Biology subjects

Liu, S.

Publications and source records attributed to Liu, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2018

Effector Gene Reshuffling Involves Dispensable Mini-chromosomes in the Wheat Blast Fungus

Newly emerged wheat blast disease is a serious threat to global wheat production. Wheat blast is caused by a distinct, exceptionally diverse lineage of the fungus causing rice blast disease. To understand genetic diversity in wheat-infecting strains, we report a near-finished reference genome of a recent field isolate generated using long read sequencing and a novel scaffolding approach with long-distance paired genomic sequences. The genome assemblage includes seven core chromosomes and sequences from a dispensable mini-chromosome that harbors effector genes normally found on the ends of core chromosomes in other strains. No mini-chromosomes were observed in an early field strain, and two mini-chromosomes from another field isolate each contain different effector homologous genes and core chromosome end sequences. The mini-chromosome is highly repetitive and is enriched in transposons occurring most frequently at core chromosome ends. Additionally, transposons in mini-chromosomes lack the characteristic signature for inactivation by repeat-induced point (RIP) mutation genome defenses. Our results, collectively, indicate that dispensable mini-chromosomes and non-dispensable core chromosomes undergo divergent evolutionary trajectories, and mini-chromosomes and core chromosome ends are coupled as a mobile, fast-evolving effector compartment in the wheat pathogen genome.\n\nSignificance statementThe emerging blast disease on wheat is proving even harder to control than the ancient, still-problematic rice blast disease. Potential wheat resistance identified using strains isolated soon after disease emergence are no longer effective in controlling recent aggressive field isolates from wheat in South America and South Asia. We report that recent wheat pathogens can contain one or two highly-variable conditionally-dispensable mini-chromosomes, each with an amalgamation of effector sequences that are duplicated or absent from pathogen core chromosome ends. Well-studied effectors found on different core chromosomes in rice pathogens appear side-by-side in wheat pathogen mini-chromosomes. The rice pathogen often overcomes deployed resistance genes by deleting triggering effector genes. Localization of effectors on mini-chromosomes, which are unstably transmitted during growth, would accelerate pathogen adaptation in the field.

genomics↗

bioRxiv2018

Transcriptome analysis of Culter alburnus gonad tissues for discovery of sex-related genes

Culter alburnus is an important commercially fish species for freshwater breeding in China, and the females grow faster than the males. However, the molecular genetic mechanism of sex determination in C.alburnus is still poorly characterized. Here, we performed de novo assembly of a transcriptome from adult fish tissues of different gender using short read sequencing technology (Illumina). Our results showed that a total of 364,650 unigenes using Trinity software were obtained, giving rise to an average of 561.92 bp per read. Among them, 70,215 sequences matched known genes, including 5,892 male-biased unigenes and 942 female-biased unigenes. Many sex-related genes and pathways were identified based on annotation information. These results would provide new insights into the genetic mechanism of C.alburnus sex determination and also establish an important foundation for further research on aquaculture breeding.

bioinformatics↗

bioRxiv2018

Longitudinally Mapping Childhood Socioeconomic Status Associations with Cortical and Subcortical Morphology

Childhood socioeconomic status (SES) impacts cognitive development and mental health, but its association with structural brain development is not yet well-characterized. Here, we analyzed 1243 longitudinally-acquired structural MRI scans from 623 youth to investigate the relation between SES and cortical and subcortical morphology between ages 5 and 25 years. We found positive associations between SES and total volumes of the brain, cortical sheet, and four separate subcortical structures. These associations were developmentally fixed rather than age-dependent. Surface-based shape analysis revealed that higher SES is associated with areal expansion of (i) lateral prefrontal, anterior cingulate, lateral temporal, and superior parietal cortices and (ii) ventrolateral thalamic, and medial amygdalo-hippocampal sub-regions. Meta-analyses of functional imaging data indicate that cortical correlates of SES are centered on brain systems subserving sensorimotor functions, language, memory, and emotional processing. We further show that anatomical variation within a subset of these cortical regions partially mediates the positive association between SES and IQ. Finally, we identify neuroanatomical correlates of SES that exist above and beyond accompanying variation in IQ. Our findings clarify the spatiotemporal patterning of SES-related neuroanatomical variation and inform ongoing efforts to dissect the causal pathways underpinning observed associations between childhood SES and regional brain anatomy.

neuroscience↗

bioRxiv2018

Single-cell Transcriptomic Landscape of Nucleated Cells in Umbilical Cord Blood

Umbilical cord blood (UCB) transplant is a therapeutic option for both pediatric and adult patients with a variety of hematologic diseases such as several types of blood cancers, myeloproliferative disorders, genetic diseases, and metabolic disorders. However, the level of cellular heterogeneity and diversity of nucleated cells in the UCB has not yet been assessed in an unbiased and systemic fashion. In the current study, nucleated cells from UCB were subjected to single-cell RNA sequencing, a technology enabled simultaneous profiling of the gene expression signatures of thousands of cells, generating rich resources for further functional studies. Here, we report the transcriptomic maps of 19,052 UCB cells, covering 11 major cell types. Many of these cell types are comprised of distinct subpopulations, including distinct signatures in NK and NKT cell types in the UCB. Pseudotime ordering of nucleated red blood cells (NRBC) identifies wave-like activation and suppression of transcription regulators, leading to a polarized cellular state, which may reflect the NRBC maturation. Progenitor cells in the UBC also consist two subpopulations with divergent transcription programs activated, leading to specific cell-fate commitment. Collectively, we provide this comprehensive single-cell transcriptomic landscape and show that it can uncover previously unrecognized cell types, pathways and gene expression regulations that may contribute to the efficacy and outcome of UCB transplant, broadening the scope of research and clinical innovations.

genomics↗

bioRxiv2018

Neuronal thresholds and correlations in the peripheral vestibular system during rotation discrimination

Neuronal and behavioral thresholds were measured simultaneously as trained male macaques performed a yaw rotation discrimination task in darkness. When corrected to account for variations in neuronal direction preferences, neurons in the vestibular nuclei and semicircular canal afferents had discrimination thresholds that were only two-fold smaller than behavioral thresholds. There was no significant trial-by-trial correlation between neuronal activity and perceptual decisions, despite the presence of significant pair-wise noise correlations. The lack of choice-related activity during rotation discrimination contrasts with the robust correlations observed previously between brainstem neurons and choices during translation perception. These results suggest task-dependent differences in subcortical processing of vestibular signals, as well as how signals related to perceptual decisions may propagate back to early stages of sensory processing.\n\nSIGNIFICANCE STATEMENTThis is the first ever simultaneous recordings of neural and behavioral thresholds during rotation discrimination. Its importance lies on the fact that the vestibular system provides an excellent model to probe origins of perception because directional selectivity signals are similar at many levels of processing, from afferents to cortex. The findings of similar neuronal and behavioral discrimination thresholds, significant inter-neuronal correlations, but lack of correlations between behavior and neuronal activity of both afferents and central brainstem neurons are intriguing and suggest task-dependent organization of early sensory areas.

neuroscience↗

bioRxiv2018

Recovered and dead outcome patients caused by influenza A (H7N9) virus infection show different pro-inflammatory cytokine dynamics during disease progress and its application in real-time prognosis

The persistent circulation of influenza A(H7N9) virus within poultry markets and human society leads to sporadic epidemics of influenza infections. Severe pneumonia and acute respiratory distress syndrome (ARDS) caused by the virus lead to high morbidity and mortality rates in patients. Hyper induction of pro-inflammatory cytokines, which is known as \"cytokine storm\", is closely related to the process of viral infection. However, systemic analyses of H7N9 induced cytokine storm and its relationship with disease progress need further illuminated. In our study we collected 75 samples from 24 clinically confirmed H7N9-infected patients at different time points after hospitalization. Those samples were divided into three groups, which were mild, severe and fatal groups, according to disease severity and final outcome. Human cytokine antibody array was performed to demonstrate the dynamic profile of 80 cytokines and chemokines. By comparison among different prognosis groups and time series, we provide a more comprehensive insight into the hypercytokinemia caused by H7N9 influenza virus infection. Different dynamic changes of cytokines/chemokines were observed in H7N9 infected patients with different severity. Further, 33 cytokines or chemokines were found to be correlated with disease development and 11 of them were identified as potential therapeutic targets. Immuno-modulate the cytokine levels of IL-8, IL-10, BLC, MIP-3a, MCP-1, HGF, OPG, OPN, ENA-78, MDC and TGF-{beta} 3 are supposed to be beneficial in curing H7N9 infected patients. Apart from the identification of 35 independent predictors for H7N9 prognosis, we further established a real-time prediction model with multi-cytokine factors for the first time based on maximal relevance minimal redundancy method, and this model was proved to be powerful in predicting whether the H7N9 infection was severe or fatal. It exhibited promising application in prognosing the outcome of a H7N9 infected patients and thus help doctors take effective treatment strategies accordingly.

immunology↗

bioRxiv2018

Practical model selection for prospective virtual screening

Virtual (computational) high-throughput screening provides a strategy for prioritizing compounds for experimental screens, but the choice of virtual screening algorithm depends on the dataset and evaluation strategy. We consider a wide range of ligand-based machine learning and docking-based approaches for virtual screening on two protein-protein interactions, PriA-SSB and RMI-FANCM, and present a strategy for choosing which algorithm is best for prospective compound prioritization. Our workflow identifies a random forest as the best algorithm for these targets over more sophisticated neural network-based models. The top 250 predictions from our selected random forest recover 37 of the 54 active compounds from a library of 22,434 new molecules assayed on PriA-SSB. We show that virtual screening methods that perform well in public datasets and synthetic benchmarks, like multi-task neural networks, may not always translate to prospective screening performance on a specific assay of interest.

biochemistry↗

bioRxiv2018

De novo computational RNA modeling into cryoEM maps of large ribonucleoprotein complexes

RNA-protein assemblies carry out many critical biological functions including translation, RNA splicing, and telomere extension. Increasingly, cryo-electron microscopy (cryoEM) is used to determine the structures of these complexes, but nearly all maps determined with this method have regions in which the local resolution does not permit manual coordinate tracing. Because RNA coordinates typically cannot be determined by docking crystal structures of separate components and existing structure prediction algorithms cannot yet model RNA-protein complexes, RNA coordinates are frequently omitted from final models despite their biological importance. To address these omissions, we have developed a new framework for De novo Ribonucleoprotein modeling in Real-space through Assembly of Fragments Together with Electron density in Rosetta (DRRAFTER). We show that DRRAFTER recovers near-native models for a diverse benchmark set of small RNA-protein complexes, as well as for large RNA-protein machines, including the spliceosome, mitochondrial ribosome, and CRISPR-Cas9-sgRNA complexes where the availability of both high and low resolution maps enable rigorous tests. Blind tests on yeast U1 snRNP and spliceosomal P complex maps demonstrate that the method can successfully build RNA coordinates in real-world modeling scenarios. Additionally, to aid in final model interpretation, we present a method for reliable in situ estimation of DRRAFTER model accuracy. Finally, we apply this method to recently determined maps of telomerase, the HIV-1 reverse transcriptase initiation complex, and the packaged MS2 genome, demonstrating that DRRAFTER can be used to accelerate accurate model building in challenging cases.

biophysics↗

bioRxiv2018

Overt social interaction and resting state in autism: core and contextual neural features

Conversation is an important and ubiquitous social behavior. Individuals with Autism Spectrum Disorder (autism) without intellectual disability often have normal structural language abilities but deficits in social aspects of communication like pragmatics, prosody, and eye contact. Previous studies of resting state activity suggest that intrinsic connections among neural circuits involved with social processing are disrupted in autism, but to date no neuroimaging study has examined neural activity during the most commonplace yet challenging social task: spontaneous conversation. Here we used functional MRI to scan autistic males (N=19) without intellectual disability and age- and IQ-matched typically developing controls (N=20) while they engaged in a total of 193 face-to-face interactions. Participants completed two kinds of tasks: Conversation, which had high social demand, and Repetition, which had low social demand. Autistic individuals showed abnormally increased task-driven inter-regional temporal correlation relative to controls, especially among social processing regions and during high social demand. Furthermore, these increased correlations were associated with parent ratings of participants social impairments. These results were then compared with previously-acquired resting-state data (56 Autism, 62 Control participants). While some inter-regional correlation levels varied by task or rest context, others were strikingly similar across both task and rest, namely increased correlation among the thalamus, dorsal and ventral striatum, somatomotor, temporal and prefrontal cortex in the autistic individuals, relative to the control groups. These results suggest a basic distinction. Autistic cortico-cortical interactions vary by context, tending to increase relative to controls during Task and decrease during Rest. In contrast, striato- and thalamocortical relationships with socially engaged brain regions are increased in both Task and Rest, and may be core to the condition of autism.

neuroscience↗

bioRxiv2018

Deconvolution of single-cell multi-omics layers reveals regulatory heterogeneity

Integrative analysis of multi-omics layers at single cell level is critical for accurate dissection of cell-to-cell variation within certain cell populations. Here we report scCAT-seq, a technique for simultaneously assaying chromatin accessibility and the transcriptome within the same single cell. We show that the combined single cell signatures enable accurate construction of regulatory relationships between cis-regulatory elements and the target genes at single-cell resolution, providing a new dimension of features that helps direct discovery of regulatory patterns specific to distinct cell identities. Moreover, we generated the first single cell integrated maps of chromatin accessibility and transcriptome in human pre-implantation embryos and demonstrated the robustness of scCAT-seq in the precise dissection of master transcription factors in cells of distinct states during embryo development. The ability to obtain these two layers of omics data will help provide more accurate definitions of \"single cell state\" and enable the deconvolution of regulatory heterogeneity from complex cell populations.

genomics↗

bioRxiv2018

Mixed-cropping systems of different rice cultivars have grain yield and quality advantages over mono-cropping systems

Mixed-cropping system is a centuries-old cropping technique that is still widely practiced in the farmers field over the globe. Increased plant diversity enhances farmland biodiversity, which would improve grain yield and quality; however, the impacts of growing different rice cultivars simultaneously were rarely investigated. In present study, five popular rice cultivars were selected and ten mixture combinations were made according to the growth period, plant height, grain yield and quality, and pest and disease resistance. Seedlings of the five cultivars and ten mixture combinations (mixed-sowing of the seeds in an equal ratio, then mixed-transplanting and finally mixed-harvesting) were grown in plastic pots under greenhouse during the early and late growing seasons in 2016. Results showed that, compared with the corresponding mono-cropping systems, almost all combinations of the mixed-cropping systems have advantages in yield related traits and grain quality. Compared with the mono-cropping systems in the early and late growing seasons in 2016, mixed-cropping systems increased the number of spikelets per panicle, seed-setting rate, and grain weight per pot and harvest index by 19.52% and 5.77%, 8.53% and 4.41%, 8.31% and 4.61%, and 10.26% and 6.98%, respectively (paired t-test). In addition, mixed-cropping systems reduced chalky rice rate and chalkiness degree by 33.12% and 43.42% and by 30.11% and 48.13% in the early and late growing seasons, respectively (paired t-test). These results may be due to enhanced SPAD indexes and photosynthetic rates at physiology maturity in mixed-cropping systems. In general, it was found that mixed-cropping with different rice cultivars have potential for increasing grain yield and improving grain quality.

ecology↗

bioRxiv2018

Identification of small regulatory RNAs involved in persister formation

Small regulatory RNA (srRNA) is widely distributed in three kingdoms of life and fulfills functions in many aspects of cellular life, but their role in bacterial persistence remains unknown. In this study, we comprehensively interrogated the expression levels of the known srRNAs on three critical time points, stage 1 (S1) where no persisters are formed, stage 2 (S2) where persisters are beginning to appear, and stage 3 (S3) where persister numbers increase significantly. Three upregulated srRNAs (OmrB, an outer member associated srRNA; RdlB, a swarming motility and curli expression regulator; McaS, a flagellar motility and biofilm formation regulator) overlapping in S2/S1 and S3/S1, together with the other four upregulated srRNAs (MicF, a ribosome binding inhibitor; MicL, an outer membrane associated srRNA; RybB, a cell envelope stress regulator; RydB, regulator of a global regulator RpoS) in S2/S1 are of special interest. By constructing deletion mutants and overexpression strains in uropathogenic E. coli strain UTI89, we tested their persister-formation capabilities in log phase and stationary phase cultures exposed to antibiotics (gentamicin, cefotaxime and levofloxacin) and stresses (heat, hyperosmosis, H2O2, and acid). The results of the deletion mutant studies showed that all the seven identified sRNAs have varying effects on persister formation with different antibiotics or stresses. Moreover, we found all the deletion mutants of these srRNAs have reduced biofilm formation. Additionally, except the McaS and the RydB overexpression strains, all of the srRNAs overexpression strains demonstrated increased persister-formation in antibiotic and stress persister assays, confirming the role of these srRNAs in persistence. Together, we identified seven srRNAs (OmrB, RdlB, McaS, MicF, MicL, RybB, and RydB) that are involved in type II persister formation for the first time. These findings provide convincing evidence for a new level of rapid persistence regulation via srRNA and furnish novel therapeutic targets for intervention.

microbiology↗

bioRxiv2018

Identification of novel genes including rpmF and yjjQ critical for Type II persister formation in Escherichia coli

Persister cells, which are characterized by inactive metabolism and tolerance to antibiotics or stresses, pose a significant challenge to the treatment of many persistent infections. Although multiple genes have been reported to be involved in persister formation through transposon mutant library screens, how persisters are formed during the natural process of persister formation as the culture transitions from log phase to stationary phase is unclear. Here, using E. coli as a model, we performed a comprehensive transcriptome analysis of gene expression profiles of successive cultures of an E. coli culture at different critical time points, starting from persister-free S1-nonexistence phase (3h) to persister appearing S2-emergence phase (4h), and persister abundant stage S3-abundance phase (5h). The differentially expressed genes ([≥]2-fold) in persister appearing stage (S1 to S2 transition) and persister abundant stage (S1 to S3) were compared, and 51 and 29 genes were identified to be up-regulated, respectively. Importantly, 13 genes (gnsA, gnsB, ybfA, yjjQ, ymdF, yhdU, csgD, yncN, rpmF, ydcX, yohJ, ssrA, rbsD) overlap in both persister S2-emergence phase and S3-abundance phase, including a member of the trans-translation pathway (ssrA) as well as an orphan toxin (ydcX), which are two well-known persister genes while the remaining 11 novel genes (gnsA, gnsB, ybfA, yjjQ, ymdF, yhdU, csgD, yncN, rpmF, yohJ, rbsD) have not been reported previously. Persister levels of 7 constructed knockout mutants ({Delta}gnsA, {Delta}ybfA, {Delta}yjjQ, {Delta}yhdU, {Delta}csgD, {Delta}yohJ and{Delta} rpmF) and 10 overexpression strains (gnsA, gnsB, ybfA, yjjQ, ymdF, yhdU, csgD, rpmF, yohJ, rbsD) in E. coli uropathogenic strain UTI89 were determined upon treatment with different cidal antibiotics (ampicillin, levofloxacin and gentamicin). Additionally, ranking of these overlapping genes according to their impact on persister levels were also performed. Two genes (rpmF encoding 50S ribosomal subunit protein L32, and yjjQ encoding a putative LuxR-type transcription factor) showed the most obvious phenotype on persister levels in both knockout and overexpression studies, which suggests they are broad and key factors for persister formation. While previous studies cannot distinguish if a given persister gene is involved in persister formation or persister survival, our findings clearly identify novel persister forming genes and pathways involving a ribosome protein and a LuxR type transcription factor during the bona fide persister formation process and may have implications for developing improved treatment of persistent infections.

microbiology↗

bioRxiv2018

Identification of Polynucleotide Phosphorylase (PNPase) in Escherichia coli Involved in Persister Formation

Despite the identification of many genes and pathways involved in the persistence phenomenon of bacteria, the mechanisms of persistence are not well understood. Here, using Escherichia coli as a model, we identified polynucleotide phosphorylase (PNPase) as a key regulator in persister formation. We successfully constructed pnp knockout mutant strain and its complemented strain, and exposed the pnp knockout mutant and complemented strain to antibiotics and stress conditions. The results showed that, compared with the wild-type W3110, the pnp knockout strain had defect in persistence to antibiotics and stress conditions, and the persistence to antibiotics and stresses was restored upon complementation. RNA-Seq was performed to identify the transcriptome profile in the pnp knockout strain compared with wild-type strain W3110, and the data revealed that 242 (166 up-regulated, and 76 down-regulated) genes were differentially expressed in the pnp knockout mutant strain. KEGG pathway analysis of the up-regulated genes showed that they were mostly mapped to metabolism and virulence pathways, most of which are positively regulated by the global regulator cyclic AMP receptor protein (CRP). Similarly, the transcription level of the crp gene in the pnp-deletion strain increased 3.22-fold in the early stationary phase. We further explored the indicators of cellular metabolism of the pnp-deletion strain, the persistence phenotype of the pnp and crp double-deletion mutant, and the transcriptional activity of crp gene. Our results indicate that PNPase controls cellular metabolism by negatively regulating the crp operon at the post-transcriptional level by targeting the 5- Untranslated Region (UTR) of the crp transcript. This study offers new insight about the persister mechanisms and provides new targets for development of new drugs against persisters for more effective treatment of persistent bacterial infections.

microbiology↗

bioRxiv2018

Broad-spectrum adaptive antibiotic resistance associated with Pseudomonas aeruginosa mucin-dependent surfing motility

Surfing motility is a novel form of surface adaptation exhibited by the nosocomial pathogen, Pseudomonas aeruginosa, in the presence of the glycoprotein mucin that is found in high abundance at mucosal surfaces especially the lungs of cystic fibrosis and bronchiectasis patients. Here we investigated the adaptive antibiotic resistance of P. aeruginosa under conditions in which surfing occurs compared to cells undergoing swimming. P. aeruginosa surfing cells were significantly more resistant to several classes of antibiotics including aminoglycosides, carbapenems, polymyxins, and fluroquinolones. This was confirmed by incorporation of antibiotics into growth medium, which revealed a concentration-dependent inhibition of surfing motility that occurred at concentrations much higher than those needed to inhibit swimming. To investigate the basis of resistance, RNA-Seq was performed and revealed that surfing influenced the expression of numerous genes. Included amongst genes dysregulated under surfing conditions were multiple genes from the Pseudomonas resistome, which are known to affect antibiotic resistance when mutated. Screening transposon mutants in these surfing-dysregulated resistome genes revealed that several of these mutants exhibited changes in susceptibility to one or more antibiotics under surfing conditions, consistent with a contribution to the observed adaptive resistance. In particular, several mutants in resistome genes, including armR, recG, atpB, clpS, nuoB, and certain hypothetical genes such as PA5130, PA3576 and PA4292, showed contributions to broad-spectrum resistance under surfing conditions and could be complemented by their respective cloned genes. Therefore, we propose that surfing adaption led to extensive multidrug adaptive resistance as a result of the collective dysregulation of diverse genes.

microbiology↗

bioRxiv2018

Improvements to the rice genome annotation through large-scale analysis of RNA-Seq and proteomics datasets

Rice (Oryza sativa) is one of the most important worldwide crops. The genome has been available for over 10 years and has undergone several rounds of annotation. We created a comprehensive database of transcripts from 29 public RNA sequencing datasets, officially predicted genes from Ensembl plants, and common contaminants in which to search for protein-level evidence. We re-analysed nine publicly accessible rice proteomics datasets. In total, we identified 420K peptide spectrum matches from 47K peptides and 8,187 protein groups. 4168 peptides were initially classed as putative novel peptides (not matching official genes). Following a strict filtration scheme to rule out other possible explanations, we discovered 1,584 high confidence novel peptides. The novel peptides were clustered into 692 genomic loci where our results suggest annotation improvements. 80% of the novel peptides had an ortholog match in the curated protein sequence set from at least one other plant species. For the peptides clustering in intergenic regions (and thus potentially new genes), 101 loci were identified, for which 43 had a high-confidence hit for a protein domain. Our results can be displayed as tracks on the Ensembl genome or other browsers supporting Track Hubs, to support re-annotation of the rice genome.

plant biology↗

bioRxiv2018

Using a System’s Equilibrium Behavior to Reduce Its Energy Dissipation in Non-Equilibrium Processes

Cells must operate far from equilibrium1, utilizing and dissipating energy continuously to maintain their organization and to avoid stasis and death. However, they must also avoid unnecessary waste of energy2. Recent studies have revealed that molecular machines are extremely efficient thermodynamically when compared to their macroscopic counterparts3,4. There are also tantalizing hints of molecular machines conserving energy while operating out of equilibrium5,6. However, the principles governing the efficient out-of-equilibrium operation of molecular machines remain a mystery. A theoretical framework has been recently formulated in which a generalized friction coefficient quantifies the energetic efficiency in non-equilibrium processes7,8. Moreover, it posits that to minimize energy dissipation, external control should drive the system along the reaction coordinate with a speed inversely proportional to the square root of that friction coefficient. Here, we test and validate the predictions of this theory by probing the non-equilibrium energetic efficiency of a single DNA hairpin subjected to unfolding and refolding protocols using a dual-trap optical tweezers.

biophysics↗

bioRxiv2018

ADS-J1 Disaggregates Semen-derived Amyloid Fibrils

Semen-derived amyloid fibrils, composing SEVI (semen-derived enhancer of viral infection) fibrils and SEM1 fibrils, could remarkably enhance HIV-1 sexual transmission and thus, are potential targets for the development of an effective microbicide. Previously, we found that ADS-J1, apart from being an HIV-1 entry inhibitor, could also potently inhibit seminal amyloid fibrillization and block fibril-mediated enhancement of viral infection. However, the remodeling effects of ADS-J1 on mature seminal fibrils were unexplored. Herein, we investigated the capacity of ADS-J1 to disassemble seminal fibrils and the potential mode of action by applying several biophysical and biochemical measurements, combined with molecular dynamic (MD) simulations. We found that ADS-J1 effectively remodeled SEVI, SEM186-107 fibrils and endogenous seminal fibrils. Unlike epi-gallocatechin gallate (EGCG), a universal amyloid fibril breaker, ADS-J1 disaggregated SEVI fibrils into monomeric peptides, which was independent of oxidation reaction. MD simulations revealed that ADS-J1 displayed strong binding potency to the full-length PAP248-286 via electrostatic interactions, hydrophobic interactions and hydrogen bonds. ADS-J1 might initially bind to the fibrillar surface and then occupy the amyloid core, which eventually lead to fibril disassembly. Furthermore, the binding of ADS-J1 with PAP248-286 might induce conformational changes of PAP248-286. Disassembled PAP248-286 might not be favor to re-aggregate into fibrils. ADS-J1 also exerts abilities to remodel a panel of amyloid fibrils, including A{beta}1-42, hIAPP1-37 and EP2 fibrils. ADS-J1 displays promising potential to be a combination microbicide and an effective lead-product to treat amyloidogenic diseases.

pharmacology and toxicology↗