Biology subjects

Liang, Z.

Publications and source records attributed to Liang, Z..

At least 181 records · Page 10Linked to original sources

bioRxiv2021

Automated skull stripping in mouse fMRI analysis using 3D U-Net

Skull stripping is an initial and critical step in the pipeline of mouse fMRI analysis. Manual labeling of the brain usually suffers from intra- and inter-rater variability and is highly time-consuming. Hence, an automatic and efficient skull-stripping method is in high demand for mouse fMRI studies. In this study, we investigated a 3D U-Net based method for automatic brain extraction in mouse fMRI studies. Two U-Net models were separately trained on T2-weighted anatomical images and T2*-weighted functional images. The trained models were tested on both interior and exterior datasets. The 3D U-Net models yielded a higher accuracy in brain extraction from both T2-weighted images (Dice > 0.984, Jaccard index > 0.968 and Hausdorff distance < 7.7) and T2*-weighted images (Dice > 0.964, Jaccard index > 0.931 and Hausdorff distance < 3.3), compared with the two widely used mouse skull-stripping methods (RATS and SHERM). The resting-state fMRI results using automatic segmentation with the 3D U-Net models are identical to those obtained by manual segmentation for both the seed-based and group independent component analysis. These results demonstrate that the 3D U-Net based method can replace manual brain extraction in mouse fMRI analysis.

neuroscience↗

bioRxiv2021

Crocin inhibited amyloid-beta (Aβ) generation via promoting non-amyloidogenic APP processing and suppressed ER stress UPR signaling in N2a/APP cells

BackgroundCrocin is a major active component of saffron (Crocus sativus) with many beneficial effects. More recently, crocin has been proposed for management of neurodegenerative diseases such as Alzheimers disease (AD). Here, we demonstrated for the first time that crocin reduced amyloid-beta (A{beta}) generation through promoting -cleavage of APP processing and inhibited ER stress by attenuating UPR signaling in N2a/APP cells. MethodologyMouse neuroblastoma N2a cells stably transfected with the Swedish mutant APP (N2a/APP) was used as a cellular model for AD pathogenesis. Vector transfected cells (N2a/vector) were employed to serve as control. The toxicity of crocin was first evaluated and non-toxic treatment of crocin (>30 {micro}M for 24 h) was used for further investigations. A{beta} levels were determined by ELISA. Expression levels of UPR signaling proteins were determined by using Western blot. ResultsCrocin significantly inhibited the protein expression of total APP in N2a/APP cells and promoted -cleavage of APP processing to increase sAPP generation, but only modestly reduced BACE-1 and PS1, suggesting A{beta} reduction by crocin was mainly associated with the non-amyloidogenic APP processing. Further investigation on ER stress related protein expressions showed that GRP78, CHOP, p-PERK, p-eIF2, p-IRE1, XBP1, ATF6 and PDI were all significantly elevated in N2a/APP cells compared to N2a/vector. Crocin effectively reduced the levels of GRP78 and CHOP, and significantly inhibited p-PERK/p-eIF2 amd AT6 while slightly reduced p-IRE1. ConclusionThe present study showed that crocin was effective at blocking A{beta} generation and inhibiting ER stress associated overactivation of UPR signaling in AD cell model N2a/APP. The results provided evidence for crocin as useful natural product for the treatment of AD.

neuroscience↗

bioRxiv2021

Exosomal MFGE8 from high glucose induced endothelial cells is involved in calcification/senescence of vascular smooth muscle cells

Vascular calcification/aging is a crucial feature of diabetic macro vasculopathy, resulting in serious cardiovascular diseases. The calcification/senescence of vascular smooth muscle cells (VSMCs) induced by hyperglycemia can cause diabetic vascular calcification/aging. However, the mechanism of VSMCs calcification/senescence involved in diabetic vascular calcification/aging remains unknown. The purpose of this study was to determine how the high glucose (HG) information in circulating blood is transmitted from vascular endothelial cells (ECs) to VSMCs, which are not contacted with blood directly. Exosomes have attracted much attention for their vital roles in regulating cell-to-cell communication. In this study, we found that milk fat globule epidermal growth factor 8 (MFGE8) was enriched in high glucose induced human umbilical vein endothelial cell exosomes (HG-HUVEC-Exo) and regulate VSMCs calcification/senescence, characterized by up-regulated expressions of alkaline phosphatase (ALP) and Runt-related transcription factor 2 (Runx2), as well as the increased mineralized nodules and senescence-associated {beta}-galactosidase (SA-{beta}-gal) positive cells. Upstream mechanism studies showed that sirtuin1 (SIRT1) was involved in VSMCs calcification/senescence by affecting the expression of MFGE8. We also found that inflammatory response mediated by IL-1{beta}, IL-6, and IL-8 was closely associated with MFGE8 and played a key role in regulating HG-HUVEC-Exo-induced VSMCs calcification/senescence. These findings provide a new insight into the mechanism of exosomal MFGE8 as a potential preventive and therapeutic target for the intervention of diabetic vascular calcification/aging.

molecular biology↗

bioRxiv2021

A New Perspective on Individual Reliability beyond Group Effects for Event-related Potentials: A Multisensory Investigation and Computational Modeling

The dominant approach in investigating the individual reliability for event-related potentials (ERPs) is to extract peak-related features at electrodes showing the strongest group effects. Such a peak-based approach implicitly assumes ERP components showing a stronger group effect are also more reliable, but this assumption has not been substantially validated and few studies have investigated the reliability of ERPs beyond peaks. In this study, we performed a rigorous evaluation of the test-retest reliability of ERPs collected in a multisensory and cognitive experiment from 82 healthy adolescents, each having two sessions. By comparing group effects and individual reliability, we found that a stronger group-level response in ERPs did not guarantee a higher reliability. Further, by simulating ERPs with a computational model, we found that the consistency between group-level ERP responses and individual reliability was modulated by inter-subject latency jitter and inter-trial variability. The current findings suggest that the conventional peak-based approach may underestimate the individual reliability in ERPs. Hence, a comprehensive evaluation of the reliability of ERP measurements should be considered in individual-level neurophysiological trait evaluation and psychiatric disorder diagnosis.

neuroscience↗

bioRxiv2021

Global Mapping of Mouse CSF Flow via HEAP-METRIC Phase-contrast MRI

Roles of Cerebrospinal fluid (CSF) in brain waste clearance and homeostasis has been increasingly recognized, thus measuring its flow dynamics could provide important information about its function and perturbance. While phase-contrast MRI can be used for non-invasive flow mapping, so far its mapping of low velocity flow (such as mouse brain CSF) is not possible. Here we developed a novel generalized Hadamard encoding based multi-band acceleration scheme dubbed HEAP-METRIC (Hadamard Encoding APproach of Multi-band Excitation for short TR Imaging aCcelerating), and with significantly increased SNR per time, HEAP-METRIC phase-contrast MRI achieved fast and accurate mapping of slow (~102 micron/s) flow. Utilizing this novel method, we revealed a heterogeneous global pattern of CSF flow in the awake mouse brain with a averaged flow of ~200 micron/s, and further found isoflurane anesthesia reduced CSF flow that was accompanied by reduction of glymphatic function. Therefore, we developed the novel HEAP-METRIC phase-contrast MRI for mapping low velocity flow, and demonstrated its capability for global mapping of mouse CSF flow and its potential alterations related to various physiological or pathological conditions.

neuroscience↗

bioRxiv2021

Cross-Individual Affective Detection Using EEG Signals with Audio-Visual Embedding

EEG signals have been successfully used in affective detection applications, which could directly capture brain dynamics and reflect emotional changes at a high temporal resolution. However, the generalized ability of the model across individuals has not been thoroughly developed yet. An involvement of other data modality, such as audio-visual information which are usually used for emotion eliciting, could be beneficial to estimate intrinsic emotions in video content and solve the individual differences problem. In this paper, we propose a novel deep affective detection model, named as EEG with audio-visual embedding (EEG-AVE), for cross-individual affective detection. Here, EEG signals are exploited to identify the individualized emotional patterns and contribute the individual preferences in affective detection; while audio-visual information is leveraged to estimate the intrinsic emotions involved in the video content and enhance the reliability of the affective detection performance. Specifically, EEG-AVE is composed of two parts. For EEG-based individual preferences prediction, a multi-scale domain adversarial neural network is developed to explore the shared dynamic, informative, and domain-invariant EEG features across individuals. For video-based intrinsic emotions estimation, a deep audio-visual feature based hypergraph clustering method is proposed to examine the latent relationship between semantic audio-visual features and emotions. Through an embedding model, both estimated individual preferences and intrinsic emotions are incorporated with shared weights and further are used together to contribute to affective detection across individuals. We conduct cross-individual affective detection experiments on two well-known emotional databases for model evaluation and comparison. The results show our proposed EEG-AVE model achieves a better performance under a leave-one-individual-out cross-validation individual-independent evaluation protocol. EEG-AVE is demonstrated as an effective model with good generalizability, which makes it a power tool for cross-individual emotion detection in real-life applications.

bioengineering↗

bioRxiv2021

Modelling Porcine NAFLD by Deletion of Leptin and defining the role of AMPK in hepatic fibrosis

Liver fibrosis occurs during chronic liver disease. Advanced liver fibrosis results in cirrhosis, liver failure and often requires liver transplantation. However, due to the lack of human models, mechanisms underlining the pathogenesis of liver fibrosis remain unclear. Recent studies implicated a central role of deranged lipid metabolism in its pathogenesis. In this study, we generated LEPTIN-deficient (LEPTIN-/-) pigs using zinc finger nuclease technology to investigate the mechanisms of liver fibrosis associated with obesity. The LEPTIN-/- pigs showed increased body fat and significant insulin resistance by 12 months of age. To resemble non-alcoholic fatty liver disease (NAFLD) patients, LEPTIN-/- pig developed the phenotypic features of fatty liver, non-alcoholic steatohepatitis (NASH) and hepatic fibrosis with age. Meanwhile, LEPTIN absence reduced phosphorylation of JAK2-STAT3 and AMPK. The alteration of JAK2-STAT3 enhanced fatty acid {beta}-oxidation, whereas inactivation of AMPK led to mitochondrial autophagy, and both contributed to increased oxidative stress in hepatocytes. Although Leptin deletion in the rat liver altered JAK2-STAT3 phosphorylation, it activated the AMPK pathway and prevented liver fibrogenesis in contrast with the LEPTIN-/- pig. To our knowledge, the LEPTIN-/- pig provides the first model recapitulating the full pathogenesis of NAFLD and its progression toward liver fibrosis. The activity of AMPK signaling pathway suggests a potential target for development of new strategies for the diagnosis and treatment of NAFLD.

developmental biology↗

bioRxiv2021

Stability of DNA methylation and chromatin accessibility in structurally diverse maize genomes

Accessible chromatin and unmethylated DNA are associated with many genes and cis-regulatory elements. Attempts to understand natural variation for accessible chromatin regions (ACRs) and unmethylated regions (UMRs) often rely upon alignments to a single reference genome. This limits the ability to assess regions that are absent in the reference genome assembly and monitor how nearby structural variants influence variation in chromatin state. In this study, de novo genome assemblies for four maize inbreds (B73, Mo17, Oh43 and W22) are utilized to assess chromatin accessibility and DNA methylation patterns in a pan-genome context. The number of UMRs and ACRs that can be identified is more accurate when chromatin data is aligned to the matched genome rather than a single reference genome. While there are UMRs and ACRs present within genomic regions that are not shared between genotypes, these features are substantially enriched within shared regions, as determined by chromosomal alignments. Characterization of UMRs present within shared genomic regions reveals that most UMRs maintain the unmethylated state in other genotypes with only a small number being polymorphic between genotypes. However, the majority of UMRs between genotypes only exhibit partial overlaps suggesting that the boundaries between methylated and unmethylated DNA are dynamic. This instability is not solely due to sequence variation as these partially overlapping UMRs are frequently found within genomic regions that lack sequence variation. The ability to compare chromatin properties among individuals with structural variation enables pan-epigenome analyses to study the sources of variation for accessible chromatin and unmethylated DNA. Article summaryRegions of the genome that have accessible chromatin or unmethylated DNA are often associated with cis-regulatory elements. We assessed chromatin accessibility and DNA methylation in four structurally diverse maize genomes. There are accessible or unmethylated regions within the non-shared portions of the genomes but these features are depleted within these regions. Evaluating the dynamics of methylation and accessibility between genotypes reveals conservation of features, albeit with variable boundaries suggesting some instability of the precise edges of unmethylated regions.

plant biology↗

bioRxiv2021

In vivo co-registered hybrid-contrast imaging by successive photoacoustic tomography and magnetic resonance imaging

Magnetic resonance imaging (MRI) and photoacoustic tomography (PAT) are two advanced imaging modalities that offer two distinct image contrasts: MRI has a multi-parameter contrast mechanism that provides excellent anatomical soft tissue contrast, whereas PAT is capable of mapping tissue physiological metabolism and exogenous contrast agents with optical specificity. Attempts have been made to integrate these two modalities, but rigid and reliable registration of the images for in vivo imaging is still challenging. In this paper, we present a complete hardware-software solution for the successive acquisition and co-registration of PAT and MRI images in in vivo animal studies. Based on commercial PAT and MRI scanners, our solution includes a 3D-printed dual-modality animal imaging bed, a 3-D spatial image co-registration algorithm with bi-model markers, and a robust modality switching protocol for in vivo imaging studies. Using the proposed solution, we successfully demonstrated co-registered hybrid-contrast PAT-MRI imaging that simultaneously display multi-scale anatomical, functional and molecular characteristics on healthy and cancerous living mice. Week-long longitudinal dual-modality imaging of tumor development reveals information on size, border, vascular pattern, blood oxygenation, and molecular probe metabolism of the tumor micro-environment at the same time. Additionally, by incorporating soft-tissue information in the co-registered MRI image, we further show that PAT image quality could be enhanced by MRI-guided light fluence correction. The proposed methodology holds the promise for a wide range of pre-clinical research applications that benefit from the PAT-MRI dual-modality image contrast.

bioengineering↗

bioRxiv2021

Ku70 suppresses alternative end-joining in G1-arrested progenitor B cells

Classical nonhomologous end-joining (C-NHEJ) repairs DNA double-stranded breaks (DSBs) throughout interphase but predominates in G1-phase when homologous recombination is unavailable. Complexes containing the Ku70/80 ("Ku") and XRCC4/Ligase IV (Lig4) core C-NHEJ factors are required, respectively, for sensing and joining DSBs. While XRCC4/Ligase IV are absolutely required for joining RAG1/2-endonucease ("RAG")-initiated DSBs during V(D)J recombination in G1-phase progenitor lymphocytes, cycling cells deficient for XRCC4/Ligase IV also can join chromosomal DSBs by alternative end-joining (A-EJ) pathways. Restriction of V(D)J recombination by XRCC4/Ligase IV-mediated joining has been attributed to RAG shepherding V(D)J DSBs exclusively into the C-NHEJ pathway. Here, we report that A-EJ of DSB ends generated by RAG1/2, Cas9:gRNA and Zinc finger endonucleases in Lig4-deficient G1-arrested progenitor B cell lines is suppressed by Ku. Thus, while diverse DSBs remain largely as free broken ends in Lig4-deficient G1-arrested progenitor B cells, deletion of Ku70 increases DSB rejoining and translocation levels to those observed in Ku70-deficient counterparts. Correspondingly, while RAG-initiated V(D)J DSB joining is abrogated in Lig4-deficient G1-arrested progenitor B cell lines, joining of RAG-generated DSBs in Ku70-deficient and Ku70/Lig4 double-deficient lines occurs through a translocation-like A-EJ mechanism. Thus, in G1-arrested, Lig4-deficient progenitor B cells are functionally end-joining suppressed due to Ku-dependent blockage of A-EJ, potentially, in association with G1-phase down-regulation of Ligase1. Finally, we suggest that differential impacts of Ku-deficiency versus Lig4-deficiency on V(D)J recombination, neuronal apoptosis, and embryonic development results from Ku-mediated inhibition of A-EJ in the G1 cell cycle phase in Lig4-defcient developing lymphocyte and neuronal cells. Significance StatementAlternative end-joining (A-EJ) is implicated in oncogenic translocations and mediating DNA double-strand break (DSB) repair in cycling cells when classical nonhomologous endjoining (C-NHEJ) factors of the C-NHEJ Ligase complex are absent. However, V(D)J recombination-associated DSBs that occur in G1 cell cycle-phase progenitor lymphocytes are joined exclusively by the C-NHEJ pathway. Until now, however, the overall mechanisms that join general DSBs in G1-phase progenitor B cells had not been fully elucidated. Here, we report that Ku, a core C-NHEJ double-strand break recognition complex, directs repair of a variety of different targeted DSBs towards C-NHEJ and suppresses A-EJ in G1-phase cells. We suggest this Ku activity explains how Ku-deficiency can rescue the neuronal development and embryonic lethality phenotype of Ligase 4-deficient mice.

genetics↗

bioRxiv2021

Applying cis-regulatory codes to predict conserved and variable heat and cold stress response in maize

Changes in gene expression are important for response to abiotic stress. Transcriptome profiling performed on maize inbred and hybrid genotypes subjected to heat or cold stress identifies many transcript abundance changes in response to these environmental conditions. Motifs that are enriched near differentially expressed genes were used to develop machine learning models to predict gene expression responses to heat or cold. The best performing models utilize the sequences both upstream and downstream of the transcription start site. Prediction accuracies could be improved using models developed for specific co-expression clusters compared to using all up- or down-regulated genes or by only using motifs within unmethylated regions. Comparisons of expression responses in multiple genotypes were used to identify genes with variable response and to identify cis- or trans-regulatory variation. Models trained on B73 data have lower performance when applied to Mo17 or W22, this could be improved by using models trained on data from all genotypes. However, the models have low accuracy for correctly predicting genes with variable responses to abiotic stress. This study provides insights into cis-regulatory motifs for heat- and cold-responsive gene expression and provides a framework for developing models to predict expression response to abiotic stress across multiple genotypes. One sentence summaryTranscriptome profiling of maize inbred and hybrid seedlings subjected to heat or cold stress was used to identify key cis-regulatory elements and develop models to predict gene expression responses.

plant biology↗

bioRxiv2021

Aberrant Dynamic Functional Connectivity of Default Mode Network in Schizophrenia and Links to Symptom Severity

BackgroundSchizophrenia affects around 1% of the global population. Functional connectivity extracted from resting-state functional magnetic resonance imaging (rs-fMRI) has previously been used to study schizophrenia and has great potential to provide novel insights into the disorder. Some studies have shown abnormal functional connectivity in the default mode network of individuals with schizophrenia, and more recent studies have shown abnormal dynamic functional connectivity (dFC) in individuals with schizophrenia. However, DMN dFC and the link between abnormal DMN dFC and symptom severity have not been well characterized. MethodResting-state fMRI data from subjects with schizophrenia (SZ) and healthy controls (HC) across two datasets were analyzed independently. We captured seven maximally independent subnodes in the DMN by applying group independent component analysis and estimated dFC between subnode time courses using a sliding window approach. A clustering method separated the dFCs into five reoccurring brain states. A feature selection method modeled the difference between SZs and HCs using the state-specific FC features. Finally, we used the transition probability of a hidden Markov model to characterize the link between symptom severity and dFC in SZ subjects. ResultsWe found decreases in the connectivity of the anterior cingulate cortex (ACC) and increases in the connectivity between the precuneus (PCu) and the posterior cingulate cortex (PCC) (i.e., PCu/PCC) of SZ subjects. In SZ, the transition probability from a state with weaker PCu/PCC and stronger ACC connectivity to a state with stronger PCu/PCC and weaker ACC connectivity increased with symptom severity. ConclusionsTo our knowledge, this was the first study to investigate DMN dFC and its link to schizophrenia symptom severity. We identified reproducible neural states in a data-driven manner and demonstrated that the strength of connectivity within those states differed between SZs and HCs. Additionally, we identified a relationship between SZ symptom severity and the dynamics of DMN functional connectivity. We validated our results across two datasets. These results support the potential of dFC for use as a biomarker of schizophrenia and shed new light upon the relationship between schizophrenia and DMN dynamics.

neuroscience↗

bioRxiv2020

Quantifying liquid-liquid phase separation property of chromatin under physiological conditions using Hi-MS and Hi-C

BackgroundLiquid-liquid phase separation (LLPS) is an important organizing principle for biomolecular condensation and chromosome compartmentalization. However, while many proteins have been reported to undergo LLPS, quantitative and global analysis of chromatin LLPS property remains absent. ResultsHere, by combing chromatin associated protein pull-down, quantitative proteomics and 1,6-hexanediol treatment, we developed Hi-MS and defined anti-1,6-HD index of chromatin-associated proteins (AICAP) to quantitative measurement of LLPS property of chromatin-associated proteins in their endogenous state and physiological abundance. The AICAP values were verified by previously reported experiments and were reproducible across different MS platforms. Moreover, the AICAP values were highly correlate with protein functions. Proteins act in active/regulatory biological process often exhibit low AICAP values, while proteins act in structural and repressed biological process often exhibit high AICAP values. We further revealed that chromatin organization changes more in compartment A than B, and the changes in chromatin organization at various levels, including compartments, TADs and loops are highly correlated to the LLPS properties of their neighbor nuclear condensates. ConclusionsOur work provided the first global quantitative measurement of LLPS properties of chromatin-associated proteins and higher-order chromatin structure, and demonstrate that the active/regulatory chromatin components, both protein (trans) and DNA (cis), exhibit more hydrophobicity-dependent LLPS properties than the repressed/structural chromatin components.

cell biology↗

bioRxiv2020

The selfish nature in interpersonal exchange among adolescents: imposing the kind and submitting to the exploitative

Cooperation is essential for success in society. Research consistently showed that adolescents are less cooperative than adults, which is often attributed to underdeveloped mentalizing that limits their expectations of others. However, the internal computations underlying this reduced cooperation remain largely unexplored. This study compared cooperation between adolescents and adults using a repeated Prisoners Dilemma Game. Adolescents cooperated less than adults, particularly after their partners cooperation. Computational modeling revealed that adults increased their intrinsic reward for reciprocating when their partner continued cooperating, a pattern absent in adolescents. Both computational modeling and self-reported ratings showed that adolescents did not differ from adults in building expectations of their partners cooperation. Therefore, the reduced cooperation appears driven by a lower intrinsic reward for reciprocity, reflecting a stronger motive to prioritize self-interest, rather than a deficiency in predicting others cooperation in social learning. These findings provide insights into the developmental trajectory of cooperation from adolescence to adulthood.

animal behavior and cognition↗

bioRxiv2020

Airway bacterial and fungal microbiome in chronic obstructive pulmonary disease

BackgroundLittle is known about airway mycobiome, and its relationship with bacterial microbiome in chronic obstructive pulmonary disease (COPD). MethodsHere we report the first simultaneous characterization of sputum bacterial and fungal microbiome in 84 stable COPD and 29 healthy subjects, using 16S ribosomal DNA and fungal internal transcribed spacer DNA sequencing. ResultsAscomycota predominated over Basidiomycota in fungal microbiome both in COPD patients and healthy controls. Meyerozyma, Candida, Aspergillus and Schizophyllum were most abundant at the genus level. There was a significant inverse correlation between bacterial and fungal microbial diversity, both of which altered in opposite directions in COPD patients versus controls, and in frequent versus non-frequent exacerbators. An enhanced bacterial-fungal ecological interaction was observed in COPD patients, which was characterized by higher proportion of co-occurrence intrakingdom interactions and co-exclusive interkingdom interactions. In COPD, four mutually co-occurring fungal operational taxonomic units (OTUs) in Candida palmioleophila, Aspergillus and Sordariomycetes exhibited co-exclusive relationships with other fungal OTUs, which was specifically present in frequent exacerbators but not in non-frequent exacerbators. Conversely, the mutual co-occurrence interactions between bacterial OTUs in Rothia mucilaginosa, Streptococcus, Veillonella and Prevotella, showed up in non-frequent exacerbators but not in frequent exacerbators. The perturbed bacterial-fungal interactions in COPD were associated with increased airway inflammatory mediators such as IL-6 and IL-8. InterpretationThe disruption of airway bacterial-fungal community balance, characterized by the loss of commensal bacterial taxa and enriched pathogenic fungal taxa, is implicated in COPD. The airway mycobiome is an important cofactor mediating COPD pathogenic infection and host inflammation. Clinical Trial Registrationwww.clinicaltrials.gov (NCT 03240315).

microbiology↗

bioRxiv2020

Defining a Global Map of Functional Group Based 3D Ligand-binding Motifs

Uncovering conserved 3D protein-ligand binding patterns at the basis of functional groups (FGs) shared by a variety of small molecules can greatly expand our knowledge of protein-ligand interactions. Despite that conserved binding patterns for a few commonly used FGs have been reported in the literature, large-scale identification and evaluation of FG-based 3D binding motifs are still lacking. Here, we developed AFTME, an alignment-free method for automatic mapping of 3D motifs to different FGs of a specific ligand through two-dimensional clustering. Applying our method to 233 nature-existing ligands, we defined 481 FG-binding motifs that are highly conserved across different ligand-binding pockets. Systematic analysis further reveals four main classes of binding motifs corresponding to distinct sets of FGs. Combinations of FG-binding motifs facilitate proteins to bind a wide spectrum of ligands with various binding affinities. Finally, we showed that these general binding patterns are also applicable to target-drug interactions, providing new insights into structure-based drug design.

bioinformatics↗

bioRxiv2020

Advanced eMAGE for highly efficient combinatorial editing of a stable genome

Eukaryotic multiplex genome engineering (eMAGE) offers a powerful tool to generate precise combinatorial genome modifications in Saccharomyces cerevisiae. We optimize the design of synthetic oligonucleotides and enrichment of edited populations to increase editing frequencies up to 90%, reduce workflow time by 40%, and engineer a tunable mismatch repair system to lower the rate of spontaneous mutations [~]17-fold. These advances transiently evade genome maintenance to introduce multiple edits at high efficiencies in a stable genetic background, expanding utility of eMAGE in eukaryotic cells.

synthetic biology↗

bioRxiv2020

Genetic and epigenetic contributions to variation in transposable element expression responses to abiotic stress in maize

O_LITransposable elements (TEs) pervade most eukaryotic genomes but the repetitive nature of TEs has complicated the analysis of their expression. Although the majority of TEs are silent, we document the activation of some TEs during abiotic stress. C_LIO_LITE expression was monitored in seedling leaf tissue of maize inbreds subjected to heat or cold stress conditions. DNA methylation profiles and comparative genomics were used to probe the variability of TE expression responses. C_LIO_LIAlthough there was no evidence for a genome-wide activation of TEs, a subset of TE families generate transcripts only in stress conditions. There is substantial variation for which TE families exhibit stress-responsive expression in the three genotypes. The stress-responsive activation of a TE family can often be attributed to a small number of elements in the family. These elements that are activated often contain small regions lacking DNA methylation, while fully methylated elements are rarely expressed. A comparison of the expression of specific TEs in different maize genotypes reveals high levels of variability that can be attributed to both genome content differences and epigenetic variation. C_LIO_LIThis study provides insights into the genetic and epigenetic factors that influence TE regulation in normal and stress conditions. C_LI

plant biology↗