Biology subjects

He, F.

Publications and source records attributed to He, F..

At least 109 records · Page 6Linked to original sources

bioRxiv2020

Repopulating Kupffer Cells Originate Directly from Hematopoietic Stem Cells

Kupffer cells (KCs) originate from yolk sac progenitors before birth. Throughout adulthood, they self-maintain independently from the input of circulating monocytes (MOs) at stead state, and are replenished within 2 weeks after having been depleted, but the origin of repopulating KCs in adult remains unclear. The current paradigm dictates that repopulating KCs originate from preexisting KCs or monocytes, but there remains a lack of fate-mapping evidence. In current study, we firstly traced the fate of preexisting KCs and that of monocytic cells with tissue-resident macrophage-specific and monocytic cell-specific fate mapping mouse models, respectively, and found no evidences that repopulating KCs originate from preexisting KCs or MOs. Secondly, we performed genetic lineage tracing to determine the type of progenitor cells involved in response to KC depletion in mice, and found that in response to KC depletion, hematopoietic stem cells (HSCs) proliferated in the bone marrow, mobilized into the blood, adoptively transferred into the liver and differentiated into KCs. Finally, we traced the fate of HSCs in a HSC-specific fate-mapping mouse model, in context of chronic liver inflammation induced by repeated carbon tetrachloride treatment, and confirmed that repopulating KCs originated directly from HSCs. Taken together, these findings provided strong in vivo fate-mapping evidences that repopulating KCs originate directly from Hematopoietic stem cells not from preexisting KCs or from MOs. SignificanceThere is a standing controversy in the field regarding the cellular origin of repopulating macrophages. This paper provides strong in vivo fate-mapping evidences that repopulating KCs originate directly from hematopoietic stem cells not from preexisting KCs or from MOs, which presenting a completely novel understanding of the cellular origin of repopulating Kupffer Cells and shedding light on the divergent roles of KCs in liver homeostasis and diseases.

cell biology↗

bioRxiv2020

The landscape of micro-inversions provides clues for population genetic analysis of humans

BackgroundVariations in the human genome have been studied extensively. However, little is known about the role of micro-inversions (MIs), generally defined as small (<100 bp) inversions, in human evolution, diversity, and health. Depicting the pattern of MIs among diverse populations is critical for interpreting human evolutionary history and obtaining insight into genetic diseases. ResultsIn this paper, we explored the distribution of MIs in genomes from 26 human populations and 7 nonhuman primate genomes and analyzed the phylogenetic structure of the 26 human populations based on the MIs. We further investigated the functions of the MIs located within genes associated with human health. With hg19 as the reference genome, we detected 6,968 MIs among the 1,937 human samples and 24,476 MIs among the 7 nonhuman primate genomes. The analyses of MIs in human genomes showed that the MIs were rarely located in exonic regions. Nonhuman primates and human populations shared only 82 inverted alleles, and Africans had the most inverted alleles in common with nonhuman primates, which was consistent with the "Out of Africa" hypothesis. The clustering of MIs among the human populations also coincided with human migration history and ancestral lineages. ConclusionsWe propose that MIs are potential evolutionary markers for investigating population dynamics. Our results revealed the diversity of MIs in human populations and showed that they are essential to constructing human population relationships and have a potential effect on human health.

genomics↗

bioRxiv2020

The untapped potential of conservation journals to promote freshwater biodiversity

Freshwater ecosystems are amongst the most diverse ecosystems on the planet. They are subject to intense and increasing threats and have a higher proportion of threatened and extinct species than terrestrial or marine realms. Concurrently, freshwater ecosystems are largely underrepresented in both conservation research and actions arguably as a consequence of less popularity and promotion. To test this assumption, we used cover images as a proxy of exposure and promotion opportunities provided by conservation journals. We collected information on cover images of 18 conservation journals from 1997 to 2016 and data on citations and Altmetric scores of papers published in them. We found that freshwater ecosystems (10.4%) were featured less often than marine (15.2%) or terrestrial (74.4%) ecosystems on covers of these journals. All 15 most featured species are from terrestrial or marine ecosystems, with 14 of them being large vertebrates such as elephants, big cats, rhinos, polar bears, and marine turtles. None of the 95 species featured more than once on the covers of conservation journals spend their whole life history in fresh waters, i.e. they are at least partly associated with terrestrial or marine ecosystems. Our results indicated that cover-featured studies received more attention from academia and the general public, i.e. showed higher citations and Altmetric scores, than non-featured ones within the same issue. By featuring freshwater species and habitats on covers, therewith providing more exposure opportunities, conservation journals hold the potential to promote biodiversity conservation in fresh waters. Scientists can help that endeavour by submitting freshwater-related photos together with their manuscripts for review, therewith providing more options for editors to portray freshwater species and habitats and to ultimately raise awareness and appreciation of freshwater life.

scientific communication and education↗

bioRxiv2020

Whole-genome sequencing of multiple isolates of Puccinia triticina reveals asexual lineages evolving by recurrent mutations.

BackgroundThe wheat leaf rust fungus, Puccinia triticina Erikss. is a worldwide pathogen of tetraploid durum and hexaploid wheat. Many races of P. triticina differ for virulence to specific leaf rust resistance genes and are found in most wheat-growing regions of the world. Wheat cultivars with effective leaf rust resistance exert selection pressure on P. triticina populations for virulent race types. The objectives of this study were to examine whole-genome sequence data of 121 P. triticina isolates and to gain insight into race evolution. The collection included isolates comprising many different race phenotypes collected worldwide from common wheat in the U.S. and the European Union together with isolates from durum wheat. One isolate from the wild wheat relative Aegilops speltoides, and two from Ae. cylindrica were also included for comparison. ResultsBased on 121,907 variants identified relative to the reference race 1-1 genome, the isolates were clustered into 11 major lineages with 100% bootstrap support. The isolates were also grouped based on variation in approximately 1400 secreted resistance interactor candidate proteins. In gene-coding regions, all groups had high ratios of non-synonymous to synonymous mutations and nonsense to readthrough mutations. ConclusionsBased on total variation or variation in the secreted protein genes, isolates grouped the same indicating that variants were distributed across the entire genome. Our results suggest that recurrent mutation and selection play a major role in differentiation within the clonal lineages.

genomics↗

bioRxiv2020

Cis-regulatory evolution spotlights species differences in the adaptive potential of gene expression plasticity

Phenotypic plasticity is the variation in phenotype that a single genotype can produce in different environments and, as such, is an important component of individual fitness. However, whether the effect of new mutations, and hence evolution, depends on the direction of plasticity remains controversial. Here, we identify the cis-acting modifications that have reshaped gene expression in response to dehydration stress in three Arabidopsis species. Our study shows that the direction of effects of most cis-regulatory variants differentiating the response between A. thaliana and the sister species A. lyrata and A. halleri depends on the direction of pre-existing plasticity in gene expression. A comparison of the rate of cis-acting variant accumulation in each lineage indicates that the selective forces driving adaptive evolution in gene expression favors regulatory changes that magnify the stress response in A. lyrata. The evolutionary constraints measured on the amino-acid sequence of these genes support this interpretation. In contrast, regulatory changes that mitigate the plastic response to stress evolved more frequently in A. halleri. Our results demonstrate that pre-existing plasticity can be a stepping stone for adaptation, but its selective remodeling differs between lineages.

evolutionary biology↗

bioRxiv2020

Visualizing anesthesia-induced vasodilation of cerebral vasculature using multi-exposure speckle imaging

BackgroundAnesthetized animal models are used extensively during neurophysiological and behavioral studies despite systemic effects from anesthesia that undermine both accurate interpretation and translation to awake human physiology. The majority of work examining the impact of anesthesia on cerebral blood flow (CBF) has been restricted to before and after measurements with limited spatial resolution. New MethodWe used multi-exposure speckle imaging (MESI), an advanced form of laser speckle contrast imaging (LSCI), to characterize the dynamics of isoflurane anesthesia induction on cerebral vasculature and blood flow in the mouse brain. ResultsThe large anatomical changes caused by isoflurane are depicted with wide-field imagery and video highlighting the induction of general anesthesia. Within minutes of exposure, both vessel diameter and blood flow increased drastically compared to the awake state and remained elevated for the duration of imaging. An examination of the dynamics of anesthesia induction reveals that blood flow increased faster in arteries than in veins or parenchyma regions. Comparison with Existing MethodsMESI offers robust hemodynamic measurements across large fields-of-view and high temporal resolutions sufficient for continuous visualization of cerebrovascular events featuring major changes in blood flow. ConclusionThe large alterations caused by isoflurane anesthesia to the cortical vasculature and CBF are readily characterized using MESI. These changes are unrepresentative of normal physiology and provide further evidence that neuroscience experiments would benefit from transitioning to un-anesthetized awake animal models.

neuroscience↗

bioRxiv2020

A yeast BiFC-seq method for genome-wide interactome mapping

Genome-wide physical protein-protein interaction (PPI) mapping remains a major challenge for current technologies. Here, we report a high-efficiency yeast bimolecular fluorescence complementation method coupled with next-generation DNA sequencing (BiFC-seq) for interactome mapping. We applied this technology to systematically investigate an intraviral network of Ebola virus (EBOV). Two-thirds (9/13) of known interactions of EBOV were recaptured and five novel interactions were discovered. Next, we used BiFC-seq method to map the interactome of the tumor protein p53. We identified 97 interactors of p53 with more than three quarters are novel. Furthermore, in more complex background, we screened potential interactors by pooling two BiFC-libraries together, and revealing a network of 229 interactions among 205 proteins. These results show that BiFC-seq is a highly sensitive, rapid and economical method in genome-wide interactome mapping.

genomics↗

bioRxiv2020

The carboxyl-terminus of RAN translated GGGGCC nucleotide repeat expansions modulates toxicity in models of ALS/FTD

An intronic hexanucleotide repeat expansion in C9ORF72 causes familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This repeat is thought to elicit toxicity through RNA mediated protein sequestration and repeat-associated non-AUG (RAN) translation of dipeptide repeat proteins (DPRs). We generated a series of transgenic Drosophila models expressing GGGGCC (G4C2) repeats either inside of an artificial intron within a GFP reporter or within the 5 UTR of GFP placed in different downstream reading frames. Expression of 484 intronic repeats elicited minimal alterations in eye morphology, viability, longevity, or larval crawling but did trigger RNA foci formation, consistent with prior reports. In contrast, insertion of repeats into the 5 UTR elicited differential toxicity that was dependent on the reading frame of GFP relative to the repeat. Greater toxicity correlated with a short and unstructured carboxyl terminus in the glycine-arginine (GR) RAN protein reading frame. This change in C-terminal sequence triggered nuclear accumulation of all three RAN DPRs. A similar differential toxicity and dependence on the GR carboxyl terminus was observed when repeats were expressed in rodent neurons. The presence of the native carboxyl-termini across all three reading frames was partly protective. Taken together, these findings suggest that carboxyl terminal sequences outside of the repeat region may alter the behavior and toxicity of dipeptide repeat proteins derived from GGGGCC repeats.

genetics↗

bioRxiv2020

Differential chromatin accessibility landscape reveals the structural and functional features of the allopolyploid wheat chromosomes

BackgroundWe have a limited understanding of how the complexity of the wheat genome influences the distribution of chromatin states along the homoeologous chromosomes. Using a differential nuclease sensitivity (DNS) assay, we investigated the chromatin states in the coding and transposon element (TE) -rich repetitive regions of the allopolyploid wheat genome. ResultsWe observed a negative chromatin accessibility gradient along the telomere-centromere axis with mostly open and closed chromatin located in the distal and pericentromeric regions of chromosomes, respectively. This trend was mirrored by the TE-rich intergenic regions, but not by the genic regions, which showed similar averages of chromatin accessibility levels along the chromosomes. The genes proximity to TEs was negatively associated with chromatin accessibility. The chromatin states of TEs was dependent on their type, proximity to genes, and chromosomal position. Both the distance between genes and TE composition appear to play a more important role in the chromatin accessibility along the chromosomes than chromosomal position. The majority of MNase hypersensitive regions were located within the TEs. The DNS assay accurately predicted previously detected centromere locations. SNPs located within more accessible chromatin explain a higher proportion of genetic variance for a number of agronomic traits than SNPs located within closed chromatin. ConclusionsThe chromatin states in the wheat genome are shaped by the interplay of repetitive and gene-encoding regions that are predictive of the functional and structural organization of chromosomes, providing a powerful framework for detecting genomic features involved in gene regulation and prioritizing genomic variation to explain phenotypes.

genomics↗

bioRxiv2020

Analytical models for β-diversity and the power-law scaling of β-deviation

O_LI{beta}-diversity is a primary biodiversity pattern for inferring community assembly. A randomized null model that generates a standardized {beta}-deviation has been widely used for this purpose. However, the null model has been much debated and its application is limited to abundance data. C_LIO_LIHere we derive analytical models for {beta}-diversity to address the debate, clarify the interpretation, and extend the application to occurrence data. C_LIO_LIThe analytical analyses show unambiguously that the standardized {beta}-deviation is a quantification of the effect size of non-random spatial distribution of species on {beta}-diversity for a given species abundance distribution. It robustly scales with sampling effort following a power law with exponent of 0.5. This scaling relationship offers a simple method for comparing {beta}-diversity of communities of different sizes. C_LIO_LIAssuming logseries distribution for the metacommunity species abundance distribution, our model allows for calculation of the standardized {beta}-deviation using occurrence data plus a datum on the total abundance. C_LIO_LIOur theoretical model justifies and generalizes the use of the {beta} null model for inferring community assembly rules. C_LI

ecology↗

bioRxiv2020

Novel non-transposable-element regulation patterns of KZFP family reveal new drivers of its rapid evolution

One striking feature of the large KRAB-containing zinc finger protein (KZFP) family is its rapid expansion and divergence since its formation about 400 million years ago. However, the evolutionary characteristics of KRAB domains, C2H2 zinc fingers and the full protein of KZFPs have not been fully analyzed. As for the drivers of the rapid evolution, its partly due to their coevolution with transposable elements (TEs). But their diverse functions besides inhibiting TEs suggest other reasons exist. Here we address these two issues by the systematic analysis of the divergence time and diversification pattern of KZFPs at three aspects and the functional analysis of the potential target genes besides TEs. We found that old-zinc-finger-containing KZFPs tend to have varied and disordered KRAB domains, indicating there are two ways of the evolution of KZFPs, including the variation of KRAB domains and the diversification of zinc fingers. Among them, the divergence of zinc fingers mainly contributes to the rapid evolution of KZFPs. Thus, we mainly focused on the functional requirements of the evolution of zinc fingers. Different from the classical regulation pattern of this family, we found and experimentally confirmed that KZFPs tend to bind to non-TE regions and can positively regulate target genes. Although most young genes tend to be with a low expression level, young-zinc-finger-containing KZFPs tend to be highly expressed in early embryonic development or early mesoderm differentiation, indicating their particular evolutionarily novel functional roles in these two processes. We further validated a young KZFP, ZNF611, can bind to non-TE region of STK38 gene and positively regulates its expression in ESCs. The emergence of new sequence in STK38 promoter may drive the evolution of zinc fingers in ZNF611. Finally, we proposed a two-way evolution model of KZFP family.

evolutionary biology↗

bioRxiv2020

Exploration of target spaces in the human genome for protein and peptide drugs

MotivationProtein and peptide drugs, after decades of development have grown into a major drug class of the marketplace. Target identification and validation is crucial for their discovery, and bioinformatics estimation of candidate targets based on characteristics of successful target proteins will help improve efficiency and success rate of target selection. However, owing to the development history of the pharmaceutical industry, previous systematic exploration of target space mainly focused on traditional small-molecule drugs, whereas that for protein and peptide drugs is blank. Here we systematically explored target spaces in the human genome specially for protein and peptide drugs. ResultsWe found that compared with other proteins, targets of both successful protein and peptide drugs have their own characteristics in many aspects and are also significantly different from those of traditional small-molecule drugs. Further based on these features, we developed effective genome-wide target estimation models respectively for protein and peptide drugs.

bioinformatics↗

bioRxiv2020

Polygenic adaptation of rosette growth variation in Arabidopsis thaliana populations

The rate at which plants grow is a major functional trait in plant ecology. However, little is known about its evolution in natural populations. Here, we investigate evolutionary and environmental factors shaping variation in the growth rate of Arabidopsis thaliana. We used plant diameter as a proxy to monitor plant growth over time in environments that mimicked latitudinal differences in the intensity of natural light radiation, across a set of 278 genotypes sampled within four broad regions, including an outgroup set of genotypes from China. A field experiment conducted under natural conditions confirmed the ecological relevance of the observed variation. All genotypes markedly expanded their rosette diameter when the light supply was decreased, demonstrating that environmental plasticity is a predominant source of variation to adapt plant size to prevailing light conditions. Yet, we detected significant levels of genetic variation both in growth rate and growth plasticity. Genome-wide association studies revealed that only 2 single nucleotide polymorphisms associate with genetic variation for growth above Bonferroni confidence levels. However, marginally associated variants were significantly enriched among genes with an annotated role in growth and stress reactions. Polygenic scores computed from marginally associated variants confirmed the polygenic basis of growth variation. For both light regimes, phenotypic divergence between the most distantly related population (China) and the various regions in Europe is smaller than the variation observed within Europe, indicating that some level of stabilizing selection constrains the evolution of growth rate. We observed that Spanish genotypes, however, reach a significantly larger size than Northern European genotypes. Tests of adaptive divergence and analysis of the individual burden of deleterious mutations reveal that adaptive processes have played a more important role in shaping regional differences in rosette growth than maladaptive evolution.

evolutionary biology↗

bioRxiv2020

AI-aided design of novel targeted covalent inhibitors against SARS-CoV-2

The focused drug repurposing of known approved drugs (such as lopinavir/ritonavir) has been reported failed for curing SARS-CoV-2 infected patients. It is urgent to generate new chemical entities against this virus. As a key enzyme in the life-cycle of coronavirus, the 3C-like main protease (3CLpro or Mpro) is the most attractive for antiviral drug design. Based on a recently solved structure (PDB ID: 6LU7), we developed a novel advanced deep Q-learning network with the fragment-based drug design (ADQN-FBDD) for generating potential lead compounds targeting SARS-CoV-2 3CLpro. We obtained a series of derivatives from those lead compounds by our structure-based optimization policy (SBOP). All the 47 lead compounds directly from our AI-model and related derivatives based on SBOP are accessible in our molecular library at https://github.com/tbwxmu/2019-nCov. These compounds can be used as potential candidates for researchers in their development of drugs against SARS-CoV-2.

pharmacology and toxicology↗

bioRxiv2020

Multimodal mapping of neural activity and cerebral blood flow reveals long-lasting neurovascular dissociations after small-scale strokes

Neurovascular coupling, the close spatial and temporal relationship between neural activity and hemodynamics, is disrupted in pathological brain states. To understand the altered neurovascular relationship in brain disorders, longitudinal, simultaneous mapping of neural activity and hemodynamics is critical yet challenging to achieve. Here, we employ a multimodal neural platform in a mouse model of stroke and realize long-term, spatially-resolved tracking of intracortical neural activity and cerebral blood flow in the same brain regions. We observe a pronounced neurovascular dissociation that occurs immediately after small-scale strokes, becomes the most severe a few days after, lasts into chronic periods, and varies with the level of ischemia. Neuronal deficits extend spatiotemporally whereas restoration of cerebral blood flow occurs sooner and reaches a higher relative value. Our findings reveal the neurovascular impact of mini-strokes and inform the limitation of neuroimaging techniques that infer neural activity from hemodynamic responses.

neuroscience↗

bioRxiv2020

Global Screening of Sentrin-Specific Protease Family Substrates in SUMOylation

Post-translational modification of proteins by the addition of small ubiquitin-related modifier (SUMO) is a dynamic process, in which deSUMOylation is carried out by members of the Sentrin/SUMO-specific protease (SENP) family. While identification of SUMOylation sites at global scale has made great progress, much less effort has been made on the SENP family-dependent deSUMOylation. Here we report a dataset of 3,763 high confident SUMO1 modification sites and their dependence on the 6 members of SENP proteins. Interrogation of the dataset led to the discovery that SENP3 regulates the innate immune response via deSUMOylation of DHX15 and PCBP2 and recruitment of inflammatory molecules. Collectively, this dataset presents a site-resolved network of the SUMO-SENP system, providing information for potential substrates of the SENP proteins.

biochemistry↗

bioRxiv2020

Distinct midbrain response statistics are associated with sound recognition and discrimination during the construction of natural sound textures

The perception of sound textures, a class of natural sounds defined by statistical sound structure such as fire wind, and rain, has been proposed to arise through the integration of time-averaged summary statistics. Where and how the auditory system might encode these summary statistics to create internal representations of these stationary sounds, however, is unknown. Here, using natural textures and synthetic variants with reduced statistics, we show that summary statistics modulate the correlations between frequency organized neuron ensembles in the awake rabbit inferior colliculus. These neural ensemble correlation statistics capture high-order sound structure and allow for accurate neural decoding in a single trial recognition task with evidence accumulation times approaching 1 s. In contrast, the average activity across the neural ensemble (neural spectrum) provides a fast (tens of ms) and salient signal that contributes primarily to texture discrimination. Intriguingly, perceptual studies in human listeners reveals analogous trends: the sound spectrum is integrated quickly and serves as salient discrimination cue while high-order sound statistics are integrated slowly and contribute substantially more towards recognition. The findings suggest statistical sound cues such as the sound spectrum and correlation structure are represented by distinct response statistics in auditory midbrain ensembles, and that these neural response statistics may have dissociable roles and time scales for the recognition and discrimination of natural sounds. SIGNIFICANCE STATEMENTBeing able to recognize and discriminate natural sounds, such as from a running stream, a crowd clapping, or ruffling leaves is a critical task of the normal functioning auditory system. Humans can easily perform such tasks, yet they can be particularly difficult for the hearing impaired and they challenge our most sophisticated computer algorithms. This difficulty is attributed to the complex physical structure of such natural sounds and the fact they are not unique: they vary randomly in a statistically defined manner from one excerpt to the other. Here we provide the first evidence, to our knowledge, that the central auditory system is able to encode and utilize statistical sound cues for natural sound recognition and discrimination behaviors.

neuroscience↗

bioRxiv2020

SPARC promotes insulin secretion through down-regulation of RGS4 protein in pancreatic beta-cells

SPARC-deficient mice have been shown to exhibit impaired glucose tolerance and insulin secretion, but the underlying mechanism remains unknown. Here, we show that SPARC enhanced the promoting effect of Muscarinic receptor agonist oxotremorine-M on insulin secretion in cultured mouse islets. Overexpression of SPARC down-regulated RGS4, a negative regulator of {beta}-cell M3 muscarinic receptors. Conversely, knockdown of SPARC up-regulated RGS4 in Min6 cells. RGS4 was up-regulated in islets from sparc -/- mice, which correlated with decreased glucose-stimulated insulin secretion (GSIS). Furthermore, inhibition of RGS4 restored GSIS in sparc -/- mice, and knockdown of RGS4 partially decreased the promoting effect of SPARC on oxotremorine-M stimulated insulin secretion. Phosphoinositide 3-kinase (PI3K) inhibitor LY-294002 abolished SPARC-induced down-regulation of RGS4. Taken together, our data revealed that SPARC promoted GSIS by inhibiting RGS4 in pancreatic {beta} cells.

cell biology↗