Biology subjects

Williams, K.

Publications and source records attributed to Williams, K..

At least 55 records · Page 3Linked to original sources

bioRxiv2022

Divergent MEK/ERK and AMPK signaling dictate lipogenic plasticity and dependence on fatty acid synthesis in Glioblastoma

Deregulated de novo lipid synthesis (DNLS) is a potential druggable vulnerability in Glioblastoma (GBM), a highly lethal and incurable cancer. Yet the molecular mechanisms that determine susceptibility to DNLS-targeted therapies remain unknown, and the lack of brain-penetrant inhibitors of DNLS has prevented their clinical evaluation as GBM therapeutics. Here, we report that YTX-7739, a clinical-stage, brain-penetrant inhibitor of stearoyl CoA desaturase (SCD), triggers lipotoxicity in patient-derived GBM stem-like cells (GSCs) and inhibits fatty acid desaturation in GSCs orthotopically implanted in mice. When administered as a single agent, or particularly in combination with the first line GBM chemotherapy, Temozolomide (TMZ), YTX-7739 showed therapeutic efficacy in orthotopic GSC mouse models owing to its lipotoxicity and its ability to impair DNA damage repair. Leveraging genetic, pharmacological, and physiological manipulation of key signaling nodes in gliomagenesis, we uncover that aberrant MEK/ERK signaling and its repression of the energy sensor AMP-activated protein kinase (AMPK) primarily drives therapeutic vulnerability to SCD and other DNLS inhibitors. Conversely, AMPK activation mitigates lipotoxicity and renders GSCs impervious to the loss of DNLS, both in culture and in vivo, by decreasing the saturation state of phospholipids and diverting toxic lipids into lipid droplets. Altogether, our findings reveal mechanisms of metabolic plasticity in GSCs and provide a framework for rational integration of DNLS-targeted therapies for the treatment of GBM.

cancer biology↗

bioRxiv2022

Vocalization categorization behavior explained by a feature-based auditory categorization model

Vocal animals produce multiple categories of calls with high between- and within-subject variability, over which listeners must generalize to accomplish call categorization. The behavioral strategies and neural mechanisms that support this ability to generalize are largely unexplored. We previously proposed a theoretical model that accomplished call categorization by detecting features of intermediate complexity that best contrasted each call category from all other categories. We further demonstrated that some neural responses in the primary auditory cortex were consistent with such a model. Here, we asked whether a feature-based model could predict call categorization behavior. We trained both the model and guinea pigs on call categorization tasks using natural calls. We then tested categorization by the model and guinea pigs using temporally and spectrally altered calls. Both the model and guinea pigs were surprisingly resilient to temporal manipulations, but sensitive to moderate frequency shifts. Critically, model performance quantitatively matched guinea pig behavior to a remarkable degree. By adopting different model training strategies and examining features that contributed to solving specific tasks, we could gain insight into possible strategies used by animals to categorize calls. Our results validate a model that uses the detection of intermediate-complexity contrastive features to accomplish call categorization.

neuroscience↗

bioRxiv2021

In silico analyses of maleidride biosynthetic gene clusters

Maleidrides are a family of structurally related fungal natural products, many of which possess diverse, potent bioactivities. Previous identification of several maleidride biosynthetic gene clusters, and subsequent experimental work, has determined the core set of genes required to construct the characteristic medium-sized alicyclic ring with maleic anhydride moieties. Through genome mining, this work has used these core genes to discover ten entirely novel maleidride biosynthetic gene clusters, amongst both publicly available genomes, and encoded within the genome of the previously un-sequenced epiheveadride producer Wicklowia aquatica CBS125634. We have undertaken phylogenetic analyses and comparative bioinformatics on all known and putative maleidride biosynthetic gene clusters to gain further insights regarding these unique biosynthetic pathways.

bioinformatics↗

bioRxiv2021

Muscle group specific transcriptomic and DNA methylation differences related to developmental patterning in FSHD

Muscle groups throughout the body are specialized in function and are specified during development by position specific gene regulatory networks. In developed tissue, myopathies affect muscle groups differently. Facioscapulohumeral muscular dystrophy, FSHD, affects upper body and tibialis anterior (TA) muscles earlier and more severely than others such as quadriceps. To investigate an epigenetic basis for susceptibility of certain muscle groups to disease, we perform DNA methylation and RNA sequencing on primary patient derived myoblasts from TA and quadricep for both control and FSHD2 as well as RNA-seq for myoblasts from FSHD1 deltoid, bicep and TA over a time course of differentiation. We find that TA and quadricep retain methylation and expression differences in transcription factors that are key to muscle group specification during embryogenesis. FSHD2 patients have differences in DNA methylation and expression related to SMCHD1 mutations and FGF signaling. Genes induced specifically in FSHD are more highly expressed in commonly affected muscle groups. We find a set of genes that distinguish more susceptible muscle groups including development-associated TFs and genes involved in WNT signaling. Adult muscle groups therefore retain transcriptional and DNA methylation differences associated with development, which may contribute to susceptibility in FSHD.

genomics↗

bioRxiv2021

Mapping and modeling the genomic basis of differential RNA isoform expression at single-cell resolution with LR-Split-seq

Alternative RNA isoforms are defined by promoter choice, alternative splicing, and polyA site selection. Although differential isoform expression is known to play a large regulatory role in eukaryotes, it has proved challenging to study with standard short-read RNA-seq because of the uncertainties it leaves about the full-length structure and precise termini of transcripts. The rise in throughput and quality of long-read sequencing now makes it possible, in principle, to unambiguously identify most transcript isoforms from beginning to end. However, its application to single-cell RNA-seq has been limited by throughput and expense. Here, we develop and characterize long-read Split-seq (LR-Split-seq), which uses a combinatorial barcoding-based method for sequencing single cells and nuclei with long reads. We show that LR-Split-seq can associate isoforms with cell types with relative economy and design flexibility. We characterize LR-Split-seq for whole cells and nuclei by using the well-studied mouse C2C12 system in which mononucleated myoblast cells differentiate and fuse into multinucleated myotubes. We show that the overall results are reproducible when comparing long- and short-read data from the same cell or nucleus. We find substantial evidence of differential isoform expression during differentiation including alternative transcription start site (TSS) usage. We integrate the resulting isoform expression dynamics with snATAC-seq chromatin accessibility to validate TSS-driven isoform choices. LR-Split-seq provides an affordable method for identifying cluster-specific isoforms in single cells that can be further quantified with companion deep short-read scRNA-seq from the same cell populations.

genomics↗

bioRxiv2021

Osteomacs support osteoclast-mediated resorption and contribute to bone pathology in a postmenopausal osteoporosis mouse model

Osteal macrophages (osteomacs) support osteoblast function and promote bone anabolism, but their contribution to osteoporosis has not been explored. While mouse ovariectomy models have been repeatedly used, variation in strain, experimental design and assessment modalities, have contributed to no single model being confirmed as comprehensively replicating the full gamut of osteoporosis pathological manifestations. We validated an ovariectomy model in adult C3H/HeJ mice and demonstrated that it presents with human post-menopausal osteoporosis features, including reduced bone volume in axial and appendicular bone and bone loss in both trabecular and cortical bone including increased cortical porosity. Bone loss was associated with increased osteoclasts on trabecular and endocortical bone and decreased osteoblasts on trabecular bone. Importantly, this OVX model was characterised by delayed fracture healing. Using this validated model, we demonstrated that osteomacs are increased post-ovariectomy on both trabecular and endocortical bone. Dual F4/80 (pan-macrophage marker) and TRAP staining revealed osteomacs frequently located near TRAP+ osteoclasts and containing TRAP+ intracellular vesicles. Using an in vivo inducible macrophage depletion model that does not simultaneously deplete osteoclasts, we observed that osteomac loss was associated with elevated extracellular TRAP in bone marrow interstitium and increased serum TRAP. Using in vitro high-resolution confocal imaging of mixed osteoclast-macrophage cultures on bone substrate, we observed macrophages juxtaposed to osteoclast basolateral functional secretory domains scavenging degraded bone by-products. These data demonstrate a role for osteomacs in supporting osteoclastic bone resorption through phagocytosis and sequestration of resorption by-products. Finally, using Siglec1 knockout mice, we demonstrated that loss of the macrophage-restricted molecule Siglec-1/CD169 is sufficient to cause age-associated low bone mass, emphasizing the macrophages, independent of osteoclasts, contribute to optimal skeletal health. Overall, our data expose a novel role for osteomacs in supporting osteoclast function and provide the first evidence of their involvement in osteoporosis pathogenesis.

immunology↗

bioRxiv2021

Uncovering the Gene Regulatory Networks Underlying Macrophage Polarization Through Comparative Analysis of Bulk and Single-Cell Data

Gene regulatory networks (GRNs) provide a powerful framework for studying cellular differentiation. However, it is less clear how GRNs encode cellular responses to everyday microenvironmental cues. Macrophages can be polarized and potentially repolarized based on environmental signaling. In order to identify the GRNs that drive macrophage polarization and the heterogeneous single-cell subpopulations that are present in the process, we used a high-resolution time course of bulk and single-cell RNA-seq and ATAC-seq assays of HL-60-derived macrophages polarized towards M1 or M2 over 24 hours. We identified transient M1 and M2 markers, including the main transcription factors that underlie polarization, and subpopulations of naive, transitional, and terminally polarized macrophages. We built bulk and single-cell polarization GRNs to compare the recovered interactions and found that each technology recovered only a subset of known interactions. Our data provide a resource to study the GRN of cellular maturation in response to microenvironmental stimuli in a variety of contexts in homeostasis and disease.

genomics↗

bioRxiv2021

Formation and Spontaneous Long-Term Repatterning of Headless Planarian Flatworms

Regeneration requires the production of large numbers of new cells, and thus cell division regulators, particularly ERK signaling, are critical in regulating this process. In the highly regenerative planarian flatworm, questions remain as to whether ERK signaling controls overall regeneration or plays a head-specific role. Here we show that ERK inhibition in the 3 days following amputation delays regeneration, but that all tissues except the head can overcome this inhibition, resulting in headless regenerates. This prevention of head regeneration happens to a different degree along the anterior-posterior axis, with very anterior wounds regenerating heads even under ERK inhibition. Remarkably, 4 to 18 weeks after injury, the headless animals induced by ERK inhibition remodel to regain single-headed morphology, in the absence of further injury, in a process driven by Wnt/{beta}-catenin signaling. Interestingly, headless animals are likely to exhibit unstable axial polarity, and cutting or fissioning prior to remodeling can result in body-wide reversal of anterior-posterior polarity. Our data reveal new aspects of how ERK signaling regulates regeneration in planaria and show anatomical remodeling on very long timescales.

developmental biology↗

bioRxiv2020

Identifying rare, medically-relevant genetic variation in a diverse population: opportunities and pitfalls

PurposeTo evaluate the effectiveness and specificity of population-based genomic screening in Alabama. MethodsThe Alabama Genomic Health Initiative (AGHI) has enrolled and evaluated 5,369 participants for the presence of pathogenic/likely pathogenic (P/LP) variants using the Illumina Global Screening Array (GSA), with validation of all P/LP variants via Sanger sequencing in a CLIA-certified laboratory before return of results. ResultsAmong 131 variants identified by the GSA that were evaluated by Sanger sequencing, 67 (51%) were false positives (FP). For 39 of the 67 FP variants, a benign/likely benign variant was present at or near the targeted P/LP variant. Importantly, African-Americans were significantly enriched for FP variants, likely due to a higher rate of non-targeted alternative alleles close to array-targeted P/LP variants. ConclusionIn AGHI, we have implemented an array-based process to screen for highly penetrant genetic variants in actionable disease genes. We demonstrate the need for clinical validation of array-identified variants in direct-to-consumer or population testing, especially for diverse populations.

genetics↗

bioRxiv2020

Relationship of DUX4 and target gene expression in FSHD myocytes

Facioscapulohumeral dystrophy (FSHD) is linked to misexpression of the transcription factor, DUX4. Although DUX4 target gene expression is often readily detectable, analysis of DUX4 expression has been limited due to its low expression in patient samples. Recently, single cell/nucleus RNA-sequencing was used to detect the native expression of DUX4 for the first time, but important spatial relationships with its target gene expression was missing. Furthermore, dynamics of DUX4 expression during myoblast differentiation has not been fully explored. In order to study the spatiotemporal relationship of DUX4 and key target genes, we performed RNA FISH on immortalized FSHD2 patient skeletal muscle cells. Using two probe sets, DUX4 transcripts were detected in 1-4% of myotubes after 3-day differentiation in vitro. We found that DUX4 transcripts mainly localize as foci in one or two nuclei in a myotube compared to abundant accumulation of the target gene transcripts in the cytoplasm. Over a 13-day differentiation timecourse, DUX4 expression without target gene expression significantly increased and peaked at day 7. Target gene expression correlates better with DUX4 expression early in differentiation while the expression of target genes without detectable DUX4 transcripts increases later. Consistently, shRNA depletion of DUX4-activated transcription factors, DUXA and LEUTX, specifically repressed a DUX4-target gene, KDM4E, later in differentiation, suggesting that following the initial activation by DUX4, target genes themselves contribute to the maintenance of downstream gene expression. Together, in situ detection of the DUX4 and target gene transcripts provided new insight into dynamics of DUX4 transcriptional network in FSHD patient myocytes. Significance StatementFSHD is the third most common muscular dystrophy and is associated with upregulation of DUX4, a transcription factor, and its target genes. Although target genes are easily detectable in FSHD, low frequency DUX4 upregulation in patient myocytes is difficult to detect, and examining the relationship and dynamics of DUX4 and target gene expression without artificial overexpression of DUX4 has been challenging. Using RNAScope with highly specific probes, we detect the endogenous DUX4 and target gene transcripts in situ in patient skeletal myotubes during differentiation in vitro. Our study reveals a unique DUX4 expression pattern and its relationship to the expression of target genes, and evidence for self-sustainability of the target gene network. The study provides important new insights into the FSHD disease mechanism.

genetics↗

bioRxiv2020

Under-the-radar dengue virus infections in natural populations of Aedes aegypti mosquitoes

The incidence of locally acquired dengue infections increased during the last decade in the United States, compelling a sustained research effort on the dengue mosquito vector, Aedes aegypti, and its microbiome, which has been shown to influence virus transmission success. We examined the metavirome of four populations of Ae. aegypti mosquitoes collected in 2016-2017 from Manatee County, Florida. Unexpectedly, we discovered that dengue virus serotype 4 (DENV4) was circulating in these mosquito populations, representing the first documented case of such a phenomenon in the absence of a local DENV4 human case in this county over a two-year period. We confirmed that all of the mosquito populations carried the same DENV4 strain, assembled its full genome, validated infection orthogonally by reverse transcriptase PCR, traced the virus origin, estimated the time period of its introduction to the Caribbean region, as well as explored the viral genetic signatures and mosquito-specific virome associations that potentially mediated DENV4 persistence in mosquitoes. We discuss the significance of prolonged maintenance of these DENV4 infections in Ae. aegypti that occurred in the absence of a DENV4 human index case in Manatee County with respect to the inability of current surveillance paradigms to detect mosquito vector infections prior to a potential local outbreak. ImportanceSince 1999, dengue outbreaks in the continental United States (U.S.) involving local transmission have occurred episodically and only in Florida and Texas. In Florida, these episodes appear to be coincident with increased introductions of dengue virus into the region through human travel and migration from endemic countries. To date, the U.S. public health response to dengue outbreaks is largely reactive, and implementation of comprehensive arbovirus surveillance in advance of predictable transmission seasons, which would enable proactive preventative efforts, remains unsupported. The significance of our finding is that it is the first documented report of non-outbreak DENV4 transmission and maintenance within a local mosquito vector population in the continental U.S.in the absence of a human case during a two-year time period. Our data suggest that molecular surveillance of mosquito populations in high-risk, high tourism areas of the U.S., may allow for proactive, targeted vector control before potential arbovirus outbreaks.

ecology↗

bioRxiv2020

The snowmelt niche differentiates three microbial life strategies that influence soil nitrogen availability during and after winter

Soil microbial biomass can reach its annual maximum pool size beneath the winter snowpack and is known to decline abruptly following snowmelt in seasonally snow-covered ecosystems. Observed differences in winter versus summer microbial taxonomic composition also suggests that phylogenetically conserved traits may permit winter-versus summer-adapted microorganisms to occupy distinct niches. In this study, we sought to identify archaea, bacteria, and fungi that are associated with the soil microbial bloom overwinter and the subsequent biomass collapse following snowmelt at a high-altitude watershed in central Colorado, USA. Archaea, bacteria, and fungi were categorized into three life strategies (Winter-Adapted, Snowmelt-Specialist, Spring-Adapted) based on changes in abundance during winter, the snowmelt period, and after snowmelt in spring. We calculated indices of phylogenetic relatedness (archaea and bacteria) or assigned functional attributes (fungi) to organisms within life strategies to infer whether phylogenetically conserved traits differentiate Winter-Adapted, Snowmelt-Specialist, and Spring-Adapted groups. We observed that the soil microbial bloom was correlated in time with a pulse of snowmelt infiltration, which commenced 65 days prior to soils becoming snow-free. A pulse of nitrogen (N, as nitrate) occurred after snowmelt, along with a collapse in the microbial biomass pool size, and an increased abundance of nitrifying archaea and bacteria (e.g., Thaumarchaeota, Nitrospirae). Winter- and Spring-Adapted archaea and bacteria were phylogenetically clustered, suggesting that phylogenetically conserved traits allow Winter- and Spring-Adapted archaea and bacteria to occupy distinct niches. In contrast, Snowmelt-Specialist archaea and bacteria were phylogenetically overdispersed, suggesting that the key mechanism(s) of the microbial biomass crash are likely to be density-dependent (e.g., trophic interactions, competitive exclusion) and affect organisms across a broad phylogenetic spectrum. Saprotrophic fungi were the dominant functional group across fungal life strategies, however, ectomycorrhizal fungi experienced a large increase in abundance in spring. If well-coupled plant-mycorrhizal phenology currently buffers ecosystem N losses in spring, then changes in snowmelt timing may alter ecosystem N retention potential. Overall, we observed that the snowmelt separates three distinct soil niches that are occupied by ecologically distinct groups of microorganisms. This ecological differentiation is of biogeochemical importance, particularly with respect to the mobilization of nitrogen during winter, before and after snowmelt.

microbiology↗

bioRxiv2019

Reptile-like physiology in Early Jurassic stem-mammals

There is uncertainty regarding the timing and fossil species in which mammalian endothermy arose, with few studies of stem-mammals on key aspects of endothermy such as basal or maximum metabolic rates, or placing them in the context of living vertebrate metabolic ranges. Synchrotron X-ray imaging of incremental tooth cementum shows two Early Jurassic stem-mammals, Morganucodon and Kuehneotherium, had lifespans (a basal metabolic rate proxy) considerably longer than comparably sized living mammals, but similar to reptiles, and that Morganucodon had femoral blood flow rates (a maximum metabolic rate proxy) intermediate between living mammals and reptiles. This shows maximum metabolic rates increased evolutionarily before basal rates, and that contrary to previous suggestions of a Triassic origin, Early Jurassic stem-mammals lacked the endothermic metabolism of living mammals.One Sentence Summary Surprisingly long lifespans and low femoral blood flow suggest reptile-like physiology in key Early Jurassic stem-mammals.View Full Text

paleontology↗

bioRxiv2019

Nuclear poly(A) tail size is regulated by Cnot1 during the serum response

The poly(A) tail removal from mRNAs introduces a delay between mRNA synthesis and decay. We measured levels and poly(A) tail sizes of serum-induced mRNAs and used mathematical modelling to compare their deadenylation time with the delay in decay and found that they are indeed correlated. Discrepancies between our data and the polyadenylation models at later time points after the peak of induction led us to investigate the size of the poly(A) tails on newly made mRNA. Surprisingly, new serum-induced mRNAs synthesised late in induction had short poly(A) tails (around A25) in the nucleus. In addition, newly made constitutive mRNAs had medium sized poly(A) tails (around A50). To see if deadenylation was responsible for the new short poly(A) tails, we depleted Cnot1, a subunit of the CCR4/NOT deadenylase. Cnot1 depletion led to slower deadenylation of cytoplasmic mRNAs, as expected, but also decreased transcription and led to longer nuclear mRNA poly(A) tails. These observations implicate CCR4/NOT in regulating both the transcription and the nuclear poly(A) tail size of serum-induced mRNAs. Detection of some chromatin-associated mRNAs with long poly(A) tails suggested that nuclear deadenylation is an early event. Our data show that initial poly(A) tail size of mRNAs can be regulated and is not always 200-250 nucleotides, adding a novel layer to the control of gene expression.

molecular biology↗

bioRxiv2019

Human cardiac-fibrosis-on-a-chip model recapitulates disease hallmarks and can serve as a platform for drug screening

While interstitial fibrosis plays a significant role in heart failure, our understanding of disease progression in humans is limited. To address this limitation, we have engineered a cardiac-fibrosis-on-a-chip model consisting of a microfabricated device with live force measurement capabilities using co-cultured human cardiac fibroblasts and pluripotent stem cell-derived cardiomyocytes. Transforming growth factor-{beta} was used as a trigger for fibrosis. Here, we have reproduced the classic hallmarks of fibrosis-induced heart failure including high collagen deposition, increased tissue stiffness, BNP secretion, and passive tension. Force of contraction was significantly decreased in fibrotic tissues that displayed a transcriptomic signature consistent with human cardiac fibrosis/heart failure. Treatment with an anti-fibrotic drug decreased tissue stiffness and BNP secretion, with corresponding changes in the transcriptomic signature. This model represents an accessible approach to study human heart failure in vitro, and allows for testing anti-fibrotic drugs while facilitating the real-time assessment of cardiomyocyte function.

bioengineering↗

bioRxiv2019

Analysis of Vibrio cholerae genomes using a novel bioinformatic tool identifies new, active Type VI Secretion System gene clusters

BackgroundLike many bacteria, Vibrio cholerae, which causes fatal cholera, deploys a harpoon-like Type VI Secretion System (T6SS) to compete against other microbes in environmental and host settings. The T6SS punctures adjacent cells and delivers toxic effector proteins that are harmless to bacteria carrying cognate immunity factors. Only four effector/immunity pairs encoded on one large and three auxiliary gene clusters have been characterized from largely clonal, patient-derived strains of V. cholerae. ResultsWe sequenced two dozen V. cholerae strain genomes from diverse sources and developed a novel and adaptable bioinformatic tool based on Hidden Markov Models. We identified two new T6SS auxiliary gene clusters; one, Aux 5, is described here. Four Aux 5 loci are present in the host strain, each with an atypical effector/immunity gene organization. Structural prediction of the putative effector indicated it is a lipase, which we name TleV1 (Type VI lipase effector Vibrio, TleV1). Ectopic TleV1 expression induced toxicity in E. coli, which was rescued by co-expression of the TleV1 immunity factor. A clinical V. cholerae reference strain expressing the Aux 5 cluster used TleV1 to lyse its parental strain upon contact via its T6SS but was unable to kill parental cells expressing TleV1s immunity factor. ConclusionWe developed a novel bioinformatic method and identified new T6SS gene clusters in V. cholerae. We also showed the TleV1 toxin is delivered in a T6SS-manner by V. cholerae and can lyse other bacterial cells. Our web-based tool may be modified to identify additional novel T6SS genomic loci in diverse bacterial species.

microbiology↗

bioRxiv2018

Single-nucleus RNA-seq identifies divergent populations of FSHD2 myotube nuclei

FSHD is characterized by the misexpression of DUX4 in skeletal muscle. However, DUX4 is lowly expressed in patient samples and analysis of the consequences of DUX4 expression has largely relied on artificial overexpression. To better understand the native expression profile of DUX4 and its targets, we performed pooled RNA-seq differentiation time-course in FSHD2 patient-derived primary myoblasts and identified early-and late-induced sets of FSHD-associated genes. Using single-cell and single-nucleus RNA-seq on FSHD2 myoblasts and myotubes respectively, we captured DUX4 expression in single-nuclei and found that only some DUX4 targets are coexpressed. We identified two populations of FSHD myotube nuclei with distinct transcriptional profiles. One population is highly enriched with DUX4 and FSHD related genes, including the DUX4 paralog DUXA ("FSHD-Hi"). The other population has no expression of DUX4 and expresses low amounts of FSHD related genes ("FSHD-Lo"), but is marked by the expression of CYTL1 and CHI3L1. "FSHD-Hi" myotube nuclei upregulated a set of transcription factors (TFs) that may form a self-sustaining network of gene dysregulation, which perpetuates this disease after DUX4 is no longer expressed.

genomics↗

bioRxiv2018

Individualised MRI training for paediatric neuroimaging in autism spectrum disorders: A child-focused approach

Magnetic Resonance Imaging (MRI) in paediatric cohorts is often complicated by reluctance to enter the scanner and head motion-related imaging artefacts. The MRI scanner environment is highly unusual and may distress younger cohorts, especially in children with sensory sensitivity and separation anxiety. The issue is particularly challenging in children with Autism Spectrum Disorders (ASD), where delivery of instructions for novel task demands in an unfamiliar setting may be limited or less effective due to communication disorder or intellectual disability. These issues together often give rise to excessive head motion that can significantly reduce the quality of images acquired, or render data unusable. Here we report an individualised MRI training procedure that enables young children with ASD to better tolerate the MRI scanner environment based on a child-focused approach and an individualised familiarisation strategy. The training procedure was implemented in a locally recruited study of monozygotic twins (n=12; 6 twin pairs; age range 7.1 to 12.85 years) concordant or discordant for ASD. MRI image quality indices were better or comparable to images acquired from an independent multi-centre ASD cohort. The success of these findings is promising and may be useful to improve the quality of paediatric neuroimaging in similar clinical populations.

neuroscience↗