Biology subjects

Wang, D.

Publications and source records attributed to Wang, D..

At least 775 records · Page 43Linked to original sources

bioRxiv2018

Efficient Multivariate Analysis Algorithms for Longitudinal Genome-wide Association Studies

MotivationCurrent dynamic phenotyping system introduces time as an extra dimension to genome-wide association studies (GWAS), which helps to explore the mechanism of dynamical genetic control for complex longitudinal traits. However, existing methods for longitudinal GWAS either ignore the covariance among observations of different time points or encounter computational efficiency issues.\n\nResultsWe herein developed efficient genome-wide multivariate association algorithms (GMA) for longitudinal data. In contrast to existing univariate linear mixed model analyses, the proposed new method has improved statistic power for association detection and computational speed. In addition, the new method can analyze unbalanced longitudinal data with thousands of individuals and more than ten thousand records within a few hours. The corresponding time for balanced longitudinal data is just a few minutes.\n\nAvailability and ImplementationWe wrote a software package to implement the efficient algorithm named GMA (https://github.com/chaoning/GMA), which is available freely for interested users in relevant fields.

bioinformatics↗

bioRxiv2018

Multilayer network analysis of miRNA and protein expression profiles in breast cancer patients

MiRNAs and proteins play important roles in different stages of tumor development and serve as biomarkers for the early diagnosis of cancer. A new algorithm that combines machine learning algorithms and multilayer complex network analysis is hereby proposed to explore the potential diagnostic values of miRNAs and proteins. XGBoost and random forest algorithms were employed to exclude unrelated miRNAs and proteins, and the most significant candidates were retained for the further analysis. Given these candidates possible functional relationships to one other, a multilayer complex network was constructed to identify miRNAs and proteins that could serve as biomarkers for breast cancer. Proteins and miRNAs that are nodes in the network were subsequently categorized into two network layers considering their distinct functions. Maximal information coefficient (MIC) was applied to assess intralayer and interlayer connection. The betweenness centrality was used as the first measurement of the importance of the nodes within each single layer. To further characterize the interlayer interaction between miRNAs and proteins, the degree of the nodes was chosen as the second measurement to map their signalling pathways. By combining these two measurements into one score and comparing the difference of the same candidate between normal tissue and cancer tissue, this novel multilayer network analysis could be applied to successfully identify molecules associated with breast cancer.

bioinformatics↗

bioRxiv2018

Unraveling the genetic architecture of grain size in einkorn wheat through linkage and homology mapping, and transcriptomic profiling

HighlightGenome-wide linkage and homology mapping revealed 17 genomic regions through a high-density einkorn wheat genetic map constructed using RAD-seq, and transcription levels of 20 candidate genes were explored using RNA-seq.\n\nAbstractUnderstanding the genetic architecture of grain size is a prerequisite to manipulate the grain development and improve the yield potential in crops. In this study, we conducted a whole genome-wide QTL mapping of grain size related traits in einkorn wheat by constructing a high-density genetic map, and explored the candidate genes underlying QTL through homologous analysis and RNA sequencing. The high-density genetic map spanned 1873 cM and contained 9937 SNP markers assigned to 1551 bins in seven chromosomes. Strong collinearity and high genome coverage of this map were revealed with the physical maps of wheat and barley. Six grain size related traits were surveyed in five agro-climatic environments with 80% or more broad-sense heritability. In total, 42 QTL were identified and assigned to 17 genomic regions on six chromosomes and accounted for 52.3-66.7% of the phenotypic variations. Thirty homologous genes involved in grain development were located in 12 regions. RNA sequencing provided 4959 genes differentially expressed between the two parents. Twenty differentially expressed genes involved in grain size development and starch biosynthesis were mapped to nine regions that contained 26 QTL, indicating that the starch biosynthesis pathway played a vital role on grain development in einkorn wheat. This study provides new insights into the genetic architecture of grain size in einkorn wheat, the underlying genes enables the understanding of grain development and wheat genetic improvement, and the map facilitates the mapping of quantitative traits, map-based cloning, genome assembling and comparative genomics in wheat taxa.

genetics↗

bioRxiv2018

Quantification and discovery of sequence determinants of protein per mRNA amount in 29 human tissues

Despite their importance in determining protein abundance, a comprehensive catalogue of sequence features controlling protein-to-mRNA (PTR) ratios and a quantification of their effects is still lacking. Here we quantified PTR ratios for 11,575 proteins across 29 human tissues using matched transcriptomes and proteomes. We analyzed the contribution of known sequence determinants of protein synthesis and degradation and 15 novel mRNA and protein sequence motifs that we found by association testing. While the dynamic range of PTR ratios spans more than 2 orders of magnitude, our integrative model predicts PTR ratios at a median precision of 3.2-fold. A reporter assay provided significant functional support for two novel UTR motifs and a proteome-wide competition-binding assay identified motif-specific bound proteins for one motif. Moreover, our direct comparison of protein to RNA levels led to a new metrics of codon optimality. Altogether, this study shows that a large fraction of PTR ratio variance across genes can be predicted from sequence and identified many new candidate post-transcriptional regulatory elements in the human genome.

systems biology↗

bioRxiv2018

A deep proteome and transcriptome abundance atlas of 29 healthy human tissues

Genome-, transcriptome- and proteome-wide measurements provide valuable insights into how biological systems are regulated. However, even fundamental aspects relating to which human proteins exist, where they are expressed and in which quantities are not fully understood. Therefore, we have generated a systematic, quantitative and deep proteome and transcriptome abundance atlas from 29 paired healthy human tissues from the Human Protein Atlas Project and representing human genes by 17,615 transcripts and 13,664 proteins. The analysis revealed that few proteins show truly tissue-specific expression, that vast differences between mRNA and protein quantities within and across tissues exist and that the expression levels of proteins are often more stable across tissues than those of transcripts. In addition, only ~2% of all exome and ~7% of all mRNA variants could be confidently detected at the protein level showing that proteogenomics remains challenging, requires rigorous validation using synthetic peptides and needs more sophisticated computational methods. Many uses of this resource can be envisaged ranging from the study of gene/protein expression regulation to protein biomarker specificity evaluation to name a few.

systems biology↗

bioRxiv2018

Effect of Live Attenuated Influenza Vaccine on Pneumococcal Carriage

The widely used nasally-administered Live Attenuated Influenza Vaccine (LAIV) alters the dynamics of naturally occurring nasopharyngeal carriage of Streptococcus pneumoniae in animal models. Using a human experimental model (serotype 6B) we tested two hypotheses: 1) LAIV increased the density of S. pneumoniae in those already colonised; 2) LAIV administration promoted colonisation. Randomised, blinded administration of LAIV or nasal placebo either preceded bacterial inoculation or followed it, separated by a 3-day interval. The presence and density of S. pneumoniae was determined from nasal washes by bacterial culture and PCR. Overall acquisition for bacterial carriage were not altered by prior LAIV administration vs. controls (25/55 [45.5%] vs 24/62 [38.7%] respectively, p=0.46). Transient increase in acquisition was detected in LAIV recipients at day 2 (33/55 [60.0%] vs 25/62 [40.3%] in controls, p=0.03). Bacterial carriage densities were increased approximately 10-fold by day 9 in the LAIV recipients (2.82 vs 1.81 log10 titers, p=0.03). When immunisation followed bacterial acquisition (n=163), LAIV did not change area under the bacterial density-time curve (AUC) at day 14 by conventional microbiology (primary endpoint), but significantly reduced AUC to day 27 by PCR (p=0.03). These studies suggest that LAIV may transiently increase nasopharyngeal density of S. pneumoniae. Transmission effects should therefore be considered in the timing design of vaccine schedules.\n\nTrial registrationThe study was registered on EudraCT (2014-004634-26)\n\nFundingThe study was funded by the Bill and Melinda Gates Foundation and the UK Medical Research Council.

immunology↗

bioRxiv2018

Co-outbreak of ST37 and a novel ST3006 Klebsiella pneumoniae from multi-site infection in a neonatal intensive care unit, Fuzhou, China

BackgroundThe outbreak of carbapenems resistant Klebsiella pneumoniae (K. pneumoniae) is a serious public health problem, especially in the neonatal intensive care unit (NICU).\n\nMethodsFifteen strains of K. pneumoniae were isolated from seven neonates during June 3-28, 2017 in a NICU. Antimicrobial susceptibility was determined by the Vitek 2 system and micro-broth dilution method. Multi-locus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) were used to analyse the genetic relatedness of isolates. Genome sequencing and gene function analyses were performed for investigating pathogenicity and drug resistance and screening genomic islands.\n\nFindingsTwo K. pneumoniae clones were identified from seven neonates, one ST37 strain and another new sequence type ST3006. The ST37 strain exhibited multi-drug resistance genes and resistance to carbapenem. MLST and PFGE showed that 15 strains were divided into three groups, with a high level of homology. Gene sequencing and analysis indicated that KPN1343 harboured 12 resistance genes, 15 genomic islands and 205 reduced virulence genes. KPN1344 harboured four resistance genes, 19 genomic islands and 209 reduced virulence genes.\n\nConclusionCo-outbreak of K. pneumoniae involved two clones, ST36 and ST3006, causing multi-site infection. Genome sequencing and analysis is an effective method for studying bacterial resistance genes and their functions.

microbiology↗

bioRxiv2018

Long-read sequencing identified a causal structural variant in an exome-negative case and enabled preimplantation genetic diagnosis

For a proportion of individuals judged clinically to have a recessive Mendelian disease, only one pathogenic variant can be found from clinical whole exome sequencing (WES), posing a challenge to genetic diagnosis and genetic counseling. Here we describe a case study, where WES identified only one pathogenic variant for an individual suspected to have glycogen storage disease type Ia (GSD-Ia), which is an autosomal recessive disease caused by bi-allelic mutations in the G6PC gene. Through Nanopore long-read whole-genome sequencing, we identified a 7kb deletion covering two exons on the other allele, suggesting that complex structural variants (SVs) may explain a fraction of cases when the second pathogenic allele is missing from WES on recessive diseases. Both breakpoints of the deletion are within Alu elements, and we designed Sanger sequencing and quantitative PCR assays based on the breakpoints for preimplantation genetic diagnosis (PGD) for the family planning on another child. Four embryos were obtained after in vitro fertilization (IVF), and an embryo without deletion in G6PC was transplanted after PGD and was confirmed by prenatal diagnosis, postnatal diagnosis, and subsequent lack of disease symptoms after birth. In summary, we present one of the first examples of using long-read sequencing to identify causal yet complex SVs in exome-negative patients, which subsequently enabled successful personalized PGD.

genetics↗

bioRxiv2018

Molecular Detection of H.pylori Antibiotic-Resistant Genes and Bioinformatics Predictive Analysis

To explore the mutation characteristics of H.pylori resistance-related genes to antibiotics of clarithromycin, levofloxacin and metronidazole. 23S rRNA, gyrA, gyrB, rdxA and frxA genes were amplified and sequenced, respectively. Their structural alteration after mutation was predicted using bioinformatics software. In the clarithromycin-resistant strains, the mutation rate in site A2143G was 74.2% (n=23). The mutations in sites C1883T, C2131T and T2179G might cause structural alteration. In the levofloxacin-resistant strains, the mutation rates in 87 (N to K/I) and 91 (D to N/Y/G) of gyrA were 28.6% (n=16) and 12.5% (n =7), respectively. Meanwhile, one of the mutation strains in site 91 was accompanied by D99N variation. Additionally, a D143E mutation was found in one drug-resistant strain. Some changes of tertiary structure occurred after these mutations. The mutation types of RdxA protein consisted of protein truncation caused by premature stop codons (n=26, 33.3%), frameshift mutations (n=8, 10.3%), FMN-binding sites (n=16, 20.5%) and the others (n=11, 14.1%). Predictive analysis showed that mutations in the first three groups and the A118S of the last group could lead to structural alteration. Our study suggested the clarithromycin-resistant sites of H.pylori were mainly located in A2143G of 23S rRNA. C1883T, C2131T and T2179G might also be related to resistance. Levofloxacin resistance was mainly based on the amino acid changes in 87 and 91 sites of gyrA. The new sites D99N and D143E might also be associated with resistance. Metronidazole resistance was related to RdxA protein truncation, frameshift, and FMN binding. The new site A118S might also be linked to drug resistance.

microbiology↗

bioRxiv2018

Anti-BP180 Autoantibodies Are Present in Stroke and Recognize Human Cutaneous BP180 and BP180-NC16A

BackgroundCurrent evidence has revealed a significant association between bullous pemphigoid (BP) and neurological diseases (ND), including stroke, but the incidence of BP autoantibodies in patients with stroke has not previously been investigated.\n\nObjectiveOur study aims to assess BP antigen-specific antibodies in stroke patients.\n\nMethods100 patients with stroke and 100 healthy controls were randomly selected to measure anti-BP180/230 IgG autoantibodies by enzyme-linked immunosorbent assay (ELISA), salt split indirect immunofluorescence (IIF) and immunoblotting against human cutaneous BP180 and BP180-NC16A.\n\nResultsAnti-BP180 autoantibodies were found in 14(14.0%) patients with stroke and 5(5.0 %) of controls by ELISA (p<0.05). Sera from 13(13.0%) patients with stroke and 3(3.0 %) controls reacted with 180-kDa proteins from human cutis extract (p<0.05). 11(11.0%) of stroke and 2(2.0 %) of control sera recognized the human recombinant full length BP180 and NC16A (p<0.05). The anti-BP180-positive patients were significantly younger than the negative patients in stroke (p<0.001).\n\nLimitationsLongitudinal changes in antibody titers and long-term clinical outcome for a long duration were not fully investigated.\n\nConclusionDevelopment of anti-BP180 autoantibodies occur at a higher frequency after stroke, suggesting BP180 as a shared autoantigen in stroke with BP and providing novel insights into BP pathogenesis in aging.

neuroscience↗

bioRxiv2018

Illuminating microbial metabolic activities in the dark deep ocean with metaproteomics

The deep ocean is the largest habitat on earth and holds diverse microbial life forms. Significant advances have been made in microbial diversity and their genomic potential in the deep ocean, however, little is known about microbial metabolic activity that is crucial to regulate the bathypelagic carbon sequestration. Here, we characterized proteomes covering large particulate (>0.7 m), small particulate (0.2-0.7 m) and dissolved (10 kDa-0.2 m) fractions collected at a depth of 3000 m in the South China Sea. The Rhodospirillales, SAR324, SAR11, Nitrosinae/Tectomicrobia were the major contributors in the particulate fraction whereas Alteromonadales and viruses dominated the dissolved counterpart. Frequent detection of transcription or translation proteins in the particulate fractions indicated active metabolism of SAR324, Archaea, SAR11, and possible viable surface microbes, e.g. Prochlorococcus. Transporters for diverse substrates were the most abundant functional groups, and numerous spectra of formate dehydrogenases and glycine betaine transporters unveiled the importance of methylated compounds for the survival of deep-sea microbes. Notably, abundant non-viral proteins, especially transporters and cytoplasmic proteins, were detected in the dissolved fraction, indicating their potential roles in nutrient scavenging and the stress response. Our size-based proteomic study implied the holistic microbial activity mostly acting on the labile dissolved organic matter as well as the potential activities of surface microbes and dissolved non-viral proteins in the deep ocean.\n\nImportanceThe deep ocean produces one third of the biological CO2 in the ocean. However, little is known about metabolic activity of the bathypelagic microbial community which is crucial for understanding the biogeochemical cycling of organic matter, especially the formation of bulk refractory dissolved organic matter (DOM), one of the largest reservoirs of reduced carbon on Earth. This study provided the protein evidence firstly including both particulate and dissolved fractions to comprehensively decipher the active microbes and metabolic processes involved in the DOM recycling in the deep ocean. Our data supported the hypothesis of the carbon and energy supply from the labile DOM after the solution of sinking particles to the bathypelagic microbial community.

microbiology↗

bioRxiv2018

EZH2 co-opts gain-of-function p53 mutants to promote cancer growth and metastasis

With the unfolding of more and more cancer-driven gain-of-function (GOF) mutants of p53, it is important to define a common mechanism to systematically target different mutants rather than develop strategies tailored to inhibit each mutant individually. Here, using RNA immunoprecipitation sequencing (RIP-seq) we identified EZH2 as a p53 mRNA-binding protein. EZH2 bound to the internal ribosome entry site (IRES) in the 5 untranslated region (5UTR) of p53 mRNA and enhanced p53 protein translation in a methyltransferase-independent manner. EZH2 augmented p53 GOF mutant-mediated cancer growth and metastasis by increasing p53 GOF mutant protein level. EZH2 overexpression associated with the worse outcome only in patients with p53-mutated cancer. Depletion of EZH2 by antisense oligonucleotides inhibited p53 GOF mutant-mediated cancer growth. Our findings reveal a non-methyltransferase function of EZH2 that controls protein translation of p53 GOF mutants, inhibition of which causes synthetic lethality in cancer cells expressing p53 GOF mutants.

cancer biology↗

bioRxiv2018

Cancer therapy with a CRISPR-assistant telomerase-activating gene expression system

Telomerase is silent in most normal somatic cells while active in 90% of tumor cells. Various telomerase activity inhibitors have been developed to treat cancer but all failed due to side effects. Here we acted oppositely to develop a cancer therapy named telomerase-activating gene expression (Tage) by utilizing the telomerase activity in tumor cells. By using CRISPR/Cas9 functions, the Tage system can effectively kill various cancer cells, including HepG2, HeLa, PANC-1, MDA-MB-453, A549, HT-29, SKOV-3, Hepa1-6, and RAW264.7, without effecting normal cells. By using homothallic switching endonuclease and adeno-associated virus, the Tage system realizes its in vivo application. The virus-loaded Tage system can significantly and specifically kill the cancer cells in mice by intravenous drug administration without side effects or toxicity.\n\nOne Sentence Summary: Killing cancer cells in body with a gene therapy missile detonated by telomerase.

cancer biology↗

bioRxiv2018

Brain-Specific Deletion of GIT1 Impairs Cognition and Alters Phosphorylation of Synaptic Protein Networks Implicated in Schizophrenia Susceptibility

Despite tremendous effort, the molecular and cellular basis of cognitive deficits in schizophrenia remain poorly understood. Recent progress in elucidating the genetic architecture of schizophrenia has highlighted the association of multiple loci and rare variants that may impact susceptibility. One key example, given their potential etiopathogenic and therapeutic relevance, is a set of genes that encode proteins that regulate excitatory glutamatergic synapses in brain. A critical next step is to delineate specifically how such genetic variation impacts synaptic plasticity and to determine if and how the encoded proteins interact biochemically with one another to control cognitive function in a convergent manner. Towards this goal, here we study the roles of GPCR-kinase interacting protein 1 (GIT1), a synaptic scaffolding and signaling protein with damaging coding variants found in schizophrenia patients, as well as copy number variants found in patients with neurodevelopmental disorders. We generated conditional neural-selective GIT1 knockout mice and find that these mice have deficits in fear conditioning learning and spatial memory. Using global quantitative phospho-proteomics, we revealed that GIT1 deletion in brain perturbs specific networks of GIT1-interacting synaptic proteins. Importantly, several schizophrenia and neurodevelopmental disorder risk genes are present within these networks. We propose that GIT1 regulates the phosphorylation of a network of synaptic proteins and other critical regulators of neuroplasticity, and that perturbation of these networks may contribute to cognitive deficits observed in schizophrenia and neurodevelopmental disorders.

neuroscience↗

bioRxiv2018

Single-molecule optical mapping enables accurate molecular diagnosis of facioscapulohumeral muscular dystrophy (FSHD)

Facioscapulohumeral Muscular Dystrophy (FSHD) is a common adult muscular dystrophy in which the muscles of the face, shoulder blades and upper arms are among the most affected. FSHD is the only disease in which \"junk\" DNA is reactivated to cause disease, and the only known repeat array-related disease where fewer repeats cause disease. More than 95% of FSHD cases are associated with copy number loss of a 3.3kb tandem repeat (D4Z4 repeat) at the subtelomeric chromosomal region 4q35, of which the pathogenic allele contains less than 10 repeats and has a specific genomic configuration called 4qA. Currently, genetic diagnosis of FSHD requires pulsed-field gel electrophoresis followed by Southern blot, which is labor-intensive, semi-quantitative and requires long turnaround time. Here, we developed a novel approach for genetic diagnosis of FSHD, by leveraging Bionano Saphyr single-molecule optical mapping platform. Using a bioinformatics pipeline developed for this assay, we found that the method gives direct quantitative measurement of repeat numbers, can differentiate 4q35 and the highly paralogous 10q26 regions, can determine the 4qA/4qB allelic configuration, and can quantitate levels of post-zygotic mosaicism. We evaluated this approach on 5 patients (including two with post-zygotic mosaicism) and 2 patients (including one with post-zygotic mosaicism) from two separate cohorts, and had complete concordance with Southern blots, but with improved quantification of repeat numbers resolved between haplotypes. We concluded that single-molecule optical mapping is a viable approach for molecular diagnosis of FSHD and may be applied in clinical diagnostic settings once more validations are performed.

genomics↗

bioRxiv2018

A Novel QconCAT-Based Proteomics Method for Determining Allele-Specific Protein Expression (ASPE): a New Approach to Identify Cis-acting Genetic Variants

Measuring allele-specific expression (ASE) is a powerful approach for identifying cis-regulatory genetic variants. Here we developed a novel targeted proteomics method for quantification of allele-specific protein expression (ASPE) based on scheduled high resolution multiple reaction monitoring (sMRM-HR) with a heavy stable isotope-labeled quantitative concatamer (QconCAT) internal protein standard. This strategy was applied to the determination of the ASPE of UGT2B15 in human livers using the common UGT2B15 nonsynonymous variant rs1902023 (i.e. Y85D) as the marker to differentiate expressions from the two alleles. The QconCAT standard contains both the wild type tryptic peptide and the Y85D mutant peptide at a ratio of 1:1 to ensure accurate measurement of the ASPE of UGT2B15. The results from 18 UGT2B15 Y85D heterozygotes revealed that the ratios between wild type Y allele and mutant D allele varied from 0.60 to 1.46, indicating the presence of cis-regulatory variants. In addition, we observed no significant correlations between the ASPE and mRNA ASE of UGT2B15, suggesting the involvement of different cis-acting variants in regulating the transcription and translation processes of the gene. This novel ASPE approach provides a powerful tool for capturing cis-genetic variants involved in post-transcription processes, an important yet understudied area of research.

molecular biology↗

bioRxiv2018

Single-cell transcriptome of antler stem cells from antlerogenic periosteum

Antler regeneration, a stem cell-based epimorphic process, has potential as a valuable model for regenerative medicine. A pool of antler stem cells (ASCs) for antler development is located in the antlerogenic periosteum (AP). However, whether this ASC pool is homogenous or heterogeneous has not been fully evaluated. In this study, we produced a comprehensive transcriptome dataset at the single-cell level for the ASCs based on the 10x Genomics platform (scRNA-seq). A total of 4,565 ASCs were sequenced and classified into a large cell cluster, indicating that the ASCs resident in the AP are likely to be a homogeneous population. The scRNA-seq data revealed that tumor-related genes were highly expressed in these homogeneous ASCs: i.e. TIMP1, TMSB10, LGALS1, FTH1, VIM, LOC110126017 and S100A4. Results of screening for stem cell markers suggest that the ASCs may be considered as a special type of stem cell between embryonic (CD9) and adult (CD29, CD90, NPM1 and VIM) stem cells. Our results provide the first comprehensive transcriptome analysis at the single-cell level for the ASCs, and identified only one major cell type resident in the AP and some key stem cell genes, which may hold the key to why antlers, the unique mammalian organ, can fully regenerate once lost.

cell biology↗

bioRxiv2018

Single-trial Phase Entrainment of Theta Oscillations in Sensory Regions Predicts Human Associative Memory Performance

Episodic memories are rich in sensory information and often contain integrated information from different sensory modalities. For instance, we can store memories of a recent concert with visual and auditory impressions being integrated in one episode. Theta oscillations have recently been implicated in playing a causal role synchronizing and effectively binding the different modalities together in memory. However, an open question is whether momentary fluctuations in theta synchronization predict the likelihood of associative memory formation for multisensory events. To address this question we presented movies and sounds with their luminance and volume modulated at theta (4 Hz), with a phase offset at 0{degrees} or 180{degrees} with respect to each other. This allowed us to entrain the visual and auditory cortex in a synchronous (0{degrees}) or asynchronous manner (180{degrees}). Participants were asked to remember the association between a movie and a sound while having their EEG activity recorded. Associative memory performance was significantly enhanced in the synchronous (0{degrees}) compared to the asynchronous (180{degrees}) condition. Source-level analysis demonstrated that the physical stimuli effectively entrained their respective cortical areas with a corresponding phase offset. Importantly, the strength of entrainment during encoding correlated with the efficacy of associative memory such that small phase differences between visual and auditory cortex predicted a high likelihood of correct retrieval in a later recall test. These findings suggest that theta oscillations serve a specific function in the episodic memory system: Binding the contents of different modalities into coherent memory episodes.\n\nSignificance StatementHow multi-sensory experiences are bound to form a coherent episodic memory representation is one of the fundamental questions in human episodic memory research. Evidence from animal literature suggests that the relative timing between an input and theta oscillations in the hippocampus is crucial for memory formation. We precisely controlled the timing between visual and auditory stimuli and the neural oscillations at 4 Hz using a multisensory entrainment paradigm. Human associative memory formation depends on coincident timing between sensory streams processed by the corresponding brain regions. We provide evidence for a significant role of relative timing of neural theta activity in human episodic memory on a single trial level, which reveals a crucial mechanism underlying human episodic memory.

neuroscience↗