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Guan, S.

Publications and source records attributed to Guan, S..

28 records · Page 2Linked to original sources

Individual differences reveal similarities in serial dependencies across perceptual tasks, but no relation to serial dependencies for oculomotor behavior

Serial dependence effects from one trial to the next have been observed across a wide range of perceptual tasks, as well as for oculomotor behavior. This opens up the question of whether the effects observed across all of these studies share underlying mechanisms. Here we measured the same group of observers across four different tasks, two perceptual (color judgments and orientation judgments) and two oculomotor (tracking of moving targets and the pupil light reflex). On the group level, we observed significant attractive serial dependence effects for all tasks, except the pupil response. The rare absence of a serial dependence effect for the reflex like pupil light response suggests that sequential effects require cortical processing or even higher-level cognition. In the following step, we leveraged reliable individual differences between observers in the other tasks to test whether there is a trait-like behavior of some observers showing stronger serial dependence effects across all of these tasks. We observed a significant relationship in the strength of serial dependence for the two perceptual experiments, but no relation between the perceptual tasks and oculomotor behavior. This indicates, differences in processing between perception and oculomotor control and the absence of a general trait-like behavior that affects all tasks similarly. However, the shared variance in the strength of serial dependence effects across different perceptual tasks indicates the importance of a similar positive decision bias present, that is reliably different between observers and consistent across different serial dependence tasks.

neuroscience↗

Organometallic Pillarplexes that bind DNA 4-way Holliday Junctions and Forks.

Holliday 4-way junctions are key to important biological DNA processes (insertion, recombination and repair) and are dynamic structures which adopt either open or closed conformations, with the open conformation being the biologically active form. Tetracationic metallo-supramolecular pillarplexes display aryl faces about a cylindrical core giving them an ideal structure to interact with the central cavities of open DNA junctions. Combining experimental studies and MD simulations we show that an Au pillarplex can bind DNA 4-way junctions (Holliday junctions) in their open form, a binding mode not accessed by synthetic agents before. The Au pillarplexes can bind designed 3-way junctions too but their large size leads them to open up and expand that junction, disrupting the base pairing which manifests in an increase in hydrodynamic size and a lower junction thermal stability. At high loading they re-arrange both 4-way and 3-way junctions into Y-shaped DNA forks to increase the available junction-like binding sites. The structurally related Ag pillarplexes show similar DNA junction binding behaviour, but a lower solution stability. This pillarplex binding contrasts with (but complements) that of the metallo-supramolecular cylinders, which prefer 3-way junctions and we show can rearrange 4-way junctions into 3-way junction structures. The pillarplexes ability to bind open 4-way junctions creates exciting possibilities to modulate and switch such structures in biology, as well as in synthetic nucleic acid nanostructures where they are key interconnecting components. Studies in human cells, confirm that the pillarplexes do reach the nucleus, with antiproliferative activity at levels similar to those of cisplatin. The findings provide a new roadmap for targeting higher order junction structures using a metallo-supramolecular approach, as well as expanding the toolbox available to design bioactive junction-binders into organometallic chemistry. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/522759v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@10fac36org.highwire.dtl.DTLVardef@1f32f9forg.highwire.dtl.DTLVardef@bb8d72org.highwire.dtl.DTLVardef@1433de5_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

Trans-species microRNA loci in the parasitic plant Cuscuta campestris have a U6-like snRNA promoter

Small regulatory RNAs can move between organisms during pathogenic interactions and regulate gene expression in the recipient. If and how such "trans-species" small RNAs are distinguished from normal small RNAs is not known. The parasitic plant Cuscuta campestris produces a number of microRNAs that specifically accumulate at the interface between parasite and host, several of which have been demonstrated to have trans-species activity. We find that induction of C. campestris interface-induced microRNAs was similar regardless of host species, and can be replicated in haustoria stimulated to develop in the complete absence of a host. We also find that the loci encoding C. campestris interface-induced microRNAs are distinguished by a common 10 base-pair cis-regulatory element. This element is identical to a previously described upstream sequence element used by all plant small nuclear RNA loci. The sequence context of this element strongly suggests U6-like transcription by RNA polymerase III. The element promotes accumulation of interface-induced miRNAs in a heterologous system. This common promoter element distinguishes C. campestris interface-induced microRNA loci from other plant small RNAs; other plant small RNA loci are transcribed by polymerases II or IV, and lack any common promoter motifs. Our data suggest that C. campestris interface-induced miRNAs are produced in a manner distinct from canonical miRNAs. All confirmed C. campestris microRNAs with confirmed trans-species activity are interface-induced and possess these features. We speculate that this distinct production may allow these miRNAs to be exported to hosts.

plant biology↗

Respiratory mucosal vaccination of peptide-poloxamine-DNA nanoparticles provides complete protection against lethal SARS-CoV-2 challenge

The ongoing SARS-CoV-2 pandemic represents a brutal reminder of the continual threat of mucosal infectious diseases. Mucosal immunity may provide robust protection at the predominant sites of SARS-CoV-2 infection. However, it remains unclear whether respiratory mucosal administration of DNA vaccines could confer protective immune responses against SARS-CoV-2 challenge due to the insurmountable barriers posed by the airway. Here, we applied self-assembled peptide-poloxamine nanoparticles with mucus-penetrating properties for pulmonary inoculation of a COVID-19 DNA vaccine (pSpike/PP-sNp). Not only displays the pSpike/PP-sNp superior gene-transfection and favorable biocompatibility in the mouse airway, but pSpike/PP-sNp promotes a tripartite immunity consisting of systemic, cellular and mucosal immune responses that are characterized by mucosal IgA secretion, high levels of neutralizing antibodies, and resident memory phenotype T-cell responses in the lungs of mice. Most importantly, pSpike/PP-sNp completely eliminates SARS-CoV-2 infection in both upper and lower respiratory tracts and enables 100% survival rate of mice following lethal SARS-CoV-2 challenge. Our findings indicate PP-sNp might be a promising platform in mediating DNA vaccines to elicit all-around mucosal immunity against SARS-CoV-2.

immunology↗

The Fc-mediated effector functions of a potent SARS-CoV-2 neutralizing antibody, SC31, isolated from an early convalescent COVID-19 patient, are essential for the optimal therapeutic efficacy of the antibody

SARS-CoV-2-neutralizing antibodies are promising therapeutics for COVID-19. However, little is known about the mechanisms of action of these antibodies or their effective dosing windows. We report the discovery and development of SC31, a potent SARS-CoV-2 neutralizing IgG1 antibody, originally isolated from a convalescent patient at day 27 after the onset of symptoms. Neutralization occurs via a binding epitope that maps within the ACE2 interface of the SARS-CoV-2 Spike protein, conserved across all common circulating SARS-CoV-2 mutants. In SARS-CoV-2 infected K18-human ACE2 transgenic mice, SC31 demonstrated potent survival benefit by dramatically reducing viral load concomitant with attenuated pro-inflammatory responses linked to severe systemic disease, such as IL-6. Comparison with a Fc-null LALA variant of SC31 demonstrated that optimal therapeutic efficacy of SC31 requires intact Fc-mediated effector functions that can further induce an IFN{gamma}-driven anti-viral immune response. Dose-dependent efficacy for SC31 was observed down to 5mg/kg when dosed before the activation of lung inflammatory responses. Importantly, despite Fc{gamma}R binding, no evidence of antibody dependent enhancement was observed with the Fc-competent SC31 even at sub-therapeutic doses. Therapeutic efficacy was confirmed in SARS-CoV-2-infected hamsters, where SC31 again significantly reduced viral load, decreased lung lesions and inhibited progression to severe disease manifestations. This study underlines the potential for significant COVID-19 patient benefit for the SC31 antibody that justifies rapid advancement to the clinic, as well as highlighting the importance of appropriate mechanistic and functional studies during development. One Sentence SummaryAnti-SARS-CoV-2 IgG1 antibody SC31 controls infection in vivo by blocking SP:ACE2 binding and triggering a Fc-mediated anti-viral response.

microbiology↗

EM-seq: Detection of DNA Methylation at Single Base Resolution from Picograms of DNA

Bisulfite sequencing is widely used to detect 5mC and 5hmC at single base resolution. However, bisulfite treatment damages DNA resulting in fragmentation, loss of DNA and biased sequencing data. To overcome this, we developed Enzymatic Methyl-seq (EM-seq), an enzymatic based approach that uses as little as 100 pg of DNA. EM-seq outperformed bisulfite converted libraries in all metrics examined including coverage, duplication, sensitivity and nucleotide composition. EM-seq libraries displayed even GC distribution, improved correlation across input amounts as well as increased representation of genomic features. These data indicate that EM-seq is more accurate and reliable than whole genome bisulfite sequencing (WGBS).

genomics↗

Non-destructive enzymatic deamination enables single molecule long read sequencing for the determination of 5-methylcytosine and 5-hydroxymethylcytosine at single base resolution.

The predominant methodology for DNA methylation analysis relies on the chemical deamination by sodium bisulfite of unmodified cytosine to uracil to permit the differential readout of methylated cytosines. Bisulfite treatment damages the DNA leading to fragmentation and loss of long-range methylation information. To overcome this limitation of bisulfite treated DNA we applied a new enzymatic deamination approach, termed EM-seq (Enzymatic Methyl-seq) to long-range sequencing technologies. Our methodology, named LR-EM-seq (Long Range Enzymatic Methyl-seq) preserves the integrity of DNA allowing long-range methylation profiling of 5-mC and 5-hmC over several kilobases of genomic DNA. When applied to known differentially methylated regions (DMR), LR-EM-seq achieves phasing of over 5 kb resulting in broader and better defined DMRs compared to previously reported. This result demonstrated the importance of phasing methylation for biologically relevant questions and the applicability of LR-EM-seq for long range epigenetic analysis at single molecule and single nucleotide resolution.

genomics↗

DDIA: data dependent-independent acquisition proteomics - DDA and DIA in a single LC-MS/MS run

Data dependent acquisition (DDA) and data independent acquisition (DIA) are traditionally separate experimental paradigms in bottom-up proteomics. In this work, we developed a strategy combining the two experimental methods into a single LC-MS/MS run. We call the novel strategy, data dependent-independent acquisition proteomics, or DDIA for short. Peptides identified by conventional and robust DDA identification workflow provide useful information for interrogation of DIA scans. Deep learning based LC-MS/MS property prediction tools, developed previously can be used repeatedly to produce spectral libraries facilitating DIA scan extraction. A complete DDIA data processing pipeline, including modules for iRT vs RT calibration curve generation, DIA extraction classifier training, FDR control has been developed. A key advantage of the DDIA method is that it requires minimal information for processing its data.\n\nGRAPHIC ABSTRACT\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC=\"FIGDIR/small/802231v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (16K):\norg.highwire.dtl.DTLVardef@a631c6org.highwire.dtl.DTLVardef@10dc3a0org.highwire.dtl.DTLVardef@a65061org.highwire.dtl.DTLVardef@e72627_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

A NOVEL MECHANISM FOR NF-κB-ACTIVATION VIA IκB-AGGREGATION: IMPLICATIONS FOR HEPATIC MALLORY-DENK-BODY INDUCED INFLAMMATION

Background & AimsMallory-Denk-bodies (MDBs) are hepatic protein aggregates associated with inflammation both clinically and in MDB-inducing models. Similar protein aggregation in neurodegenerative diseases also triggers inflammation and NF-{kappa}B activation. However, the precise mechanism that links protein aggregation to NF{kappa}B-activation and inflammatory response remains unclear.\n\nMethodsHerein, we find that treating primary hepatocytes with MDB-inducing agents (N-methylprotoporphyrin, protoporphyrin IX (PPIX), or ZnPPIX) elicited an I{kappa}B-loss with consequent NF-{kappa}B activation. We characterized the underlying mechanism in detail using hepatocytes from various knockout mice and MEF cell lines and multiple approaches including immunoblotting, EMSA, RT-PCR, confocal immunofluorescence microscopy, affinity immunoprecipitation, and protein solubility assays. Additionally, we performed rigorous proteomic analyses to identify the proteins aggregating upon PPIX treatment and/or co-aggregating with I{kappa}B.\n\nResultsFour known mechanisms of I{kappa}B-loss were probed and excluded. Immunofluorescence analyses of ZnPPIX-treated cells coupled with 8 M urea/CHAPS-extraction revealed that this I{kappa}B-loss was due to its sequestration along with I{kappa}B{beta} into insoluble aggregates. Through proteomic analyses we identified 47 aggregation-prone proteins that co-aggregate with I{kappa}B through direct interaction or proximity. Of these ZnPPIX-aggregation targets, the nucleoporins Nup153 and Nup358/RanBP2 were identified through RNA-interference, as likely mediators of I{kappa}B-nuclear import.\n\nConclusionWe discovered a novel mechanism of inflammatory NF-{kappa}B activation through I{kappa}B-sequestration into insoluble aggregates along with interacting aggregation-prone proteins. This mechanism may account for the protein aggregate-induced inflammation observed in MDB-associated liver diseases, thereby identifying novel targets for therapeutic intervention. Because of inherent commonalities this MDB cell model is a bona fide protoporphyric model, making these findings equally relevant to the liver inflammation associated with clinical protoporphyria.\n\nLay SummaryMallory-Denk-bodies (MDBs) are hepatic protein aggregates commonly featured in many liver diseases. MDB-presence is associated with the induction of inflammatory responses both clinically and in all MDB-inducing models. Similar protein aggregation in neurodegenerative diseases is also known to trigger inflammation and NF{kappa}B pathway activation via an as yet to be characterized non-canonical mechanism. Herein using a MDB-inducing cell model, we uncovered a novel mechanism for NF{kappa}B activation via cytosolic I{kappa}B-sequestration into insoluble aggregates. Furthermore, using a proteomic approach, we identified 47 aggregation-prone proteins that interact and co-aggregate with I{kappa}B. This novel mechanism may account for the protein aggregate-induced inflammation observed in liver diseases, thereby identifying novel targets for therapeutic intervention.

cell biology↗

Distinct Patterns of the Autofluorescence of Body Surface: Potential Novel Diagnostic Biomarkers for Stable Coronary Artery Disease and Myocardial Infarction

Searches for new biomarkers of stable coronary artery disease (SCAD) and myocardial infarction (MI) are critical for therapeutic efficacy of the diseases. In this study we tested our hypothesis that distinct patterns of autofluorescence (AF) of skin and fingernails may become novel diagnostic biomarkers for MI and SCAD. Our study has indicated that SCAD and MI have distinct patterns of AF of their body surface: First, the AF intensity of the MI patients is significantly higher than that of the Healthy and Low-Risk group in their right and left Centremetacarpus, Ventroforefinger, Dorsal Index Finger and Ventribrachium, while the AF intensity of the SCAD patients is significantly higher than that of the Healthy and Low-Risk group in their right and left Index Fingernails and Dorsal Antebrachium; and second, the AF asymmetry of the MI patients is significantly higher than that of the Healthy and Low-Risk group in their Centremetacarpus, Ventroforefinger, Index Fingernails and Dorsal Antebrachium, while the AF asymmetry of the SCAD patients is significantly higher than that of the Healthy and Low-Risk group in their Ventroforefinger, Dorsal Index Finger, Dorsal Centremetacarpus and Index Fingernails. Moreover, the AF pattern of acute ischemic stroke is markedly different from those of SCAD and MI. The oxidative stress in the plasma of the MI and SCAD patients may cause the increased AF by altering the AF of keratins. Collectively, our study has indicated that SCAD and MI patients have distinct patterns of AF changes, which may become novel diagnostic biomarkers for SCAD and MI.

biophysics↗