The Study to Explore Early Development (SEED): A Multisite Epidemiologic Study of Autism by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) Network

The Study to Explore Early Development (SEED), a multisite investigation addressing knowledge gaps in autism phenotype and etiology, aims to: (1) characterize the autism behavioral phenotype and associated developmental, medical, and behavioral conditions and (2) investigate genetic and environmental risks with emphasis on immunologic, hormonal, gastrointestinal, and sociodemographic characteristics. SEED uses a case–control design with population-based ascertainment of children aged 2–5 years with an autism spectrum disorder (ASD) and children in two control groups—one from the general population and one with non-ASD developmental problems. Data from parent-completed questionnaires, interviews, clinical evaluations, biospecimen sampling, and medical record abstraction focus on the prenatal and early postnatal periods. SEED is a valuable resource for testing hypotheses regarding ASD characteristics and causes

A framework for human microbiome research

A variety of microbial communities and their genes (the microbiome) exist throughout the human body, with fundamental roles in human health and disease. The National Institutes of Health (NIH)-funded Human Microbiome Project Consortium has established a population-scale framework to develop metagenomic protocols, resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomic data available to the scientific community. Here we present resources from a population of 242 healthy adults sampled at 15 or 18 body sites up to three times, which have generated 5,177 microbial taxonomic profiles from 16S ribosomal RNA genes and over 3.5 terabases of metagenomic sequence so far. In parallel, approximately 800 reference strains isolated from the human body have been sequenced. Collectively, these data represent the largest resource describing the abundance and variety of the human microbiome, while providing a framework for current and future studies

Structure, function and diversity of the healthy human microbiome

Author Posting. © The Authors, 2012. This article is posted here by permission of Nature Publishing Group. The definitive version was published in Nature 486 (2012): 207-214, doi:10.1038/nature11234.Studies of the human microbiome have revealed that even healthy individuals differ remarkably in the microbes that occupy habitats such as the gut, skin and vagina. Much of this diversity remains unexplained, although diet, environment, host genetics and early microbial exposure have all been implicated. Accordingly, to characterize the ecology of human-associated microbial communities, the Human Microbiome Project has analysed the largest cohort and set of distinct, clinically relevant body habitats so far. We found the diversity and abundance of each habitat’s signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals. The project encountered an estimated 81–99% of the genera, enzyme families and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata. These results thus delineate the range of structural and functional configurations normal in the microbial communities of a healthy population, enabling future characterization of the epidemiology, ecology and translational applications of the human microbiome.This research was supported in part by National Institutes of Health grants U54HG004969 to B.W.B.; U54HG003273 to R.A.G.; U54HG004973 to R.A.G., S.K.H. and J.F.P.; U54HG003067 to E.S.Lander; U54AI084844 to K.E.N.; N01AI30071 to R.L.Strausberg; U54HG004968 to G.M.W.; U01HG004866 to O.R.W.; U54HG003079 to R.K.W.; R01HG005969 to C.H.; R01HG004872 to R.K.; R01HG004885 to M.P.; R01HG005975 to P.D.S.; R01HG004908 to Y.Y.; R01HG004900 to M.K.Cho and P. Sankar; R01HG005171 to D.E.H.; R01HG004853 to A.L.M.; R01HG004856 to R.R.; R01HG004877 to R.R.S. and R.F.; R01HG005172 to P. Spicer.; R01HG004857 to M.P.; R01HG004906 to T.M.S.; R21HG005811 to E.A.V.; M.J.B. was supported by UH2AR057506; G.A.B. was supported by UH2AI083263 and UH3AI083263 (G.A.B., C. N. Cornelissen, L. K. Eaves and J. F. Strauss); S.M.H. was supported by UH3DK083993 (V. B. Young, E. B. Chang, F. Meyer, T. M. S., M. L. Sogin, J. M. Tiedje); K.P.R. was supported by UH2DK083990 (J. V.); J.A.S. and H.H.K. were supported by UH2AR057504 and UH3AR057504 (J.A.S.); DP2OD001500 to K.M.A.; N01HG62088 to the Coriell Institute for Medical Research; U01DE016937 to F.E.D.; S.K.H. was supported by RC1DE0202098 and R01DE021574 (S.K.H. and H. Li); J.I. was supported by R21CA139193 (J.I. and D. S. Michaud); K.P.L. was supported by P30DE020751 (D. J. Smith); Army Research Office grant W911NF-11-1-0473 to C.H.; National Science Foundation grants NSF DBI-1053486 to C.H. and NSF IIS-0812111 to M.P.; The Office of Science of the US Department of Energy under Contract No. DE-AC02-05CH11231 for P.S. C.; LANL Laboratory-Directed Research and Development grant 20100034DR and the US Defense Threat Reduction Agency grants B104153I and B084531I to P.S.C.; Research Foundation - Flanders (FWO) grant to K.F. and J.Raes; R.K. is an HHMI Early Career Scientist; Gordon&BettyMoore Foundation funding and institutional funding fromthe J. David Gladstone Institutes to K.S.P.; A.M.S. was supported by fellowships provided by the Rackham Graduate School and the NIH Molecular Mechanisms in Microbial Pathogenesis Training Grant T32AI007528; a Crohn’s and Colitis Foundation of Canada Grant in Aid of Research to E.A.V.; 2010 IBM Faculty Award to K.C.W.; analysis of the HMPdata was performed using National Energy Research Scientific Computing resources, the BluBioU Computational Resource at Rice University

Familial Autoimmune Thyroid Disease as a Risk Factor for Regression in Children with Autism Spectrum Disorder: A CPEA Study

A multicenter study of 308 children with Autism Spectrum Disorder (ASD) was conducted through the Collaborative Programs of Excellence in Autism (CPEA), sponsored by the National Institute of Child Health and Human Development, to compare the family history of autoimmune disorders in children with ASD with and without a history of regression. A history of regression was determined from the results of the Autism Diagnostic Interview-Revised (ADI-R). Family history of autoimmune disorders was obtained by telephone interview. Regression was significantly associated with a family history of autoimmune disorders (adjusted OR=1.89; 95% CI: 1.17, 3.10). The only specific autoimmune disorder found to be associated with regression was autoimmune thyroid disease (adjusted OR=2.09; 95% CI: 1.28, 3.41).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43035/1/10803_2005_Article_71.pd

ST6GAL1-mediated aberrant sialylation promotes prostate cancer progression.

Aberrant glycosylation is a universal feature of cancer cells, and cancer-associated glycans have been detected in virtually every cancer type. A common change in tumour cell glycosylation is an increase in α2,6 sialylation of N-glycans, a modification driven by the sialyltransferase ST6GAL1. ST6GAL1 is overexpressed in numerous cancer types, and sialylated glycans are fundamental for tumour growth, metastasis, immune evasion, and drug resistance, but the role of ST6GAL1 in prostate cancer is poorly understood. Here, we analyse matched cancer and normal tissue samples from 200 patients and verify that ST6GAL1 is upregulated in prostate cancer tissue. Using MALDI imaging mass spectrometry (MALDI-IMS), we identify larger branched α2,6 sialylated N-glycans that show specificity to prostate tumour tissue. We also monitored ST6GAL1 in plasma samples from >400 patients and reveal ST6GAL1 levels are significantly increased in the blood of men with prostate cancer. Using both in vitro and in vivo studies, we demonstrate that ST6GAL1 promotes prostate tumour growth and invasion. Our findings show ST6GAL1 introduces α2,6 sialylated N-glycans on prostate cancer cells and raise the possibility that prostate cancer cells can secrete active ST6GAL1 enzyme capable of remodelling glycans on the surface of other cells. Furthermore, we find α2,6 sialylated N-glycans expressed by prostate cancer cells can be targeted using the sialyltransferase inhibitor P-3FAX -Neu5Ac. Our study identifies an important role for ST6GAL1 and α2,6 sialylated N-glycans in prostate cancer progression and highlights the opportunity to inhibit abnormal sialylation for the development of new prostate cancer therapeutics. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

ST6GAL1-mediated aberrant sialylation promotes prostate cancer progression

Aberrant glycosylation is a universal feature of cancer cells, and cancer-associated glycans have been detected in virtually every cancer type. A common change in tumour cell glycosylation is an increase in α2,6 sialylation of N-glycans, a modification driven by the sialyltransferase ST6GAL1. ST6GAL1 is overexpressed in numerous cancer types, and sialylated glycans are fundamental for tumour growth, metastasis, immune evasion, and drug resistance, but the role of ST6GAL1 in prostate cancer is poorly understood. Here, we analyse matched cancer and normal tissue samples from 200 patients and verify that ST6GAL1 is upregulated in prostate cancer tissue. Using MALDI imaging mass spectrometry (MALDI-IMS), we identify larger branched α2,6 sialylated N-glycans that show specificity to prostate tumour tissue. We also monitored ST6GAL1 in plasma samples from >400 patients and reveal ST6GAL1 levels are significantly increased in the blood of men with prostate cancer. Using both in vitro and in vivo studies, we demonstrate that ST6GAL1 promotes prostate tumour growth and invasion. Our findings show ST6GAL1 introduces α2,6 sialylated N-glycans on prostate cancer cells and raise the possibility that prostate cancer cells can secrete active ST6GAL1 enzyme capable of remodelling glycans on the surface of other cells. Furthermore, we find α2,6 sialylated N-glycans expressed by prostate cancer cells can be targeted using the sialyltransferase inhibitor P-3FAX-Neu5Ac. Our study identifies an important role for ST6GAL1 and α2,6 sialylated N-glycans in prostate cancer progression and highlights the opportunity to inhibit abnormal sialylation for the development of new prostate cancer therapeutics

Abnormalities in Gamma-band Responses to Language Stimuli in First-degree Relatives of Children with Autism Spectrum Disorder: An MEG Study

Background Synchronous neural oscillatory activity in the gamma range (30–80 Hz) has been shown to be abnormal in individuals with autism spectrum disorders (ASD) and their first-degree relatives in response to simple auditory stimuli. Gamma-band abnormalities in ASD probands have been seen in response to language stimuli, but this has not been investigated in first-degree relatives. This is of particular interest given that language impairments are a core symptom of ASD and may be part of the broad autism phenotype (BAP) seen in relatives. Methods Magnetoencephalography recordings during a continuous word recognition task were obtained for 23 parents of a child with ASD (pASD) and 28 adult control participants. Total and evoked gamma-band activity, as well as inter-trial phase-locking factor (PLF), were measured in response to the task. Beta-band activity was also measured, due to its suggested role in language processing. Participants completed a series of language measures to assess the relationship between brain activity and language function, and lateralization of task-related activity was assessed. Results The pASD group showed increased evoked gamma and beta activity, while controls had decreased evoked activity. Additionally, while both groups showed a reduction in total gamma power (commonly seen in language tasks), this reduction was more prominent in the control group. The pASD group demonstrated significantly worse performance on a measure of phonology compared to controls. Significant but distinct relationships were found between gamma/beta activity and language measures within the two groups. In addition, while the overall task generally elicited left lateralized responses, pASD showed greater left lateralization than controls in some regions of interest. Conclusions Abnormalities in oscillatory responses to language were seen in pASD that are consistent with previous findings in ASD probands. Gamma-band responses to language stimuli have not previously been assessed in first-degree relatives of ASD probands and these findings are supportive of gamma-band activity as a heritable, neurophysiological biomarker of ASD. The possible relationship seen between language function and neural activity in the current study should be investigated further to assess if oscillatory response abnormalities may contribute to behavioural manifestations of the BAP

Early intersubjective skills and the understanding of intentionality in young children with Down syndrome.

This study examined the relationship between early intersubjective skills (joint attention and affect sharing) and the development of the understanding of intentionality in 16 young children with Down syndrome (DS) and 16 developmentally matched children with other developmental disabilities (DD). The study of intentionality focuses on how children come to understand the goal-directed actions of others and is an important precursor to the development of more complex social cognitive skills, such as theory of mind. Joint attention and affect sharing were examined using the Early Social Communication Scales (Mundy, Sigman, & Kasari, 1990; Seibert, Hogan, & Mundy, 1982). Meltzoff's (1995) behavioral reenactment paradigm was used to examine the understanding of intentionality. For children with DS, higher rates of affect sharing were associated with poorer intention reading abilities. This pattern was not observed in children with other DD. These results suggest that the intersubjective strengths associated with DS may not support the development of intentionality-interpretation skills. Future research is needed to explore if children with DS have the joint attention behaviors needed to be intentional

Early intersubjective skills and the understanding of intentionality in young children with Down syndrome.

This study examined the relationship between early intersubjective skills (joint attention and affect sharing) and the development of the understanding of intentionality in 16 young children with Down syndrome (DS) and 16 developmentally matched children with other developmental disabilities (DD). The study of intentionality focuses on how children come to understand the goal-directed actions of others and is an important precursor to the development of more complex social cognitive skills, such as theory of mind. Joint attention and affect sharing were examined using the Early Social Communication Scales (Mundy, Sigman, & Kasari, 1990; Seibert, Hogan, & Mundy, 1982). Meltzoff's (1995) behavioral reenactment paradigm was used to examine the understanding of intentionality. For children with DS, higher rates of affect sharing were associated with poorer intention reading abilities. This pattern was not observed in children with other DD. These results suggest that the intersubjective strengths associated with DS may not support the development of intentionality-interpretation skills. Future research is needed to explore if children with DS have the joint attention behaviors needed to be intentional

Rapid Facial Reactions to Emotional Facial Expressions in Typically Developing Children and Children with Autism Spectrum Disorder

Typical adults mimic facial expressions within 1000 ms, but adults with autism spectrum disorder (ASD) do not. These rapid facial reactions (RFRs) are associated with the development of social–emotional abilities. Such interpersonal matching may be caused by motor mirroring or emotional responses. Using facial electromyography (EMG), this study evaluated mechanisms underlying RFRs during childhood and examined possible impairment in children with ASD. Experiment 1 found RFRs to happy and angry faces (not fear faces) in 15 typically developing children from 7 to 12 years of age. RFRs of fear (not anger) in response to angry faces indicated an emotional mechanism. In 11 children (8–13 years of age) with ASD, Experiment 2 found undifferentiated RFRs to fear expressions and no consistent RFRs to happy or angry faces. However, as children with ASD aged, matching RFRs to happy faces increased significantly, suggesting the development of processes underlying matching RFRs during this period in ASD