Courtney Irwin

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder caused by genetic or environmental perturbations during early development. Diagnoses are dependent on the identification of behavioral abnormalities that likely emerge well after the disorder is established, leaving critical developmental windows uncharacterized. This is further complicated by the incredible clinical and genetic heterogeneity of the disorder that is not captured in most mammalian models. In recent years, advancements in stem cell technology have created the opportunity to model ASD in a human context through the use of pluripotent stem cells (hPSCs), which can be used to generate 2D cellular models as well as 3D unguided- and region-specific neural organoids. These models produce profoundly intricate systems, capable of modeling the developing brain spatiotemporally to reproduce key developmental milestones throughout early development. When complemented with multi-omics, genome editing, and electrophysiology analysis, they can be used as a powerful tool to profile the neurobiological mechanisms underlying this complex disorder. In this review, we will explore the recent advancements in hPSC-based modeling, discuss present and future applications of the model to ASD research, and finally consider the limitations and future directions within the field to make this system more robust and broadly applicable.

Copy number variations (CNVs) are associated with psychiatric and neurodevelopmental disorders (NDDs), and most, including the recurrent 15q13.3 microdeletion disorder, have unknown disease mechanisms. We used a heterozygous 15q13.3 microdeletion mouse model and patient iPSC-derived neurons to reveal developmental defects in neuronal maturation and network activity. To identify the underlying molecular dysfunction, we developed a neuron-specific proximity-labeling proteomics (BioID2) pipeline, combined with patient mutations, to target the 15q13.3 CNV genetic driverOTUD7A.OTUD7Ais an emerging independent NDD risk gene with no known function in the brain, but has putative deubiquitinase function. The OTUD7A protein–protein interaction network included synaptic, axonal, and cytoskeletal proteins and was enriched for ASD and epilepsy risk genes (Ank3, Ank2, SPTAN1, SPTBN1). The interactions between OTUD7A and Ankyrin-G (Ank3) and Ankyrin-B (Ank2) were disrupted by an epilepsy-associatedOTUD7AL233F variant. Further investigation of Ankyrin-G in mouse and human 15q13.3 microdeletion and OTUD7A^L233F/L233Fmodels revealed protein instability, increased polyubiquitination, and decreased levels in the axon initial segment, while structured illumination microscopy identified reduced Ankyrin-G nanodomains in dendritic spines. Functional analysis of human 15q13.3 microdeletion and OTUD7A^L233F/L233Fmodels revealed shared and distinct impairments to axonal growth and intrinsic excitability. Importantly, restoring OTUD7A or Ankyrin-G expression in 15q13.3 microdeletion neurons led to a reversal of abnormalities. These data reveal a critical OTUD7A-Ankyrin pathway in neuronal development, which is impaired in the 15q13.3 microdeletion syndrome, leading to neuronal dysfunction. Furthermore, our study highlights the utility of targeting CNV genes using cell type-specific proteomics to identify shared and unexplored disease mechanisms across NDDs.

Mycobacterium tuberculosisis one of the most ancient bacterial pathogens and remains the leading cause of death from a single bacterial agent. The success ofM. tuberculosisrelies greatly on its ability to parasitize and disable its host macrophages.

Review question / Objective: The aim of this review is two-fold: first, we sought to identify candidate biomarkers that could provide information on whether an individual with MDD would respond positively to common non-pharmacological treatments, and secondly, to conduct a meta-analysis to determine whether one form of common non-pharmacological treatment (namely CBT, tDCS and TMS) would produce better results over another in regards to its influence on biomarker levels. Information sources: The information sources used were: three online databases (PubMed, Scopus, and PsycINFO) to identify English-language human randomised controlled trials unrestricted by year of publication.

Spruce budworm, Choristoneura fumiferana (Clemens) (Lepidoptera: Tortricidae), is a destructive defoliator found throughout the Nearctic boreal forest. This pest has a broad geographic range and shows regional variation in key life history traits. These population differences may represent important adaptations to local environmental conditions and reflect underlying genetic diversity. Existing laboratory colonies of spruce budworm do not capture this regional variation, so we established five new spruce budworm colonies from across its range to explore regional adaptations among spruce budworm populations within common garden experiments. We present methods for establishing new spruce budworm laboratory colonies from wild populations. We describe the process of flushing, rearing, and disease screening used on these new populations to produce healthy disease-free laboratory stocks.