This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

In this paper, we report on the production of modified pullulan derivatives that have been produced in solution by ring-opening ε-caprolactone and [l]-lactide using a tin octanoate [Sn(Oct)2] catalyst system in DMSO. These derivatives designated as hexanoates (1 and 2) and dilactates (4−7) have been characterized and have varying degrees of substitution (DS). 1 and 2 were characterized by interesting thermal properties as well as crystalline morphology. From DSC analysis, 2, unlike the parent polysaccharide, appears to melt at 114 °C. The crystalline morphology of this polymer was characterized by X-ray powder diffraction and d spacings were calculated. This pullulan derivative possessed new crystallographic reflections not seen in either pullulan or poly (ε-caprolactone). The pullulan-6 dilactate samples (4−7), produced had DS values ranging from 0.1 to 0.75. Depending upon the DS, these samples were soluble in a wide range of organic solvents including acetone and methanol. Although these materials did not exhibit any observable melting transitions from inspection of DSC, glass transition temperatures were detected for 5 [DS = 0.21], 6 [DS = 0.44], and 7 [DS = 0.80], at 130, 120, and 90 °C, respectively. As confirmed by 13C NMR, the ring-opening process for all of these pullulan derivatives appears to be taking place through an acyl−oxygen cleavage, producing an ester linkage to the backbone with a hydroxy terminus.

urrent estimates of ASD prevalence reach one in 54 children born in the United States 1 , and recent clinical failures [2][3][4][5][6][7][8][9] highlight the need to expand drug development efforts. Behavioral features and severity are measured by validated observational assessment tools, as there are no imaging-based or molecular biomarkers that reliably and objectively diagnose ASD. Furthermore, autism manifests across a broad spectrum, from minimally affected individuals to those who require intense support, and there are no approved drugs for core symptoms. The etiology of ASD is poorly understood and likely multifactorial but is known to involve complex genetic risks 10 , with over 100 genes implicated to date, each with a small effect size 11 . A role for environmental risks in ASD has also been proposed, encompassing diet 12 , maternal infection 13 , exposure to toxins 14 and changes in the gut microbiome 15 . The notion that fixed genetic predispositions coupled with variable environmental risks together manifest symptom severity is intriguing from a therapeutic perspective, because correcting mutations in the genome remains challenging, and reducing potential environmental contributors is likely more tractable. Recent studies suggest that molecules produced in the GI tract can enter systemic circulation and affect immunity 16 , metabolism 17 and behavior 18 . Altered immune and metabolic profiles have been associated with various neuropsychiatric disorders, such as ASD [19][20][21] , and the microbiome and metabolome are altered in individuals with ASD 19,22 , anxiety 23 , depression 24 and schizophrenia 25 . Notably, over a dozen studies have shown changes in the fecal microbiome in several ASD cohorts compared to controls 26 , although these associations do not resolve cause or effect. Dietary habits likely contribute to the ASD microbiome 27 . Several studies have also revealed changes in the metabolome of individuals with ASD from diverse geographies 19,[28][29][30] , with reports showing dysregulation of the fecal metabolome 19,[31][32][33] . We previously identified several gut microbial metabolites that correlate with ASD-like symptoms in mice, and administration of one of these metabolites, 4-ethylphenyl sulfate (4EPS), to naive animals Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: an open-label phase 1b/2a trial

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition with hallmark behavioral manifestations including impaired social communication and restricted repetitive behavior. In addition, many affected individuals display metabolic imbalances, immune dysregulation, gastrointestinal (GI) dysfunction, and altered gut microbiome compositions. We sought to better understand non-behavioral features of ASD by determining molecular signatures in peripheral tissues. Herein, we present the untargeted metabolome of 231 plasma and 97 fecal samples from a large cohort of children with ASD and typically developing (TD) controls. Differences in lipid, amino acid, and xenobiotic metabolism discriminate ASD and TD samples. We reveal correlations between specific metabolite profiles and clinical behavior scores, and identify metabolites particularly associated with GI dysfunction in ASD. These findings support a connection between GI physiology, metabolism, and complex behavioral traits, and may advance discovery and development of molecular biomarkers for ASD. Sterol 1 1 1 Gly, Ser, Thr 0 1 1