Biology subjects

Tan, J.

Publications and source records attributed to Tan, J..

At least 145 records · Page 8Linked to original sources

bioRxiv2021

Identify phage hosts from metaviromic short reads based on deep learning and Markov chain model

Phages - viruses that infect bacteria and archaea - are dominant in the virosphere and play an important role in the microbial community. It is very important to identify the host of a given phage fragment from metavriome data for understanding the ecological impact of phage in a microbial community. State-of-the-art tools for host identification only present reliable results on long sequences within a narrow candidate host range, while there are a large number of short fragments in real metagenomic data and the taxonomic composition of a microbial community is often complicated. Here, we present a method, named HoPhage, to identify the host of a given phage fragment from metavirome data at the genus level. HoPhage integrates two modules using the deep learning algorithms and the Markov chain model, respectively. By testing on both the artificial benchmark dataset of phage contigs and the real virome data, HoPhage demonstrates a satisfactory performance on short fragments within a wide candidate host range at every taxonomic level. HoPhage is freely available at http://cqb.pku.edu.cn/ZhuLab/HoPhage/.

bioinformatics↗

bioRxiv2021

Robust clustering and interpretation ofscRNA-seq data using reference componentanalysis

MotivationThe transcriptomic diversity of the hundreds of cell types in the human body can be analysed in unprecedented detail using single cell (SC) technologies. Though clustering of cellular transcriptomes is the default technique for defining cell types and subtypes, single cell clustering can be strongly influenced by technical variation. In fact, the prevalent unsupervised clustering algorithms can cluster cells by technical, rather than biological, variation. ResultsCompared to de novo (unsupervised) clustering methods, we demonstrate using multiple benchmarks that supervised clustering, which uses reference transcriptomes as a guide, is robust to batch effects. To leverage the advantages of supervised clustering, we present RCA2, a new, scalable, and broadly applicable version of our RCA algorithm. RCA2 provides a user-friendly framework for supervised clustering and downstream analysis of large scRNA-seq data sets. RCA2 can be seamlessly incorporated into existing algorithmic pipelines. It incorporates various new reference panels for human and mouse, supports generation of custom panels and uses efficient graph-based clustering and sparse data structures to ensure scalability. We demonstrate the applicability of RCA2 on SC data from human bone marrow, healthy PBMCs and PBMCs from COVID-19 patients. Importantly, RCA2 facilitates cell-type-specific QC, which we show is essential for accurate clustering of SC data from heterogeneous tissues. In the era of cohort-scale SC analysis, supervised clustering methods such as RCA2 will facilitate unified analysis of diverse SC datasets. AvailabilityRCA2 is implemented in R and is available at github.com/prabhakarlab/RCAv2

bioinformatics↗

bioRxiv2021

Two distinct types of nodes of Ranvier support auditory nerve function in the mouse cochlea

Glial cells of the auditory nerve regulate formation of the nodes of Ranvier that are needed for regeneration of action potentials and proper hearing function. Here we identify and describe the distinct features of two novel types of Ranvier nodes--the axonal node and the ganglion node--in the mouse auditory nerve that change across the lifespan, including during myelination and postnatal development, and degenerate during aging. Cellular, molecular, and structure-function correlation evaluations revealed that nodal types are critical for different aspects of auditory nerve function. Specifically, the length of the axonal node is associated with neural processing speed and neural synchrony, whereas ganglion node development is associated with amplitude growth of the action potential. Moreover, our data indicate that dysregulation of glial cells and associated degeneration of the ganglion node structure are an important and new mechanism of auditory nerve dysfunction in age-related hearing loss.

neuroscience↗

bioRxiv2021

LncRNA SNHG1 suppresses LPS-induced acute lung injury by regulating miR-421/TIMP3 axis

Extensive evidence has revealed the crucial roles of long non-coding RNAs (lncRNAs) in acute lung injury (ALI). This study aimed to explore the mechanism of lncRNA SNHG1 in lipopolysaccharides (LPS)-induced ALI. RT-qPCR was employed to test the levels of SNHG1, miR-421 and TIMP3 in A549 cells. Cell viability and apoptosis were assessed by CCK-8 assay and flow cytometry. ELISA assay was adopted to examine the levels of inflammatory-related cytokines, including IL-1{beta}, IL-6 and TNF-. The binding sequences of miR-421 and SNHG1 or TIMP3 were predicted using starBase software. Then dual-luciferase reporter and RIP assays were adopted to verify the interaction between miR-421 and SNHG1 or TIMP3. The protein level of TIMP3 was measured by western blotting. It was found that LPS stimulation downregulated SNHG1 level and SNHG1 addition decreased viability, and induced apoptosis as well as promoted inflammatory responses in LPS-treated A549 cells. SNHG1 could sponge miR-421 and SNHG1 protected A549 cells from LPS-induced injury via inhibiting miR-421. Moreover, TIMP3 was a target of miR-421. MiR-421 silence protected A549 cells against the LPS-triggered inhibition in viability, and promotion in apoptosis and inflammatory responses. SNHG1 could upregulate TIMP3 through acting as a ceRNA of miR-421 in A549 cells. Altogether, the present study elaborated that SNHG1 inhibited LPS-stimulated ALI by modulating the miR-421/TIMP3 axis.

immunology↗

bioRxiv2021

Cooperative Communication with Humans Evolved to Emerge Early in Dogs

While we know that dogs evolved from wolves through a process of domestication, it remains unclear how this process may have affected dog cognitive development. Here we tested dog (N=44) and wolf (N=37) puppies, 5-18 weeks old, on a battery of temperament and cognition tasks. Dog puppies were more attracted to humans, read human gestures more skillfully and made more eye contact with humans than wolf puppies. The two species were similarly attracted to objects and performed similarly on nonsocial measures of memory and inhibitory control. These results demonstrate the role of domestication in enhancing the cooperative communication skills of dogs through selection on attraction to humans, which altered developmental pathways. One Sentence Summary Domestication altered dogs developmental pathways to enhance their cooperative communication with humans.

animal behavior and cognition↗

bioRxiv2020

Distinguish virulent and temperate phage-derived sequences in metavirome data with a deep learning approach

BackgroundProkaryotic viruses referred to as phages can be divided into virulent and temperate phages. Distinguishing virulent and temperate phage-derived sequences in metavirome data is important for their role in interactions with bacterial hosts and regulations of microbial communities. However there is no experimental or computational approach to classify sequences of these two in culture-independent metavirome effectively, we present a new computational method DeePhage, which can directly and rapidly judge each read or contig as a virulent or temperate phage-derived fragment. FindingsDeePhage utilizes a "one-hot" encoding form to have an overall and detailed representation of DNA sequences. Sequence signatures are detected via a deep learning algorithm, namely a convolutional neural network to extract valuable local features. DeePhage makes better performance than the most related method PHACTS. The accuracy of DeePhage on five-fold validation reach as high as 88%, nearly 30% higher than PHACTS. Evaluation on real metavirome shows DeePhage annotated 54.4% of reliable contigs while PHACTS annotated 44.5%. While running on the same machine, DeePhage reduces computational time than PHACTS by 810 times. Besides, we proposed a new strategy to explore phage transformations in the microbial community by direct detection of the temperate viral fragments from metagenome and metavirome. The detectable transformation of temperate phages provided us a new insight into the potential treatment for human disease. ConclusionsDeePhage is the first tool that can rapidly and efficiently identify two kinds of phage fragments especially for metagenomics analysis with satisfactory performance. DeePhage is freely available via http://cqb.pku.edu.cn/ZhuLab/DeePhage or https://github.com/shufangwu/DeePhage.

bioinformatics↗

bioRxiv2020

Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis

Genetic loss of function (LOF) in IL11RA infers IL11 signaling as important for fertility, fibrosis, inflammation and craniosynostosis. The impact of genetic LOF in IL11 has not been characterized. We generated IL11-knockout (Il11-/-) mice, which are born in normal Mendelian ratios, have normal hematological profiles and are protected from bleomycin-induced lung fibro-inflammation. Noticeably, baseline IL6 levels in the lungs of Il11-/- mice are lower than those of wild-type mice and are not induced by bleomycin damage, placing IL11 upstream of IL6. Lung fibroblasts from Il11-/- mice are resistant to pro-fibrotic stimulation and show evidence of reduced autocrine IL11 activity. Il11-/- female mice are infertile. Unlike Il11ra1-/- mice, Il11-/- mice do not have a craniosynostosis-like phenotype and exhibit mildly reduced body weights. These data highlight similarities and differences between LOF in IL11 or IL11RA while establishing further the role of IL11 signaling in fibrosis and stromal inflammation.

molecular biology↗

bioRxiv2020

Dietary protein increases T cell independent sIgA production through changes in gut microbiota-derived extracellular vesicles

Secretory IgA (sIgA) is a key mucosal component ensuring host-microbiota mutualism. Using nutritional geometry modelling in mice fed 10 different macronutrient-defined, isocaloric diets, we identified dietary protein as the major driver of sIgA production. Protein-driven sIgA induction was not mediated by T cell-dependent pathways or changes in gut microbiota composition. Instead, the microbiota of high-protein fed mice produced significantly higher quantities of extracellular vesicles (EV), compared to those of mice fed high-carbohydrate or high-fat diets. These EV activated TLR4 to increase the epithelial expression of IgA-inducing cytokine, APRIL, B cell chemokine, CCL28, and the IgA transporter, PIGR. We showed that succinate, produced in high concentrations by microbiota of high-protein fed animals, increased the generation of reactive oxygen species by bacteria, which in turn promoted EV production. This is the first report establishing a causal link between dietary macronutrient composition, gut microbial EV release and host sIgA response.

immunology↗

bioRxiv2020

Higher-order sensorimotor circuit of the brain' global network supports human consciousness

The neural correlates of consciousness, defined as the minimum neuronal mechanisms sufficient for any conscious percept, are usually subject to different interpretations depending on whether one uses measures of local or global brain activities. We argue that the local regions may support consciousness by serving as hubs within the brains global network. We adopt a unique functional magnetic resonance imaging resting state dataset that encompasses various conscious states, including non-rapid eye movement (NREM)-sleep, rapid eye movement (REM)-sleep, anesthesia, and brain injury patients. Using a graph-theoretical measure for detecting local hubs within the brains global network, we identify various higher-order sensory and motor regions as hubs with significantly reduced degree centrality during unconsciousness. Additionally, these regions form a sensorimotor circuit which correlates with levels of consciousness. Our findings suggest that integration of higher-order sensorimotor function may be a key mechanism of consciousness. This opens novel perspectives for therapeutic modulation of unconsciousness.

neuroscience↗

bioRxiv2020

An Easy-to-Fabricate Cell Stretching System Reveals Density-Dependent Mechanical Regulation of Collective Cell Movements in Epithelial Homeostasis

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSIntroductionC_ST_ABSMechanical forces regulate many facets of cell and tissue biology. Studying the effects of forces on cells requires real-time observations of single- and multi-cell dynamics in tissue models during controlled external mechanical input. Many of the existing devices used to conduct these studies are costly and complicated to fabricate, which reduces the availability of these devices to many laboratories. MethodsWe show how to fabricate a simple, low-cost, uniaxial stretching device, with readily available materials and instruments that is compatible with high-resolution time-lapse microscopy of adherent cell monolayers. In addition, we show how to construct a pressure controller that induces a repeatable degree of stretch in monolayers, as well as a custom MATLAB code to quantify individual cell strains. ResultsAs an application note using this device, we show that uniaxial stretch slows down cellular movements in a mammalian epithelial monolayer in a cell density-dependent manner. We demonstrate that the effect on cell movement involves the relocalization of myosin downstream of Rho-associated protein kinase (ROCK). ConclusionsThis mechanical device provides a platform for broader involvement of engineers and biologists in this important area of cell and tissue biology. We used this device to demonstrate the mechanical regulation of collective cell movements in epithelia.

bioengineering↗

bioRxiv2020

Visual Perception in the Periphery: The Role of Covert Attention Vectors in the Extraction of Semantic Information

Under covert attention, our visual perception deteriorates dramatically as eccentricity increases. This reduction of peripheral visual acuity (PVA) is partially due to the coarse sampling of the retinal ganglion cells towards the periphery, but this property cannot be solely responsible. Other factors, such as character crowding, have been studied, yet the origin of the poor PVA is not entirely understood. This gap motivated us to investigate the PVA by varying the crowding conditions systematically. Under completely crowded conditions (i.e. resembling a full page of text), PVA was observed to be eight times worse than the PVA under uncrowded conditions. By partially crowding the periphery, we obtained PVA values between the fully crowded and uncrowded conditions. On the other hand, crowding the fovea center while leaving the periphery uncrowded improved PVA relative to the uncrowded case. These results support a model for a top-down "covert attention vector" that assists the resulting PVA in a manner analogous to saccadic eye movement for overt attention. We speculate that the attention vector instructs the dorsal pathway to transform the peripheral character to the foveal center. Then, the scale-invariant log-polar retinotopy of the ventral pathway can scale the centered visual input to match the prior memory of the specific character shape.

neuroscience↗

bioRxiv2020

Intrinsic neural timescales related to sensory processing: Evidence from abnormal behavioural states

The brain exhibits a complex temporal structure which translates into a hierarchy of distinct neural timescales. An open question is how these intrinsic timescales are related to sensory or motor information processing and whether these dynamics have common patterns in different behavioural states. We address these questions by investigating the brains intrinsic timescales in healthy controls, motor (amyotrophic lateral sclerosis, locked-in syndrome), sensory (anaesthesia, unresponsive wakefulness syndrome), and progressive reduction of sensory processing (from awake states over N1, N2, N3). We employed a combination of measures from EEG resting-state data: auto-correlation window (ACW), power spectral density (PSD), and power-law exponent (PLE). Prolonged neural timescales accompanied by a shift towards slower frequencies were observed in the conditions with sensory deficits, but not in conditions with motor deficits. Our results establish that the spontaneous activitys intrinsic neural timescale is related to specifically sensory rather than motor information processing in the healthy brain. HighlightsO_LIEEG resting-state shows a hierarchy of intrinsic neural timescales. C_LIO_LISensory deficits as in disorders of consciousness lead to prolonged intrinsic neuraltimescales. C_LIO_LIClinical conditions with motor deficits do not show changes in intrinsic neural timescales.20 C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/229161v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1893c45org.highwire.dtl.DTLVardef@d4176dorg.highwire.dtl.DTLVardef@4dfaa8org.highwire.dtl.DTLVardef@183621e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Proteomic analysis identifies the E3 ubiquitin ligase Pdzrn3 as a regulatory target of Wnt5a-Ror signaling

Wnt5a-Ror signaling is a conserved pathway that regulates morphogenetic processes during vertebrate development, but its downstream signaling events remain poorly understood. Through a large-scale proteomic screen in mouse embryonic fibroblasts, we identified the E3 ubiquitin ligase Pdzrn3 as a regulatory target of the Wnt5a-Ror pathway. Upon pathway activation, Pdzrn3 is degraded in a {beta}-catenin-independent, ubiquitin-proteasome system-dependent manner. We developed a flow cytometry-based reporter to monitor Pdzrn3 abundance and delineated a signaling cascade involving Frizzled, Dishevelled, CK1, and GSK3 that regulates Pdzrn3 stability. Epistatically, Pdzrn3 is regulated independently of Kif26b, another Wnt5a-Ror effector. Wnt5a-dependent degradation of Pdzrn3 requires phosphorylation of three conserved amino acids within its C-terminal LNX3H domain, which acts as a bona fide Wnt5a-responsive element. Importantly, this phospho-dependent degradation is essential for Wnt5a-Ror modulation of cell migration. Collectively, this work establishes a new Wnt5a-Ror cell morphogenetic cascade involving Pdzrn3 phosphorylation and degradation.

developmental biology↗

bioRxiv2020

Maladaptive nutrient signalling sustains the m.3243A>G mtDNA mutation

Mutations of the mitochondrial genome (mtDNA) cause a range of profoundly debilitating clinical conditions for which treatment options are very limited. Most mtDNA diseases show heteroplasmy - tissues express both wild-type and mutant mtDNA. While the level of heteroplasmy broadly correlates with disease severity, the relationships between specific mtDNA mutations, heteroplasmy, disease phenotype and severity are poorly understood. We have carried out extensive bioenergetic, metabolomic and RNAseq studies on heteroplasmic patient derived cells carrying the most prevalent disease related mtDNA mutation, m.3243A>G. These studies reveal that the mutation promotes changes in metabolites which is associated with the upregulation of the PI3K-Akt-mTORC1 axis in patient-derived cells and tissues. Remarkably, pharmacological inhibition of PI3K, Akt, or mTORC1 activated mitophagy, reduced mtDNA mutant load and rescued cellular bioenergetic function. The rescue was prevented by inhibition of mitophagy. The PI3K-Akt-mTORC1 axis thus represents a potential therapeutic target that may benefit people suffering from the consequences of the m.3243A>G mutation.

cell biology↗

bioRxiv2020

A targeted e-learning approach to reduce student mixing during a pandemic

The COVID-19 pandemic has resulted in widespread closure of schools and universities. These institutions have turned to distance learning to provide educational continuity. Schools now face the challenge of how to reopen safely and resume in-class learning. However, there is little empirical evidence to guide decision-makers on how this can be achieved. Here, we show that selectively deploying e-learning for larger classes is highly effective at decreasing campus-wide opportunities for student-to-student contact, while allowing most in-class learning to continue uninterrupted. We conducted a natural experiment at a large university that implemented a series of e-learning interventions during the COVID-19 outbreak. Analyses of >24 million student connections to the university Wi-Fi network revealed that population size can be manipulated by e-learning in a targeted manner according to class size characteristics. Student mixing showed accelerated growth with population size according to a power law distribution. Therefore, a small e-learning dependent decrease in population size resulted in a large reduction in student clustering behaviour. Our results show that e-learning interventions can decrease potential for disease transmission while minimizing disruption to university operations. Universities should consider targeted e-learning a viable strategy for providing educational continuity during early or late stages of a disease outbreak.

scientific communication and education↗

bioRxiv2020

scConsensus: combining supervised and unsupervised clustering for cell type identification in single-cell RNA sequencing data

Clustering is a crucial step in the analysis of single-cell data. Clusters identified using unsupervised clustering are typically annotated to cell types based on differentially expressed genes. In contrast, supervised methods use a reference panel of labelled transcriptomes to guide both clustering and cell type identification. Supervised and unsupervised clustering strategies have their distinct advantages and limitations. Therefore, they can lead to different but often complementary clustering results. Hence, a consensus approach leveraging the merits of both clustering paradigms could result in a more accurate clustering and a more precise cell type annotation. We present O_SCPLOWSCC_SCPLOWCO_SCPLOWONSENSUSC_SCPLOW, an R framework for generating a consensus clustering by (i) integrating the results from both unsupervised and supervised approaches and (ii) refining the consensus clusters using differentially expressed (DE) genes. The value of our approach is demonstrated on several existing single-cell RNA sequencing datasets, including data from sorted PBMC sub-populations. O_SCPLOWSCC_SCPLOWCO_SCPLOWONSENSUSC_SCPLOW is freely available on GitHub at https://github.com/prabhakarlab/scConsensus.

bioinformatics↗

bioRxiv2020

Plasmodium falciparum-specific IgM B cells dominate in children, expand with malaria and produce parasite inhibitory IgM

IgG antibodies are known to play a central role in naturally acquired immunity to blood-stage malaria in humans, but little is known about the IgM response to blood-stage malaria, the mechanisms by which IgM may protect, or the underlying biology of Plasmodium falciparum (Pf)-specific IgM B cells. In a Mali cohort spanning infants to adults we conducted a longitudinal analysis of B cells specific for the Pf blood-stage antigens AMA1 and MSP1, as well as the comparator antigen influenza hemagglutinin (HA). At the uninfected baseline, before the malaria season, Pf-specific memory B cells (MBCs) in children are disproportionally IgM+ and only gradually shift to IgG+ with age, in contrast to HA-specific MBCs that are predominantly IgG+ from infancy to adulthood. In response to acute febrile malaria, Pf-specific IgM B cells increase in frequency and upregulate activation and co-stimulatory markers. B cell receptor (BCR) analysis showed that Pf-specific IgM B cells are somatically hypermutated at levels comparable to HA-specific IgG B cells. Finally, IgM antibodies from the plasma of malaria-exposed individuals were comparable to IgG in inhibiting Pf blood-stage growth in vitro, and significantly better at enhancing phagocytosis of Pf merozoites, suggesting that IgM may protect through both direct neutralization and opsonization. Thus, somatically hypermutated Pf-specific IgM MBCs dominate in early life, are activated and expand during acute malaria and are associated with plasma IgM that inhibits parasite growth in vitro.

immunology↗

bioRxiv2020

Distinct trends in chemical composition of proteins from metagenomes in redox and salinity gradients

Thermodynamic influences on the chemical compositions of proteins have remained enigmatic despite much work that demonstrates the impact of environmental conditions on amino acid frequencies. Here, we show that the dehydrating effect of salinity is apparent in protein sequences inferred from metagenomes and metatranscriptomes. The stoichiometric hydration state (nH2O), derived from the number of water molecules in theoretical reactions to form proteins from a particular set of basis species (glutamine, glutamic acid, cysteine, O2, H2O), decreases along salinity gradients including the Baltic Sea, Amazon River and ocean plume, and other samples from freshwater and marine environments. Analysis of other metagenomic datasets shows that differences in carbon oxidation state, rather than stoichiometric hydration state, are a stronger indicator of redox gradients than salinity gradients. These compositional metrics can help to identify thermodynamic effects in the distribution of proteins along chemical gradients at scales from geologic systems to cells.

biochemistry↗