Biology subjects

Long, X.

Publications and source records attributed to Long, X..

51 records · Page 3Linked to original sources

bioRxiv2020

How do ecological and social environments reflect parental roles in birds? A comparative analysis

Parental roles are highly diverse in animal taxa. Since caring is an important determinant of fitness, understanding the origin and maintenance of various parental care strategies is a key question in evolutionary biology. Here we investigate parental care patterns in birds, which exhibit a remarkable diversity of parental sex roles. By means of phylogenetically informed comparative analyses we investigate whether and how care provisioning is predicted by ecology and social environment. Making use of the most comprehensive dataset including 1101 species that represent 126 avian families, we show that sex differences in parental care are neither related to food type nor to nest type, two key ecological factors. However, we found an effect of the social environment, as males tend to care relatively more in in colonial species than in non-colonial species. Taken together, these results highlight the importance of social effects for evolution of diverse parental sex roles.

evolutionary biology↗

bioRxiv2020

Sequential ER stress and inflammatory responses are induced by SARS-CoV-2 ORF3 through ERphagy

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have resulted in a number of severe cases of COVID-19 and deaths worldwide. However, knowledge of SARS-CoV-2 infection, diseases and therapy remains limited, underlining the urgency of fundamental studies and drug development. Studies have shown that induction of autophagy and hijacking of autophagic machinery are essential for infection and replication of SARS-CoV-2; however, the mechanism of this manipulation and function of autophagy during SARS-CoV-2 infection remain unclear. In the present study, we identified ORF3 as an inducer of autophagy and revealed that ORF3 localizes to the ER and induces FAM134B-related ERphagy through the HMGB1-Beclin1 pathway. As a consequence, ORF3 induces ER stress and inflammatory responses through ERphagy and sensitizes cells to ER stress-induced cell death, suggesting that SARS-CoV-2 ORF3 hijacks ERphagy and then harms ER homeostasis to induce inflammatory responses through excessive ER stress. These findings reveal a sequential induction of ERphagy, ER stress and acute inflammatory responses during SARS-CoV-2 infection and provide therapeutic potential for ERphagy and ER stress-related drugs for COVID-19 treatment and prevention. ImportanceSARS-CoV-2 infection and replication require autophagosome-like double-membrane vacuoles. Inhibition of autophagy suppresses viral replication, indicating the essential role of autophagy in SARS-CoV-2 infection. However, how SARS-CoV-2 hijacks autophagy and the function of autophagy in the disease progression remain unknown. Here, we reveal that SARS-CoV-2 ORF3 induces ERphagy and consequently induces ER stress to trigger acute inflammatory responses and enhance sensitivity to ER stress-induced apoptosis. Our studies uncover ERphagy-induced inflammatory responses during SARS-CoV-2 infection and provide a promising therapeutic approach for treating SARS-CoV-2 infection and inflammatory responses in COVID-19 by manipulating autophagy and ER stress.

microbiology↗

bioRxiv2020

Individual variation in parental care drives divergence of sex roles

In many animal species, parents provide care for their offspring, but the parental roles of the two sexes differ considerably between and within species. Here, we use an individual-based simulation approach to investigate the evolutionary emergence and stability of parental roles. Our conclusions are in striking contrast to the results of analytical models. In the absence of initial differences between the sexes, our simulations do not predict the evolution of egalitarian care, but either female-biased or male-biased care. When the sexes differ in their pre-mating investment, the sex with the highest investment tends to evolve a higher level of parental care; this outcome does not depend on non-random mating or uncertainty of paternity. If parental investment evolves jointly with sexual selection strategies, evolution results in either the combination of female-biased care and female choosiness or in male-biased care and the absence of female preferences. The simulations suggest that the parental care pattern drives sexual selection, and not vice versa. Finally, our model reveals that a population can rapidly switch from one type of equilibrium to another one, suggesting that parental sex roles are evolutionarily labile. By combining simulation results with fitness calculations, we argue that all these results are caused by the emergence of individual variation in parental care strategies, a factor that was hitherto largely neglected in sex-role evolution theory.

evolutionary biology↗

bioRxiv2020

Genetic-variant hotspots and hotspot clusters in the human genome facilitating adaptation while increasing instability

BackgroundGenetic variants, underlining phenotypic diversity, are known to distribute unevenly in the human genome. A comprehensive understanding of the distributions of different genetic variants is important for insights into genetic functions and disorders. MethodsHerein, a sliding-window scan of regional densities of eight kinds of germline genetic variants, including single-nucleotide-polymorphisms (SNPs) and four size-classes of copy-number-variations (CNVs) in the human genome has been performed. ResultsThe study has identified 44,379 hotspots with high genetic-variant densities, and 1,135 hotspot clusters comprising more than one type of hotspots, accounting for 3.1% and 0.2% of the genome respectively. The hotspots and clusters are found to co-localize with different functional genomic features, as exemplified by the associations of hotspots of middle-size CNVs with histone-modification sites, work with balancing and positive selections to meet the need for diversity in immune proteins, and facilitate the development of sensory-perception and neuroactive ligand-receptor interaction pathways in the function-sparse late-replicating genomic sequences. Genetic variants of different lengths co-localize with retrotransposons of different ages on a long-with-young and short-with-all basis. Hotspots and clusters are highly associated with tumour suppressor genes and oncogenes (p < 10-10), and enriched with somatic tumour CNVs and the trait- and disease-associated SNPs identified by genome-wise association studies, exceeding tenfold enrichment in clusters comprising SNPs and extra-long CNVs. ConclusionsIn conclusion, the genetic-variant hotspots and clusters represent two-edged swords that spearhead both positive and negative genomic changes. Their strong associations with complex traits and diseases also open up a potential Common Disease-Hotspot Variant approach to the missing heritability problem.

genomics↗

bioRxiv2020

Single-cell RNA-seq of the stromal vascular fraction of adipose tissue reveals lineage-specific changes in cancer-related lymphedema

Lymphedema is a chronic tissue edema that frequently occurs following lymph node resection for cancer treatment, and is characterized by progressive swelling, chronic inflammation, excessive fibrosis and adipose deposition in the affected limbs. We still lack targeted medical therapies for this disease due to the incomplete understanding of the mechanism underlying the pathogenesis. Here, we performed single-cell RNA-seq of 70,209 cells of the stromal vascular fraction (SVF) of subcutaneous adipose tissue from patients with cancer-related lymphedema and healthy donors. Unbiased clustering revealed 21 cell clusters, which were assigned to 10 cell lineages. One of the four ASC subpopulations, c3, was significantly expanded in lymphedema, which may be related to the fibrosis and pathologic mineralization of adipose tissues in lymphedema. Dysregulated pathways and genes of ASCs in lymphedema were identified through gene set enrichment analysis and differential regulatory network analysis, which reflect the pathophysiological changes in ASCs in lymphedema: enhanced fibrosis, mineralization and proliferation as well as compromised immunosuppression capacity. In addition, we characterized the three subpopulations of macrophages, and found that the adipose tissue of lymphedema displayed immunological dysfunction characterized by a striking depletion of anti-inflammatory macrophages, i.e., LYVE+ resident-like macrophages. Cell-cell communication analysis revealed a perivascular ligand-receptor interaction module among ASCs, macrophages and vascular endothelial cells in adipose tissue. Communication changes for ASCs in lymphedema were identified. For example, PDGFD-PDGFR complex interactions were significantly enhanced between a number of lineages and ASCs, reflecting the role of PDGFD signaling in the pathophysiological changes in ASCs. Finally, we mapped the previously reported candidate genes predisposing to cancer-related lymphedema to cell subpopulations in the SVF, and found that GJC2, the most likely causal gene was highly expressed in the lymphedema-associated ASC subpopulation c3. In summary, we provided the first comprehensive analysis of cellular heterogeneity, lineage-specific regulatory changes and intercellular communication alterations of the SVF in adipose tissues from cancer-related lymphedema at a single-cell resolution. The lymphedema-associated cell subpopulations and dysregulated pathways may serve as potential targets for medical therapies. Our large-scale dataset constitutes a valuable resource for further investigations of the mechanism of cancer-related lymphedema.

cancer biology↗

bioRxiv2020

A transcriptomic taxonomy of Drosophila circadian neurons around the clock

Many different functions are regulated by circadian rhythms, including those orchestrated by discrete clock neurons within animal brains. To comprehensively characterize and assign cell identity to the 75 pairs of Drosophila circadian neurons, we optimized a single cell RNA sequencing method and assayed clock neuron gene expression at different times of day. The data identify at least 17 clock neuron categories with striking spatial regulation of gene expression. Transcription factor regulation is prominent and likely contributes to the robust circadian oscillation of many transcripts, including those that encode cell-surface proteins previously shown to be important for cell recognition and synapse formation during development. We suggest that these molecules orchestrate the temporal regulation of synapse formation and/or strength. The many other clock-regulated genes also constitute an important resource for future mechanistic and functional studies between clock neurons and/or for temporal signaling to circuits elsewhere in the fly brain.

neuroscience↗

bioRxiv2020

Single-cell RNA-seq reveals lineage-specific regulatory changes of fibroblasts and vascular endothelial cells in keloid

Keloid is a benign dermal fibrotic disorder with some features similar to malignant tumors such as hyper-proliferation, apoptosis resistance and invasion. keloid remains a therapeutic challenge in terms of high recurrence rate and lack of satisfactory medical therapies, which is partially due to the incomplete understanding of keloid pathogenesis. A thorough understanding of the cellular and molecular mechanism of keloid pathogenesis would facilitate the development of novel medical therapies for this disease. Here, we performed single-cell RNA-seq of 28,064 cells from keloid skin tissue and adjacent relatively normal tissue. Unbiased clustering revealed substantial cellular heterogeneity of the keloid tissue, which included 21 cell clusters assigned to 11 cell lineages. Differential proportion analysis revealed significant expansion for fibroblasts and vascular endothelial cells in keloid compared with control, reflecting their strong association with keloid pathogenesis. We then identified five previously unrecognized subpopulations of keloid fibroblasts and four subpopulations of vascular endothelial cells. Comparative analyses were performed to identify the dysregulated pathways, regulators and ligand-receptor interactions for keloid fibroblasts and vascular endothelial cells, the two important cell lineages in keloid pathogenesis and for medical interventions. Our results highlight the roles of transforming growth factor beta and Eph-ephrin signaling pathways in both the aberrant fibrogenesis and angiogenesis of keloid. Critical regulators and signaling receptors implicated in the fibrogenesis of other fibrotic disorders, such as TWIST1, FOXO3, SMAD3 and EPHB2, ranked at the top in the regulatory network of keloid fibroblasts. In addition, tumor-related pathways such as negative regulation of PTEN transcription were found to be activated in keloid fibroblasts and vascular endothelial cells, which may be responsible for the malignant features of keloid. Our study put novel insights into the pathogenesis of keloid, and provided potential targets for medical therapies. Our dataset also constitutes a valuable resource for further investigations of the mechanism of keloid pathogenesis.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pathology↗

bioRxiv2020

An ectosymbiosis-based mechanism of eukaryogenesis

The mechanisms proposed for eukaryogenesis are divisible into mitochondria-early and mitochondria-late ones, where the mitochondriate-eukaryotes (MTEs) were evolutionary precursors or products of the amitochondriate-eukaryotes (AMIs) respectively. Analysis of prokaryote-to-eukaryote gene transfers in eukaryogenesis showed two tranches of high-intensity transfers from prokaryotes to eukaryotes mediated by endosymbioses that gave rise to mitochondria and chloroplasts, and hundreds of medium-intensity transfers which included the transfer of hydrogenase and pyruvate: ferredoxin oxidoreductase genes from the Thermoanaerobacter-Hungateiclostridium-Sporanaerobacter group to the AMIs. Since 94.5% of these medium-intensity transfers generated more than 100 inter-proteome similarity hits between each donor-recipient pair, they were not readily explicable by horizontal gene transfers (HGTs) or endosymbioses, pointing instead to the participation of a large number of ectosymbiotic transfers. The euryarchaeon Aciduliprofundum boonei (Abo) and the gammaproteobacterium Escherichia coli (Eco) were the foremost contributors of archaeal and bacterial genes for the eukaryotic DNA-apparatus respectively, and the Abo/Eco ratios for the prokaryote-derived genes in eukaryotes decreased from Microsporidia to other AMIs, and even more so in the MTEs. These findings supported an ectosymbiosis-based mechanism of eukaryogenesis with Abo as the Archaeal Parent of Eukarya, and Microsporidia as the eukaryotes phylogenetically closest to the Last Eukaryotic Common Ancestor (LECA).

evolutionary biology↗

bioRxiv2020

Sharp tuning of head direction by somatosensory fast-spiking interneurons

Head direction (HD) information is intricately linked to spatial navigation and cognition. We recently reported the co-existence of all currently recognized spatial cell types can be found in the hindlimb primary somatosensory cortex (S1HL). In this study, we carried out an in-depth characterization of HD cells in S1HL. We show fast-spiking (FS), putative inhibitory neurons are over-represented in and sharply tuned to HD compared to regular-spiking (RS), putative excitatory neurons. These FS HD cells are non-conjunctive, rarely theta modulated, not locally connected and are enriched in layer 4/5a. Their co-existence with RS HD cells and angular head velocity (AHV) cells in a layer-specific fashion through the S1HL presents a previously unreported organization of spatial circuits. These findings challenge the notion that FS, putative inhibitory interneurons are weakly tuned to external stimuli in general and present a novel local network configuration not reported in other parts of the brain.

neuroscience↗

bioRxiv2019

Comparative single-cell transcriptomics of complete insect nervous systems

Molecular profiles of neurons influence information processing, but bridging the gap between genes, circuits, and behavior has been very difficult. Furthermore, the behavioral state of an animal continuously changes across development and as a result of sensory experience. How behavioral state influences molecular cell state is poorly understood. Here we present a complete atlas of the Drosophila larval central nervous system composed of over 200,000 single cells across four developmental stages. We develop polyseq, a python package, to perform cell-type analyses. We use single-molecule RNA-FISH to validate our scRNAseq findings. To investigate how internal state affects cell state, we optogentically altered internal state with high-throughput behavior protocols designed to mimic wasp sting and over activation of the memory system. We found nervous system-wide and neuron-specific gene expression changes. This resource is valuable for developmental biology and neuroscience, and it advances our understanding of how genes, neurons, and circuits generate behavior.

neuroscience↗

bioRxiv2019

Descent of Bacteria and Eukarya from an archaeal root of life

The three biological domains delineated based on SSU rRNAs are confronted by uncertainties regarding the relationship between Archaea and Bacteria, and the origin of Eukarya. Herein the homologies between the paralogous valyl-tRNA and isoleucyl-tRNA synthetases in a wide spectrum of species revealed vertical gene transmission from an archaeal root of life through a Primitive Archaea Cluster to an Ancestral Bacteria Cluster of species. The higher homologies of the ribosomal proteins (rProts) of eukaryotic Giardia toward archaeal relative to bacterial rProts established that an archaeal-parent rather than a bacterial-parent underwent genome merger with an alphaproteobacterium to generate Eukarya. Moreover, based on the top-ranked homology of the proteins of Aciduliprofundum among archaea toward the Giardia and Trichomonas proteomes and the pyruvate phosphate dikinase of Giardia, together with their active acquisition of exogenous bacterial genes plausibly through foodchain gene adoption, the Aciduliprofundum archaea were identified as leading candidates for the archaeal-parent of Eukarya.

evolutionary biology↗

bioRxiv2019

Nitric oxide acts as a cotransmitter in a subset of dopaminergic neurons to diversify memory dynamics

Animals employ multiple and distributed neuronal networks with diverse learning rules and synaptic plasticity dynamics to record distinct temporal and statistical information about the world. However, the molecular mechanisms underlying this diversity are poorly understood. The anatomically defined compartments of the insect mushroom body function as parallel units of associative learning, with different learning rates, memory decay dynamics and flexibility (Aso & Rubin 2016). Here we show that nitric oxide (NO) acts as a neurotransmitter in a subset of dopaminergic neurons in Drosophila. NOs effects develop more slowly than those of dopamine and depend on soluble guanylate cyclase in postsynaptic Kenyon cells. NO acts antagonistically to dopamine; it shortens memory retention and facilitates the rapid updating of memories. The interplay of NO and dopamine enables memories stored in local domains along Kenyon cell axons to be specialized for predicting the value of odors based only on recent events. Our results provide key mechanistic insights into how diverse memory dynamics are established in parallel memory systems.

neuroscience↗

bioRxiv2018

A novel somatosensory spatial navigation system outside the hippocampal formation

Spatially selective firing in the forms of place cells, grid cells, boundary vector/border cells and head direction cells are the basic building blocks of a canonical spatial navigation system centered on the hippocampal-entorhinal complex. While head direction cells can be found throughout the brain, spatial tuning outside the hippocampal formation are often non-specific or conjunctive to other representations such as a reward. Although the precise mechanism of spatially selective activities is not understood, various studies show sensory inputs (particularly vision) heavily modulate spatial representation in the hippocampal-entorhinal circuit. To better understand the contribution from other sensory inputs in shaping spatial representation in the brain, we recorded from the primary somatosensory cortex in foraging rats. To our surprise, we were able to identify the full complement of spatial activity patterns reported in the hippocampal-entorhinal network, namely, place cells, head direction cells, boundary vector/border cells, grid cells and conjunctive cells. These newly identified somatosensory spatial cell types form a spatial map outside the hippocampal formation and support the hypothesis that location information is necessary for body representation in the somatosensory cortex, and may be analogous to spatially tuned representations in the motor cortex relating to the movement of body parts. Our findings are transformative in our understanding of how spatial information is used and utilized in the brain, as well as functional operations of the somatosensory cortex in the context of rehabilitation with brain-machine interfaces.

neuroscience↗

bioRxiv2017

Forward-reverse mutation cycles between stages of cancer development

Earlier, prominent occurrences of interstitial loss-of-heterozygosities (LOHs) were found in different cancers as a type of single-nucleotide-variations (SNVs), at rates far exceeding those of the commonly investigated gain-of-heterozygosities (GOHs) type of SNVs. Herein, such co-occurrences of LOHs and GOHs were confirmed in 102 cases of four cancer types analyzed with three different next-generation sequencing platforms, comparing non-tumor, paratumor, and tumor tissues with white-blood-cell controls; and in 246 pan-cancer cases of whole-genome tumor-control pairs. Unexpectedly, large numbers of SNVs enriched with CG>TG GOHs and copy-number-variations (CNVs) proximal to these GOHs were detected in the non-tumor tissues, which were extensively reversed in paratumors showing prominent TG>CG LOHs with proximal CNVs, and less so in tumors to form forward-reverse mutation cycles. Lineage effects in the reversions, likely resulting from directional selection, supported a sequential rather than parallel mode of evolution as described in a Stage Specific Populations model of cancer development.

cancer biology↗

bioRxiv2016

Quantitative mRNA Imaging Throughout the Entire Drosophila Brain

We describe a fluorescence in situ hybridization method that permits detection of the localization and abundance of single mRNAs (smFISH) in cleared whole-mount adult Drosophila brains. The approach is rapid, multiplexable and does not require molecular amplification; it allows facile mRNA expression quantification with subcellular resolution on a standard confocal microscope. Using a custom Bessel Beam-Structured Illumination microscope (BB-SIM), we further demonstrate single-mRNA detection across the entire brain sample.

neuroscience↗