Biology subjects

Pan, Y.

Publications and source records attributed to Pan, Y..

At least 235 records · Page 13Linked to original sources

bioRxiv2020

Skin Delivery of Modified Vaccinia Ankara Viral Vectors Generates Superior T Cell Immunity Against a Respiratory Viral Challenge

Modified Vaccinia Ankara (MVA) was recently approved as a Smallpox vaccine. Transmission of Variola is by respiratory droplets, and MVA delivered by skin scarification (s.s.) protected mice far more effectively against lethal respiratory challenge with VACV than any other route of delivery, and at much lower doses. Comparisons of s.s. with intradermal, subcutaneous or intramuscular routes showed that MVAOVA s.s.-generated T cells were both more abundant and transcriptionally distinct. MVAOVA s.s. produced greater numbers of lung Ova-specific CD8+ TRM and was superior in protecting mice against lethal VACVOVA respiratory challenge. Nearly as many lung TRM were generated with MVAOVA s.s. compared to direct pulmonary immunization with MVAOVA, and both routes vaccination protected mice against lethal pulmonary challenge with VACVOVA. Strikingly, MVAOVA s.s.-generated effector T cells exhibited overlapping gene transcriptional profiles to those generated via direct pulmonary immunization. Overall, our data suggest that heterologous MVA vectors delivered via s.s. are uniquely well-suited as vaccine vectors for respiratory pathogens like COVID-19. In addition, MVA delivered via s.s. could represent a more effective dose-sparing smallpox vaccine.

immunology↗

bioRxiv2020

Repurposing low-molecular-weight drugs against the main protease of SARS-CoV-2

The coronavirus disease (COVID-19) pandemic caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected the global healthcare system. Drug repurposing is a feasible method for emergency treatment. As low-molecular-weight drugs have high potential to completely match interactions with essential SARS-CoV-2 targets, we propose a strategy to identify such drugs using the fragment-based approach. Herein, using ligand- and protein-observed fragment screening approaches, we identified niacin and hit 1 binding to the catalytic pocket of the main protease of the SARS-CoV-2 (Mpro), thereby modestly inhibiting the enzymatic activity of Mpro. Chemical shift perturbations induced by niacin and hit 1 indicate a partial overlap of their binding sites, i.e., the catalytic pocket of Mpro may accommodate derivatives with large molecular sizes. Therefore, we searched for drugs containing niacin or hit 1 pharmacophores and identified carmofur, bendamustine, triclabendazole, and emedastine; these drugs are highly capable of inhibiting protease activity. Our study demonstrates that the fragment-based approach is a feasible strategy for identifying low-molecular-weight drugs against the SARS-CoV-2 and other potential targets lacking specific drugs.

biochemistry↗

bioRxiv2020

Shared safety abolishes the recovery of learned threat

Social learning offers an efficient route to transmit information about threat and safety. To better isolate the processes that contribute to the efficacy of social safety learning, we developed a novel dyadic model of associative threat and extinction learning. In three separate social groups, we manipulated whether safety information during extinction was acquired via direct exposure to the conditioned stimulus (CS) in the presence of another individual (Direct exposure), via observation of other’s safety behavior (Vicarious exposure), or via the combination of both (Shared exposure). These groups were contrasted against a fourth group receiving direct CS exposure alone (Asocial exposure). Based on skin conductance responses, we observed that all social groups outperformed asocial learning in inhibiting the recovery of threat, but only Shared exposure abolished threat recovery. These results suggest that social safety learning is optimized by a combination of direct exposure and vicariously transmitted safety signals.Statement of relevance Humans, like other social animals, learn about threats and safety in the environment through social cues. Yet, the processes that contribute to the efficacy of social safety learning during threat transmission remain unknown. Here, we used a two-person approach to analyze skin conductance responses as participants engaged in a standard fear conditioning procedure (acquisition, extinction, and reinstatement). We found that during extinction, both (i) direct (conditioned stimulus) exposure in the presence of another individual and (ii) vicarious safety signals alone is sufficient to inhibit subsequent threat recovery, but that abolishing the recovery of conditioned threat responses requires a combination of both. This study has relevance for understanding how social information can optimize standard, asocial safety learning procedures to augment the effects of exposure on previously acquired fears. Thus, our work might help identify psychological and social strategies that can be used to counteract maladaptive fears in humans.Competing Interest StatementThe authors have declared no competing interest.View Full Text

physiology↗

bioRxiv2020

Conformational Selection in Ligand Recognition by the First Tudor Domain of PHF20L1

The first Tudor domain of PHF20L1 (PHF20L1 Tudor1) recognizes both histone methylation and non-histone methylation to play versatile roles, e.g., PHF20L1 Tudor1 binds to the oncogenic target DNA (cytosine-5) methyltransferase 1 (DNMT1) to prevent it from degradation. However, the crystal structure of the PHF20 Tudor domain, a homolog of PHF20L1, reveals a closed aromatic cage of the Tudor domain. It is thus highly desirable to interrogate the ligand-recognition mechanism of PHF20L1 Tudor1, which will in turn validate the potential druggability of this target. Here, we solved the crystal structure of the free form PHF20L1 Tudor1, which adopts the closed conformation similar to PHF20. NMR relaxation dispersion and molecular dynamics (MD) simulations suggest a pre-existing low-population conformation with a remarkable rearrangement of aromatic cage residues. Such structural rearrangement is further revealed by the crystal structures of PHF20L1 Tudor1 in complex with the lysine 142 methylated (K142me1) DNMT1, and a small molecule cosolvent 2-(N-morpholino)ethanesulfonic acid (MES), respectively. This result thus ignites interest in the discovery of small molecule inhibitors against PHF20L1 Tudor1. The hit identified from NMR fragment-based screening protrudes into the same open form aromatic cage of PHF20L1 Tudor1, and blocks the interaction between PHF20L1 Tudor1 and methylated DNMT1. Further free form crystal structures of key mutants reveal one open form and one closed form aromatic cage, which is energetically trapped observed in the NMR relaxation dispersion and MD simulations. The binding of DNMT1 with PHF20L1 Tudor1 mutants was also recapitulated in cancer cells. The mutagenesis thus alters the structure, dynamics and eventually the function of PHF20L1 Tudor1. Our results demonstrate that PHF20L1 Tudor1 utilizes the same conformational selection mechanism to recognize ligands, regardless of whether it is a natural substrate or a small molecule identified from fragment-based screening. Albeit at a low population, the pre-existing ligand-binding conformation shall shift the paradigm in the druggability assessment of a dynamic protein, even though it may lack a small molecule binding pocket in its free form structure. The inhibition of PHF20L1 paves an alternative way to target DNMT1 degradation.

biochemistry↗

bioRxiv2020

Expanding magnetic organelle biogenesis in the domain Bacteria

The discovery of membrane-enclosed, metabolically functional organelles in Bacteria and Archaea has transformed our understanding of the subcellular complexity of prokaryotic cells. However, whether prokaryotic organelles emerged early or late in evolutionary history remains unclear and limits understanding of the nature and cellular complexity of early life. Biomineralization of magnetic nanoparticles within magnetosomes by magnetotactic bacteria (MTB) is a fascinating example of prokaryotic organelles. Here, we reconstruct 168 metagenome-assembled MTB genomes from various aquatic environments and waterlogged soils. These genomes represent nearly a 3-fold increase over the number currently available, and more than double the known MTB species. Phylogenomic analysis reveals that these newly described genomes belong to 13 Bacterial phyla, six of which were previously not known to include MTB. These findings indicate a much wider taxonomic distribution of magnetosome organelle biogenesis across the domain Bacteria than previously thought. Comparative genome analysis reveals a vast diversity of magnetosome gene clusters involved in magnetosomal biogenesis in terms of gene content and synteny residing in distinct taxonomic lineages. These gene clusters therefore represent a promising, diverse genetic resource for biosynthesizing novel magnetic nanoparticles. Finally, our phylogenetic analyses of the core magnetosome proteins in this largest available and taxonomically diverse dataset support an unexpectedly early evolutionary origin of magnetosome biomineralization, likely ancestral to the origin of the domain Bacteria. These findings emphasize the potential biological significance of prokaryotic organelles on the early Earth and have important implications for our understanding of the evolutionary history of cellular complexity.

microbiology↗

bioRxiv2020

Interpersonal brain synchronization with instructor compensates for learner's sleep deprivation in interactive learning

Recent advances shifted the focus on single-brain functioning toward two-brain communication during learning interactions, following the demonstration that interpersonal brain synchronization (IBS) can track instructor-learner information exchange. Here, we investigated (i) whether sleep deprivation (SD) that potentially impacts both social interactions and learning abilities modulates IBS, and (ii) conversely whether and to what extent IBS might compensate for SD-related learning deficits. Instructors (always with regular sleep, RS) were asked to teach numerical reasoning strategies to learners (either SD or RS), during which the activity of both brains was simultaneously recorded using functional near-infrared spectroscopy (fNIRS). SD learners initially performed below their baseline level, worse than RS learners, but learning improvement was comparable between RS and SD conditions after learning with the instructor. IBS within the instructor-learner dyads was higher in the SD (vs. RS) condition in the left inferior frontal cortex. In addition, clustered IBS (estimated by nonnegative matrix factorization) was correlated with performance improvement. Finally, Granger Causality analyses revealed biased causality with higher instructor-to-learner than learner-to-instructor directionality in brain signal processing. Together, these results indicate that SD-related learning deficits can to some extent be compensated via interactions with an instructor, as reflected by increased IBS and preserved learning ability. It suggests an essential role of the instructor in driving synchrony between teaching and SD learning brains during interactions.

neuroscience↗

bioRxiv2020

Structure and mechanism of a primate ferroportin

Ferroportin is the only cellular iron exporter in human and essential for iron homoeostasis. Mutations in ferroportin are associated with hemochromatosis or ferroportin diseases characterized by a paradoxical combination of anemia and abnormal accumulation of iron in cells. Ferroportin is also the target of hepcidin, which is a hormone that downregulates ferroportin activity. However, due to a lack of three-dimensional structures, the mechanism of iron transport by ferroportin and its regulation by hepcidin remains unclear. Here we present the structure of a ferroportin from the primate Philippine tarsier (TsFpn) at 3.0 [A] resolution determined by cryo-electron microscopy. TsFpn has a structural fold common to major facilitator superfamily of transporters and the current structure is in an outward-open conformation. The structure identifies two potential ion binding sites with each site coordinated by two residues. Functional studies demonstrate that TsFpn is a H+/Fe2+ antiporter and that transport of one Fe2+ is coupled to the transport of two H+ in the opposite direction such that the transport cycle is electroneutral. Further studies show that the two ion binding sites affect transport of H+ and Fe2+ differently. The structure also provides mechanistic interpretation for mutations that cause ferroportin diseases.

biochemistry↗

bioRxiv2020

Acoustogenetic Control of CAR T Cells via Focused Ultrasound

Optogenetics can control specific molecular events in living systems, but the penetration depth of light is typically limited at hundreds of micrometers. Focused ultrasound (FUS), on the other hand, can deliver energy safely and noninvasively into tissues at depths of centimeters. Here we have developed an acoustogenetic approach using short-pulsed FUS to remotely and directly control the genetics and cellular functions of engineered mammalian cells for therapeutic purposes. We applied this acoustogenetic approach to control chimeric antigen receptor (CAR) T cells with high spatiotemporal precision, aiming to mitigate the potentially lethal "on-target off-tumor" effects of CAR T cell therapy. We first verified the controllability of our acoustogenetic CAR T cells in recognizing and killing tumor cells in vitro, and then applied this approach in vivo to suppress tumor growth of both lymphoma and prostate cancers. The results indicate that FUS-based acoustogenetics can allow the noninvasive and remote activation, without any exogenous cofactor, of different types of CAR T cells for cancer therapeutics.

bioengineering↗

bioRxiv2020

To improve the predictions of binding residues with DNA, RNA, carbohydrate, and peptide via multiple-task deep neural networks

MotivationThe interactions of proteins with DNA, RNA, peptide, and carbohydrate play key roles in various biological processes. The studies of uncharacterized protein-molecules interactions could be aided by accurate predictions of residues that bind with partner molecules. However, the existing methods for predicting binding residues on proteins remain of relatively low accuracies due to the limited number of complex structures in databases. As different types of molecules partially share chemical mechanisms, the predictions for each molecular type should benefit from the binding information with other molecules types. ResultsIn this study, we employed a multiple task deep learning strategy to develop a new sequence-based method for simultaneously predicting binding residues/sites with multiple important molecule types named MTDsite. By combining four training sets for DNA, RNA, peptide, and carbohydrate-binding proteins, our method yielded accurate and robust predictions with AUC values of 0.852, 0836, 0.758, and 0.776 on their respective independent test sets, which are 0.52 to 6.6% better than other state-of-the-art methods. More importantly, this study provides a new strategy to improve predictions by combining multiple similar tasks. Availabilityhttp://biomed.nscc-gz.cn/server/MTDsite/ Contactyangyd25@mail.sysu.edu.cn

bioinformatics↗

bioRxiv2020

Altered Temporal Variability of Local and Large-scale Resting-state Brain Functional Connectivity Patterns in Schizophrenia and Bipolar Disorder

Schizophrenia and bipolar disorder share some common clinical features and are both characterized by aberrant resting-state functional connectivity (FC). However, little is known about the common and specific aberrant features of the dynamic FC patterns in these two disorders. In this study, we explored the differences in dynamic FC among schizophrenia patients (n = 66), type I bipolar disorder patients (n = 53) and healthy controls (n = 66), by comparing temporal variabilities of FC patterns involved in specific brain regions and large-scale brain networks. Compared with healthy controls, both patient groups showed significantly increased regional FC variabilities in subcortical areas including the thalamus and basal ganglia, as well as increased inter-network FC variability between the thalamus and sensorimotor areas. Specifically, more widespread changes were found in the schizophrenia group, involving increased FC variabilities in sensorimotor, visual, attention, limbic and subcortical areas at both regional and network levels, as well as decreased regional FC variabilities in the default-mode areas. The observed alterations shared by schizophrenia and bipolar disorder may help to explain their overlapped clinical features; meanwhile, the schizophrenia-specific abnormalities in a wider range may support that schizophrenia is associated with more severe functional brain deficits than bipolar disorder.

neuroscience↗

bioRxiv2020

Alteration of fecal microbial compositions and bacterial taxa in female osteoporotic patients

BackgroundGut microbiota, mainly characterized by fecal bacterial compositions, affects human immune system and pathophysiological development. Our aim was to measure the quantitative differences of fecal bacterial compositions between osteoporotic patients and healthy subjects, and to identify novel bacterial taxa that speculate the incidence of osteoporosis in female. MethodWe recruited 104 female subjects, including 45 osteoporotic individuals and 59 healthy control. Fecal samples were collected for further analysis by 16S rRNA quantitative arrays and bioinformatics analysis. ResultsAnalyses of - and {beta}-diversity demonstrated that the diversity and composition of fecal bacterial compositions were both significant different in osteoporosis group, as compared with healthy group. Multiple bacterial genera were significantly increased (e.g., Roseburia and Bacteroides) or decreased (e.g., Streptococcus and Dorea) in the osteoporotic cases. Furthermore, the osteoporosiscould be efficiently determined by the random forest model based on differential taxa (area under ROC curve = 0.93). ConclusionThere were obvious different fecal microbial characteristics between female osteoporosis and healthy subjects. These findings provided evidence for understanding the host-gut microbiota interplay in female osteoporosis, and supported clinical applications of gut microbiota analysis for female osteoporosis diagnosis

microbiology↗

bioRxiv2019

Strategy in wheat-Fusarium dual-genome RNA-seq data processing

In RNA-seq data processing, short read alignments are usually of one species against its own genome; however, in plant-microbe interaction systems, reads from both host and pathogen samples are blended together. In contrast to single-genome, both pathogen and host reference genomes are involved in the alignment process. In such circumstances, the order of alignment to the host, the pathogen, or simultaneously to both genomes results in differences in read counts of certain genes, especially at the advanced infection stage. It is crucial to have an appropriate strategy for aligning the reads to their respective genomes, yet the existing strategies of either sequential or parallel alignment become a problem when mapping mixed reads to their corresponding reference genomes. The challenge lies in the determination of which reads belong to which species, especially when homology exists between the two genomes. This study proposes a combo-genome alignment strategy after comparing three alignment scenarios. Simulation results demonstrated that the degree of discrepancy in the results is correlated with phylogenetic distance of the two species in the mixture which was attributable to the extent of homology between the two genomes involved. This correlation was also found in the analysis using two real RNA-seq datasets of Fusarium-challenged wheat plants. Comparisons of the three RNA-seq processing strategies on three simulation datasets and two real Fusarium-infected wheat datasets showed that an alignment to a combo-genome, consisting of both host and pathogen genomes, improves mapping quality as compared to sequential alignment procedures.

bioinformatics↗

bioRxiv2019

Sensing Traction Force on Matrix Induces Cell-Cell Distant Mechanical Communications for Self-assembly

The long-range biomechanical force propagating across large scale may reserve the capability to trigger coordinative responses within cell population such as during angiogenesis, epithelial tubulogenesis, and cancer metastasis. How cells communicate in a distant manner within the group for self-assembly remains largely unknown. Here we found that airway smooth muscle cells (ASMCs) rapidly self-assembled into well-constructed network on 3D Matrigel containing type I collagen (COL), which relied on long-range biomechanical force across the matrix to direct cell-cell distant interactions. Similar results happened by HUVEC cells to mimic angiogenesis. Interestingly, single ASMCs initiated multiple extended protrusions precisely pointing to neighboring cells in distance, depending on traction force sensing. Separate ASMCs sensed each other to move directionally on both non-fibrous Matrigel and more efficiently when containing fibrous COL, but lost mutual sensing on fixed gel or coated glass due to no long-range force transmission. Beads tracking assay demonstrated distant transmission of traction force, and finite element method modeling confirmed the consistency between maximum strain distribution on matrix and cell directional movements in experiments. Furthermore, ASMCs recruited COL from the hydrogel to build fibrous network to mechanically stabilize cell network. Our results revealed for the first time that cells can sense traction force transmitted through the matrix to initiate cell-cell distant mechanical communications, resulting in cell directional migration and coordinative self-assembly with active matrix remodeling. As an interesting phenomenon, cells sound able to make phone call via long-range biomechanics, which implicates physiological importance such as for tissue pattern formation.

biophysics↗

bioRxiv2019

IRIS: Big data-informed discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing

Aberrant alternative splicing (AS) is widespread in cancer, leading to an extensive but largely unexploited repertoire of potential immunotherapy targets. Here we describe IRIS, a computational platform leveraging large-scale cancer and normal transcriptomics data to discover AS-derived tumor antigens for T-cell receptor (TCR) and chimeric antigen receptor T-cell (CAR-T) therapies. Applying IRIS to RNA-Seq data from 22 glioblastomas resected from patients, we identified candidate epitopes and validated their recognition by patient T cells, demonstrating IRISs utility for expanding targeted cancer immunotherapy.

bioinformatics↗

bioRxiv2019

Retinal ganglion cells harboring the OPTN(E50K) glaucoma mutation exhibit neurodegenerative phenotypes when derived from hPSC-derived three dimensional retinal organoids

Retinal ganglion cells (RGCs) serve as the primary connection between the eye and the brain, with this connection disrupted in glaucoma. Numerous cellular mechanisms have been associated with glaucomatous neurodegeneration, and useful models of glaucoma allow for the precise analysis of degenerative phenotypes. Human pluripotent stem cells (hPSCs) serve as powerful tools for studying human neurodegenerative diseases, particularly cellular mechanisms underlying degeneration. Thus, efforts were initially focused upon the use of hPSCs with an E50K mutation in the Optineurin (OPTN) gene. CRISPR/Cas9 gene editing was used to introduce the OPTN(E50K) mutation into existing lines of hPSCs, as well as the generation of isogenic control lines from OPTN(E50K) patient-derived hPSC lines. OPTN(E50K) RGCs exhibited numerous neurodegenerative deficits, including neurite retraction, autophagy dysfunction, apoptosis, and increased excitability. The results of this study provide an extensive analysis of the OPTN(E50K) mutation in hPSC-derived RGCs, with the opportunity to develop novel treatments for glaucoma.

neuroscience↗

bioRxiv2019

ASK1/p38-mediated NLRP3 inflammasome signaling pathway contributed to aberrant retinal angiogenesis in diabetic retinopathy

AbstractsDiabetic retinopathy is the leading cause of blindness in the working-age population in many countries. Despite the available treatments, some patients present late in the course of the disease when treatment is more difficult. Hence, it is crucial that the new targets are found and utilized in clinical therapy of diabetic retinopathy. In this study, we constructed the DR animal model and the high model in HRMEC cell to investigate the relationship between ASK1/p38 and NLRP3 in DR. The results showed that DR could cause the inflammatory response and microvascular proliferation. NLRP3 contributed to DR-mediated inflammatory development and progression, which promoted the inflammatory related cytokine expression. Meanwhile, it could promote the tube formation of retinal microvascular endothelial and angiogenesis. Moreover, further research showed that NLRP3 mediated aberrant retinal angiogenesis in diabetic retinopathy was regulated by ASK1 and p38. It suggested that ASK1/p38 could become a new target in DR treatment.

cell biology↗

bioRxiv2019

Dynamic changes in rhythmic and arrhythmic neural signatures in the subthalamic nucleus induced by anaesthesia and intubation

BackgroundSubcortical structures including the basal ganglia have been proposed to be crucial for arousal, consciousness, and behavioural responsiveness. However, how basal ganglia contributes to the loss and recovery of consciousness during anaesthesia has not been well characterized.\n\nMethodsIn this study, using local field potentials (LFPs) from subthalamic nucleus (STN) and scalp electroencephalogram in 12 Parkinsons disease patients, we investigate STN neural signatures during propofol general anaesthesia and during intubation as an arousal intervention in anaesthesia.\n\nResultsPropofol-induced anaesthesia resulted in changes in multiple frequency bands in STN LFPs, including increased low-frequency activities (slow-wave oscillation, delta, theta, and alpha bands) and decreased higher-frequency activities. This was also accompanied by increased STN-frontal cortical coherence in alpha frequency band. Beta and high-gamma activities in the STN temporally increased during intubation compared to the status of loss of consciousness. We also show that the dynamic changes in the high frequency activities (80-180 Hz) in STN LFPs induced by propofol and intubation correlated with power-law exponent in the power spectra between 2 and 80 Hz.\n\nConclusionsOur findings suggest that anaesthesia and intubation induced changes in the STN LFPs in multiple frequency bands. They are also consistent with the hypothesis that the power-law exponent in the power spectra between 2 and 80 Hz reflect the excitation/inhibition balance in the STN, which is modulated by anaesthesia and intubation, and further modulate the high frequency activity.

neuroscience↗

bioRxiv2019

Improving Social Interactive Learning through Dual Brain Stimulation

Social interactive learning denotes the ability to acquire new information from a conspecific - a prerequisite for cultural evolution and survival. As inspired by recent neurophysiological research, here we tested whether social interactive learning can be augmented by exogenously synchronizing oscillatory brain activity across an instructor and a learner engaged in a naturalistic song-learning task. We used a dual brain stimulation protocol entailing the trans-cranial delivery of synchronized electric currents in two individuals simultaneously. When we stimulated inferior frontal brain regions, with 6 Hz alternating currents being in-phase between the instructor and the learner, the dyad exhibited spontaneous and synchronized body movement. Remarkably, this stimulation also led to enhanced learning performance. A mediation analysis further disclosed that interpersonal movement synchrony acted as a partial mediator of the effect of dual brain stimulation on learning performance, i.e. possibly facilitating the effect of dual brain stimulation on learning. Our results provide a causal demonstration that inter-brain synchrony is a sufficient condition to improve real-time information transfer between pairs of individuals.\n\nSignificanceThe study of social behavior, including but not limited to social learning, is undergoing a paradigm shift moving from single- to multi-person brain research. Yet, nearly all evidence in this area is purely correlational: inter-dependencies between brains signals are used to predict success in social behavior. For instance, inter-brain synchrony has been shown to be associated with successful communication, cooperation, and joint attention. Here we took a radically different approach. We stimulated two brains simultaneously, hence manipulating inter-brain synchrony, and measured the resulting effect upon behavior in the context of a social learning task. We report that frequency- and phase-specific dual brain stimulation can lead to the emergence of spontaneous synchronized body movement between an instructor and a learner. Remarkably, this can also augment learning performance.

neuroscience↗