For example, latent 0 was driven by resting state functional connectivity patterns (rsFC) within ventral attention network in both the ASD and control. However, significant differences in the latent contribution scores between the ASD and control groups were discovered within the ventral attention network in latent 0 and the sensory/somatomotor network in latent 2. ConclusionThis study introduced latent contribution scores to interpret nonlinear patterns identified by VAEs. These scores effectively capture changes in each observed rsFC features as estimated latent representation changes, enabling an explainable deep learning model to better understand the underlying neural mechanism of ASD.

neuroscience↗

bioRxiv2023

magpie: a power evaluation method for differential RNA methylation analysis in N6-methyladenosine sequencing

MotivationRecently, novel biotechnologies to quantify RNA modifications became an increasingly popular choice for researchers who study epitran-scriptome. When studying RNA methylations such as N6-methyladenosine (m6A), researchers need to make several decisions in its experimental design, especially the sample size and a proper statistical power. Due to the complexity and high-throughput nature of m6A sequencing measurements, methods for power calculation and study design are still currently unavailable. ResultsWe propose a statistical power assessment tool, magpie, for power calculation and experimental design for epitranscriptome studies using m6A sequencing data. Our simulation-based power assessment tool will borrow information from real pilot data, and inspect various influential factors including sample size, sequencing depth, effect size, and basal expression ranges. We integrate two modules in magpie: (i) a flexible and realistic simulator module to synthesize m6A sequencing data based on real data; and (ii) a power assessment module to examine a set of comprehensive evaluation metrics. AvailabilityThe proposed power assessment tool magpie is publicly available as a R/Bioconductor package at: https://bioconductor.org/packages/magpie/.

bioinformatics↗

bioRxiv2023

Exposure-based sequence learning induces backward replay in the human visual cortex

The ability of cortical circuits to adapt in response to experience is a fundamental property of the brain. After exposure to a moving dot sequence, flashing a dot as a cue at the starting point of the sequence can elicit successive elevated responses even in the absence of the sequence. These cue-triggered elevated responses have been shown to play a crucial role in predicting future events in dynamic environments. However, temporal sequences we are exposed typically contain rich feature information. It remains unknown whether the elevated responses are feature specific and, more crucially, how the brain organizes sequence information after exposure. To address these questions, participants were exposed to a predefined sequence of four motion directions for about 30 min, followed by the presentation of the start or end motion direction of the sequence as a cue. Surprisingly, we found that cue-triggered elevated responses were not specific to any motion direction. Interestingly, motion direction information was spontaneously reactivated, and the motion sequence was backward replayed in a time-compressed manner. These effects were observed even after brief exposure. Notably, no replay events were observed when the second or third motion direction of the sequence served as a cue. Further analyses revealed that activity in the medial temporal lobe (MTL) preceded the ripple power increase in visual cortex at the onset of replay, implying a coordinated relationship between the activities in the MTL and visual cortex. Together, these findings demonstrate that visual sequence exposure induces two-fold brain plasticity that may simultaneously serve for different functional purposes. The non-feature-specific elevated responses may facilitate general processing of upcoming stimuli, whereas the feature-specific backward replay may underpin passive learning of visual sequence.

neuroscience↗

bioRxiv2023

The crystal and cryo-EM structures of PLCγ2 reveal dynamic inter-domain recognitions in autoinhibition

Abstract/SummaryPhospholipase C gamma 2 (PLC{gamma}2) plays important roles in cell signaling downstream of various membrane receptors. PLC{gamma}2 contains a multi-domain inhibitory region critical for its regulation, while it has remained unclear how these domains contribute to PLC{gamma}2 activity modulation. Here we determined three structures of human PLC{gamma}2 in autoinhibited states, which reveal dynamic interactions at the autoinhibition interface, involving the conformational flexibility of the SH3 domain in the inhibitory region, and its previously unknown interaction with a C-terminal helical domain in the core region. We also determined a structure of PLC{gamma}2 bound to the kinase domain of fibroblast growth factor receptor 1 (FGFR1), which demonstrates the recognition of FGFR1 by the nSH2 domain in the inhibitory region of PLC{gamma}2. Our results provide new structural insights into PLC{gamma}2 regulation that will facilitate future mechanistic studies to understand the entire activation process.

biochemistry↗