Biology subjects

Lin, L.

Publications and source records attributed to Lin, L..

At least 145 records · Page 8Linked to original sources

bioRxiv2023

A non-image-forming visual circuit mediates the innate fear of heights

The neural basis of fear of heights remains largely unknown. In this study, we investigated the fear response to heights in mice and observed characteristic aversive behaviors resembling human height vertigo. We identified visual input as a critical factor in mouse reactions to heights, while peripheral vestibular input was found to be nonessential for fear of heights. Unexpectedly, we found that fear of heights in naive mice does not rely on image-forming visual processing by the primary visual cortex. Instead, a subset of neurons in the ventral lateral geniculate nucleus (vLGN), which connects to the lateral/ventrolateral periaqueductal gray (l/vlPAG), drives the expression of fear associated with heights. Additionally, we observed that a subcortical visual pathway linking the superior colliculus to the lateral posterior thalamic nucleus inhibits the defensive response to height threats. These findings highlight a rapid fear response to heights threat through a subcortical visual and defensive pathway from the vLGN to the l/vlPAG.

neuroscience↗

bioRxiv2023

Basolateral Amygdala Corticotrophin Releasing Factor Receptor 2 Interacts with Nonmuscle Myosin II to Destabilize Memory

Inhibiting the actin motor ATPase nonmuscle myosin II (NMII) with blebbistatin (Blebb) in the basolateral amgydala (BLA) depolymerizes actin, resulting in an immediate, retrieval-independent disruption of methamphetamine (METH)-associated memory. The effect is highly selective, as NMII inhibition has no effect in other relevant brain regions (e.g. dorsal hippocampus [dPHC], nucleus accumbens [NAc]), nor does it interfere with associations for other aversive or appetitive stimuli, including cocaine (COC). To investigate a potential source of this specificity, pharmacokinetic differences in METH and COC brain exposure were examined. Replicating METHs longer half-life with COC did not render the COC association susceptible to disruption by NMII inhibition. Therefore, transcriptional differences were next assessed. Comparative RNA-seq profiling in the BLA, dHPC and NAc following METH or COC conditioning identified crhr2, which encodes the corticotrophin releasing factor receptor 2 (CRF2), as uniquely upregulated by METH in the BLA. CRF2 antagonism with Astressin-2B (AS2B) had no effect on METH-associated memory after consolidation, allowing for determination of CRF2 influences on NMII-based susceptibility after METH conditioning. Pretreatment with AS2B occluded the ability of Blebb to disrupt an established METH-associated memory. Alternatively, the Blebb-induced, retrieval-independent memory disruption seen with METH was mimicked for COC when combined with CRF2 overexpression in the BLA and its ligand, UCN3 during conditioning. These results indicate that BLA CRF2 receptor activation during learning can prevent stabilization of the actin-myosin cytoskeleton supporting the memory, rendering it vulnerable to disruption via NMII inhibition. CRF2 represents an interesting target for BLA-dependent memory destabilization via downstream effects on NMII.

neuroscience↗

bioRxiv2023

Latitudinal scaling of aggregation with abundance and its consequences for coexistence in species rich forests

The search for simple principles underlying the complex spatial structure and dynamics of plant communities is a long-standing challenge in ecology1-6. In particular, the relationship between the spatial distribution of plants and species coexistence is challenging to resolve in species-rich communities7-9. Analysing the spatial patterns of tree species in 21 large forest plots, we find that rare species tend to be more spatially aggregated than common species, and a latitudinal gradient in the strength of this negative correlations that increases from tropical to temperate forests. Our analysis suggests that latitudinal gradients in animal seed dispersal10 and mycorrhizal associations11,12,13 may jointly generate this intriguing pattern. To assess the consequences of negative aggregation-abundance correlations for species coexistence, we present here a framework to incorporate the observed spatial patterns into population models8 along with an analytical solution for the local extinction risk14 of species invading from low abundances in dependence of spatial structure, demographic parameters, and immigration. For example, the stabilizing effect of the observed spatial patterns reduced the local extinction risk of species when rare almost by a factor of two. Our approach opens up new avenues for integrating observed spatial patterns into mathematical theory, and our findings demonstrate that spatial patterns, such as species aggregation and segregation, can contribute substantially to coexistence in species-rich communities. This underscores the need to understand the interactions between multiple ecological processes and spatial patterns in greater detail.

ecology↗

bioRxiv2023

Transposon elements shape population divergence of rice blast fungus Magnaporthe oryzae

Dynamic transposition of transposable elements (TEs) in fungal pathogens have significant impact on genome stability, gene expression, and virulence to the host. In Magnaporthe oryzae, genome plasticity resulting from TE insertion is a major driving force leading to the rapid evolution and diversification of this fungus. Despite their importance in M. oryzae population evolution and divergence, our understanding of TEs in this context remains limited. Here we conducted a genome-wide analysis of TE transposition dynamics in the 11 most abundant TE families in M. oryzae populations. Our results show that these TEs have specifically expanded in recently isolated M. oryzae rice populations, with the presence/absence polymorphism of TE insertions highly concordant with population divergence on Geng/Japonica and Xian/Indica rice cultivars. Notably, the genes targeted by clade-specific TEs showed clade-specific expression patterns and are involved in the pathogenic process, suggesting a transcriptional regulation of TEs on targeted genes. Our study provides a comprehensive analysis of TEs in M. oryzae populations and demonstrates a crucial role of recent TE bursts in adaptive evolution and diversification of the M. oryzae rice-infecting lineage. IMPORTANCEM. oryzae is the causal agent of the destructive blast disease, which caused massive loss of yield annually worldwide. The fungus diverged into distinct clades during adaptation toward two rice subspecies, Xian/indica and Geng/japonica. Although the role of TEs in the adaptive evolution was well established, mechanisms underlying how TEs promote the population divergence of M. oryzae remains largely unknown. In this study, we reported that TEs shape the population divergence of M. oryzae by differentially regulating gene expression between Xian/Indica-infecting and Geng/Japonica-infecting populations. Our results revealed a TE insertion mediated gene expression adaption that led to the divergence of M. oryzae population infecting different rice subspecies.

genomics↗

bioRxiv2023

COP9 signalosome complex subunit-7-mediated regulation of cAMP levels contributes to autophagic degradation and pathogenesis of rice blast fungus Magnaporthe oryzae

O_LIPhoto-dependent processes, including circadian rhythm, autophagy, ubiquitination, neddylation/deneddylation, and metabolite biosynthesis, profoundly influence microbial pathogenesis. Although a photomorphogenesis signalosome (COP9/CSN) has been identified, the mechanism by which this large complex contributes to pathophysiological processes in filamentous fungi remains unclear. C_LIO_LIHere, we identified eight CSN complex subunits in the rice blast fungus Magnaporthe oryzae and functionally characterized the translocon subunits containing a nuclear export or localization signal (NES/NLS). C_LIO_LITargeted gene replacement of these CSN subunits, including MoCSN3, MoCSN5, MoCSN6, MoCSN7, and MoCSN12, attenuated vegetative growth and conidiation in M. oryzae and rendered non-pathogenic deletion strains. MoCSN7 deletion significantly suppressed arachidonic acid catabolism, compromised cell wall integrity, subverted photo-dependent ubiquitination, and abolished photo-responsiveness. Surprisingly, we also discovered that MoCSN subunits, particularly MoCsn7, are required for the cAMP-dependent regulation of autophagic flux. C_LIO_LITherefore, MoCSN significantly contributes to morphological, physiological, and pathogenic differentiation in M. oryzae by fostering cross-talk between multiple pathways. C_LI

pathology↗

bioRxiv2023

mitoSpliter: a mitochondrial RNA variants-based method for single-cell RNA-seq analysis of multiplexed samples

Single-cell RNA-seq (scRNA-seq) analysis of multiple samples separately can be costly and lead to batch effects. Exogenous barcodes or genome-wide RNA mutations can be used to demultiplex pooled scRNA-seq data, but they are experimentally or computationally challenging and limited in scope. Mitochondrial genomes are small but diverse, providing concise genotype information. We developed "mitoSplitter", an algorithm that demultiplexes samples using mitochondrial RNA (mtRNA) variants, and demonstrated that mtRNA variants can be used to demultiplex large-scale scRNA-seq data. Using affordable computational resources, mitoSplitter can accurately analyze 10 samples and 60,000 cells in 6 hours. To avoid the batch effects from separated experiments, we applied mitoSplitter to analyze the responses of five non-small cell lung cancer (NSCLC) cell lines to BET chemical degradation in a multiplexed fashion. We found the synthetic lethality of TOP2A inhibition and BET chemical degradation in BET inhibitor-resistant cells. The result indicates that mitoSplitter can accelerate the application of scRNA-seq assays in biomedical research.

bioinformatics↗

bioRxiv2023

Single-cell time-resolved multi-omics reveal apoptotic and ferroptotic heterogeneity during foam cell formation

Macrophage-derived foam cell plays a pivotal role in the plaque formation and rupture during the progression of atherosclerosis. Foam cells are destined to divergent cell fate and functions in response to external stimuli based on their internal states, which however is hidden in the traditional studies based on population of cells. Herein, we used time-resolved and single-cell multi-omics to investigate the macrophage heterogeneity along foam cell formation. Dynamic metabolome and lipidome outlined the dual regulating axis of inflammation and ferroptosis. Single cell metabolomics and lipidomics further demonstrated a macrophage continuum featuring a differed susceptibility to apoptosis and ferroptosis. Using single-cell transcriptomic profiling, we verified the divergent cell fate toward apoptosis or ferroptosis. Therefore, the molecular choreography underlying the divergent cell fate during foam cell formation was revealed, which is of high significance for the understanding of the pathogenesis of atherosclerosis and development of new drug targets.

systems biology↗

bioRxiv2023

Conflict during learning reconfigures the neural representation of positive valence and approach behaviour

Punishing and rewarding experiences can change the valence of sensory stimuli and guide animal behaviour in opposite directions, resulting in avoidance or approach. Often, however, a stimulus is encountered with both positive and negative experiences. How is such conflicting information represented in the brain and resolved into a behavioural decision? We address this question by dissecting a circuit for sexual conditioning in C. elegans. In this learning paradigm, an odour is conditioned with both a punishment (starvation) and a reward (mates) resulting in odour approach. We find that negative and positive experiences are both encoded by the neuropeptide PDF-1 being released from and acting on different neurons. Each experience creates a separate, parallel memory in the circuit for odour processing. This results in the sensorimotor representation of odour being different in naive and sexually conditioned animals despite both displaying approach. Our results reveal that the positive valence of a stimulus is not represented in the activity of any single neuron class but flexibly represented within the circuit according to the experiences and predictions associated with the stimulus.

neuroscience↗

bioRxiv2023

Decomposing intraspecific phenotypic variation: implications for species and functional diversity

Researchers have a history of seeking explanation for and understanding of diversity patterns. High-dimensional trait-based trade-offs have been hypothesized as important for maintaining species and functional diversity. These relationships have primarily been investigated at the community-level, despite the importance of intraspecific variation to diversity maintenance. The goal of this research is to determine if alternative phenotypes are present within species and the impacts of this on diversity in a tropical seedling community in China. We ask 1) do trait combinations found across species, at the community-level, also exist within species?; 2) how consistent are alternative phenotypes and their contributions to growth across species?; and 3) how do findings align with species co-occurrence patterns? We model species-specific growth with individual-level trait measurements, environmental data, and their interactions, allowing for identification of intraspecific alternative phenotypes and quantification of the contribution of variables to growth. We find that two of three species have intraspecific alternative phenotypes. Specifically, individuals within these species share a trait combination, but how they combine the traits differs depending on the type and level of soil nutrients. Furthermore, we find that similarity among species in alternative phenotypes and variables that contribute most to growth may lead to negative spatial co-occurrence of species. Overall, we find that multiple traits or interactions between traits and the environment drive species-specific strategies for growth. These results highlight how individuals are highly variable, with phenotypically different individuals having similar growth performance, and suggest how high species and functional diversity can be maintained in communities.

ecology↗

bioRxiv2023

The scheduling of adolescence with Netrin-1 and UNC5C

Dopamine axons are the only axons known to grow during adolescence. Here, using rodent models, we examined how two proteins, Netrin-1 and its receptor, UNC5C, guide dopamine axons towards the prefrontal cortex and shape behaviour. We demonstrate in mice (Mus musculus) that dopamine axons reach the cortex through a transient gradient of Netrin-1 expressing cells - disrupting this gradient reroutes axons away from their target. Using a seasonal model (Siberian hamsters; Phodopus sungorus) we find that mesocortical dopamine development can be regulated by a natural environmental cue (daylength) in a sexually dimorphic manner - delayed in males, but advanced in females. The timings of dopamine axon growth and UNC5C expression are always phase-locked. Adolescence is an ill-defined, transitional period; we pinpoint neurodevelopmental markers underlying this period.

neuroscience↗

bioRxiv2023

Benchmark and optimization of AlphaFold structures based virtual screening strategy

Recent advancements in artificial intelligence such as AlphaFold, have enabled more accurate prediction of protein three-dimensional structure from amino acid sequences. This has attracted significant attention, especially for the application of AlphaFold in drug discovery. However, how to take full advantage of AlphaFold to assist with virtual screening remains elusive. We evaluate the AlphaFold structures of 51 selected targets from the DUD-E database in virtual screening. Our analyses show that the virtual screening performance of about 35% of the AlphaFold structures is equivalent to that of DUD-E structures, and about 25% of the AlphaFold structures yield better results than the DUD-E structures. Remarkably, AlphaFold structures produce slightly better results than the Apo structures. Moreover, we develop a new consensus scoring method based on Z-score standardization and exponential function, which shows improved screening performance compared to traditional scoring methods. By implementing a multi-stage virtual screening process and the new consensus scoring method, we are able to improve the speed of virtual screening by about nine times without compromising the enrichment factor. Overall, our results provide insights into the potential use of AlphaFold in drug discovery and highlight the value of consensus scoring and multi-stage virtual screening.

bioinformatics↗

bioRxiv2022

MYSM1 co-activates ERα action via histone and non-histone deubiquitination to confer antiestrogen resistance in breast cancer

Endocrine resistance is a crucial challenge in estrogen receptor alpha (ER)-positive breast cancer (BCa) therapy. Aberrant alteration in modulation of E2/ER signaling pathway has emerged as the putative contributor for endocrine resistance in BCa. Thus, identification the efficient ER cofactor remains necessary for finding a potential therapeutic target for endocrine resistance. Herein, we have demonstrated that Myb like, SWIRM and MPN domains 1 (MYSM1) as a histone deubiquitinase is a novel ER co-activator with established Drosophila experimental model. Our results showed that MYSM1 participated in up-regulation of ER action via histone and non-histone deubiquitination. We provided the evidence to show that MYSM1 was involved in maintenance of ER stability via ER deubiquitination. Furthermore, silencing MYSM1 induced enhancement of histone H2A ubiquitination as well as reduction of histone H3K4me3 and H3Ac levels at cis regulatory elements on promoter of ER-regulated gene. In addition, MYSM1 depletion attenuated cell proliferation/growth in BCa-derived cell lines and xenograft models. Knockdown of MYSM1 increased the sensitivity of antiestrogen agents in BCa cells. MYSM1 was highly expressed in clinical BCa samples, especially in aromatase inhibitor (AI) non-responsive tissues. These findings clarify the molecular mechanism of MYSM1 as an epigenetic modifier in regulation of ER action and provide a potential therapeutic target for endocrine resistance in BCa.

cell biology↗

bioRxiv2022

Investigation of a mathematical model describing global cancer growth and treatment: An inhomogeneous model based on the generalized logistic equation

Tumor growth is manifestation of the evolution of a complex system. Researchers have limited scope of modelling studies on specific aspects or stages of the process. It has led to unsatisfactory explanation of clinical observations. We hereby demonstrated that an inhomogeneous model built on the generalized logistic equation could serve better. It was developed to describe the whole process of tumor progression, clinically observed independence of index tumor growth from spread of the disease and growth deceleration during early stage of solid tumors. It was validated by simulating the coexistence of exponential and sigmoidal growth in chronic lymphocytic leukaemia, theories of tumor heterogeneity, as well as by accommodating notions pertaining to tumor treatment and prognosis. We thought therefore it was an interesting and not unjustifiable description of actual tumor growth in human body and hoped it might encourage more researchers to look at tumor modelling from a clinical perspective.

cancer biology↗

bioRxiv2022

Persistent gene flow suggests an absence of reproductive isolation in an African antelope speciation model

African antelope diversity is a globally unique vestige of a much richer world-wide Pleistocene megafauna. Despite this, the evolutionary processes leading to the prolific radiation of African antelopes are not well understood. Here, we sequenced 145 whole genomes from both subspecies of the waterbuck, an African antelope believed to be in the process of speciation. We investigated genetic structure and population divergence and found evidence of a mid-Pleistocene separation on either side of the eastern Great Rift Valley, consistent with vicariance caused by a rain shadow along the so-called Kingdons Line. However, we also found pervasive evidence of not only isolated and recent, but also widespread historical gene flow across the Rift Valley barrier. By inferring the genome-wide landscape of variation among subspecies, we found 14 genomic regions of elevated differentiation, including a locus that may be related to each subspecies distinctive coat pigmentation pattern. We investigated these regions as candidate speciation islands. However, we observed no significant reduction in gene flow in these regions, nor any indications of selection against hybrids. Altogether, these results suggest a pattern whereby climatically driven vicariance is the most important process driving the African antelope radiation, and suggest that reproductive isolation may not set in until very late in the divergence process.

evolutionary biology↗

bioRxiv2022

A comparative atlas of single-cell chromatin accessibility in the human brain

The human brain contains an extraordinarily diverse set of neuronal and glial cell types. Recent advances in single cell transcriptomics have begun to delineate the cellular heterogeneity in different brain regions, but the transcriptional regulatory programs responsible for the identity and function of each brain cell type remain to be defined. Here, we carried out single nucleus ATAC-seq analysis to probe the open chromatin landscape from over 1.1 million cells in 42 brain regions of three neurotypical adult donors. Integrative analysis of the resulting data identified 107 distinct cell types and revealed the cell-type-specific usage of 544,735 candidate cis-regulatory DNA elements (cCREs) in the human genome. Nearly 1/3 of them displayed sequence conservation as well as chromatin accessibility in the mouse brain. On the other hand, nearly 40% cCREs were human specific, with chromatin accessibility associated with species-restricted gene expression. Interestingly, these human specific cCREs were enriched for distinct families of retrotransposable elements, which displayed cell-type-specific chromatin accessibility. We uncovered strong associations between specific brain cell types and neuropsychiatric disorders. We futher developed deep learning models to predict regulatory function of non-coding disease risk variants.

neuroscience↗

bioRxiv2022

Vascular endothelial growth factor A contributes to the increasing of mammalian respiratory epithelial permeability induced by Pasteurella multocida infection

Infections with Pasteurella multocida can cause significant zoonotic respiratory problems in both humans and animals. In vivo tests in mouse infection models were used to investigate the mechanisms of respiratory epithelial barrier dysfunction during respiratory bacterial infection with these pathogens. Results revealed that P. multocida infection significantly increased epithelial permeability and increased expression of vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS) in murine tracheae and lungs. In murine lung epithelial cell (MLE-12) models, P. multocida infection decreased the expression of tight junctions (ZO-1) and adherens junctions ({beta}-catenin, E-cadherin), but induced the activation of the hypoxia-inducible factor-1 (HIF-1) and VEGFA signaling. When expression of HIF-1 is suppressed, the induction of VEGFA and ZO-1expression by P. multocida infection is decreased. We also found that intervention of HIF-1 and VEGFA signaling affected infection outcomes caused by respiratory bacteria in mouse models. Most importantly, we demonstrated that P. multocida infection increased permeability of human respiratory epithelial cells and this process was associated with the activation of the HIF-1 and VEGFA signaling and likely contributes to the pathogenesis of P. multocida in humans. ImportanceMammalian respiratory epithelium forms the first line of defense against infections with Pasteurella multocida, an important zoonotic respiratory pathogen. In this study, we found P. multocida infection increased respiratory epithelial permeability and promoted the induction of the hypoxia-HIF-1-VEGFA axis in both mouse and murine cell models. Similar findings were also demonstrated in human respiratory epithelial cells. The results from this study gain important knowledge about the pathogenesis of P. multocida causing infections in both animals and humans.

microbiology↗

bioRxiv2022

Ratio-based quantitative multiomics profiling using universal reference materials empowers data integration

Multiomics profiling is a powerful tool to characterize the same samples with complementary features orchestrating the genome, epigenome, transcriptome, proteome, and metabolome. However, the lack of ground truth hampers the objective assessment of and subsequent choice from a plethora of measurement and computational methods aiming to integrate diverse and often enigmatically incomparable omics datasets. Here we establish and characterize the first suites of publicly available multiomics reference materials of matched DNA, RNA, proteins, and metabolites derived from immortalized cell lines from a family quartet of parents and monozygotic twin daughters, providing built-in truth defined by family relationship and the central dogma. We demonstrate that the "ratio"-based omics profiling data, i.e., by scaling the absolute feature values of a study sample relative to those of a concurrently measured universal reference sample, were inherently much more reproducible and comparable across batches, labs, platforms, and omics types, thus empower the horizontal (within-omics) and vertical (cross-omics) data integration in multiomics studies. Our study identifies "absolute" feature quantitation as the root cause of irreproducibility in multiomics measurement and data integration, and urges a paradigm shift from "absolute" to "ratio"-based multiomics profiling with universal reference materials.

systems biology↗

bioRxiv2022

Actigraphic Correlates of Neuropsychiatric Disability in Adult Patients with Focal Epilepsy

Disability in patients with epilepsy (PWE) is multifactorial: beyond seizure frequency/severity, PWE are prone to a range of neuropsychiatric, cognitive, and somatic comorbidities that significantly impact quality of life. In this study, we explored how variations in epilepsy severity and the burden of self-reported somatic/neuropsychiatric symptoms are associated with disruptions to 24h activity patterns (rest-activity rhythms, RARs), determined through wrist accelerometry/actigraphy. Continuous multiday recordings were obtained from 59 adult patients with focal epilepsy (44% male, ages 18-72), who contemporaneously provided responses to a range of validated psychometric instruments to measure the burden of anxiety, depression, sleepiness, and somatic symptoms. As a comparator, we conducted a similar psychometric-actigraphic correlation in 1761 subjects of Hispanic origin (35% male, ages 18-65) from the Study of Latinos (SOL) Sueno Ancillary Study. RARs were analyzed via a sigmoidally-transformed cosine model (quantifying RAR amplitude, steepness, acrophase and robustness) and non-parametric measures to estimate RAR stability, fragmentation, and sleep. Compared with age- and sex-matched SOL subjects, RARs from PWE subjects featured a significantly diminished amplitude, a wider rest phase and significantly more total daily sleep. Within PWE, similar RAR distortions were associated with seizure intractability and/or anticonvulsant polytherapy. In contrast, high anxiety, depression, and somatic symptom scores were associated with diminished RAR robustness and a delayed acrophase. We applied the complete SOL Sueno database to train logistic regression models to dichotomously classify anxiety, depression and sleepiness symptoms using age, sex, body mass index and a range of non-collinear RAR parameters. When tested on PWE, these models predicted prevalent anxiety and depression symptoms with modest success (accuracy [~]70%) but failed to predict subjective sleepiness. Together, these results demonstrate that RAR features may vary with depression and anxiety symptoms in ambulatory patients with focal epilepsy, potentially offering a set of objective wearable-derived endpoints to adjunct routine clinical care and drug/device treatment trials. With larger actigraphic-psychometric datasets in PWE, we may identify RAR signatures that can more precisely distinguish between variations in seizure risk, the burden of anticonvulsant therapy and prevalent mood/anxiety symptoms.

neuroscience↗