Structural deviations of the posterior fossa and the cerebellum and their cognitive links in a neurodevelopmental deletion syndrome.

High-impact genetic variants associated with neurodevelopmental disorders provide biologically-defined entry points for mechanistic investigation. The 3q29 deletion (3q29Del) is one such variant, conferring a 40-100-fold increased risk for schizophrenia, as well as high risk for autism and intellectual disability. However, the mechanisms leading to neurodevelopmental disability remain largely unknown. Here, we report the first in vivo quantitative neuroimaging study in individuals with 3q29Del (N = 24) and neurotypical controls (N = 1608) using structural MRI. Given prior radiology reports of posterior fossa abnormalities in 3q29Del, we focused our investigation on the cerebellum and its tissue-types and lobules. Additionally, we compared the prevalence of cystic/cyst-like malformations of the posterior fossa between 3q29Del and controls and examined the association between neuroanatomical findings and quantitative traits to probe gene-brain-behavior relationships. 3q29Del participants had smaller cerebellar cortex volumes than controls, before and after correction for intracranial volume (ICV). An anterior-posterior gradient emerged in finer grained lobule-based and voxel-wise analyses. 3q29Del participants also had larger cerebellar white matter volumes than controls following ICV-correction and displayed elevated rates of posterior fossa arachnoid cysts and mega cisterna magna findings independent of cerebellar volume. Cerebellar white matter and subregional gray matter volumes were associated with visual-perception and visual-motor integration skills as well as IQ, while cystic/cyst-like malformations yielded no behavioral link. In summary, we find that abnormal development of cerebellar structures may represent neuroimaging-based biomarkers of cognitive and sensorimotor function in 3q29Del, adding to the growing evidence identifying cerebellar pathology as an intersection point between syndromic and idiopathic forms of neurodevelopmental disabilities.

Photochemical dearomative skeletal modifications of heteroaromatics.

Dearomatization has emerged as a powerful tool for rapid construction of 3D molecular architectures from simple, abundant, and planar (hetero)arenes. The field has evolved beyond simple dearomatization driven by new synthetic technology development. With the renaissance of photocatalysis and expansion of the activation mode, the last few years have witnessed impressive developments in innovative photochemical dearomatization methodologies, enabling skeletal modifications of dearomatized structures. They offer truly efficient and useful tools for facile construction of highly complex structures, which are viable for natural product synthesis and drug discovery. In this review, we aim to provide a mechanistically insightful overview on these innovations based on the degree of skeletal alteration, categorized into dearomative functionalization and skeletal editing, and to highlight their synthetic utilities.

A Novel Registration Framework for Aligning Longitudinal Infant Brain Tensor Images.

Registering longitudinal infant brain images is challenging, as the infant brain undergoes rapid changes in size, shape and tissue contrast in the first months and years of life. Diffusion tensor images (DTI) have relatively consistent tissue properties over the course of infancy compared to commonly used T1 or T2-weighted images, presenting great potential for infant brain registration. Moreover, groupwise registration has been widely used in infant neuroimaging studies to reduce bias introduced by predefined atlases that may not be well representative of samples under study. To date, however, no methods have been developed for groupwise registration of tensor-based images. Here, we propose a novel registration approach to groupwise align longitudinal infant DTI images to a sample-specific common space. Longitudinal infant DTI images are first clustered into more homogenous subgroups based on image similarity using Louvain clustering. DTI scans are then aligned within each subgroup using standard tensor-based registration. The resulting images from all subgroups are then further aligned onto a sample-specific common space. Results show that our approach significantly improved registration accuracy both globally and locally compared to standard tensor-based registration and standard fractional anisotropy-based registration. Additionally, clustering based on image similarity yielded significantly higher registration accuracy compared to no clustering, but comparable registration accuracy compared to clustering based on chronological age. By registering images groupwise to reduce registration bias and capitalizing on the consistency of features in tensor maps across early infancy, our groupwise registration framework facilitates more accurate alignment of longitudinal infant brain images.

Differences in regional brain structure in toddlers with autism are related to future language outcomes.

Language and social symptoms improve with age in some autistic toddlers, but not in others, and such outcome differences are not clearly predictable from clinical scores alone. Here we aim to identify early-age brain alterations in autism that are prognostic of future language ability. Leveraging 372 longitudinal structural MRI scans from 166 autistic toddlers and 109 typical toddlers and controlling for brain size, we find that, compared to typical toddlers, autistic toddlers show differentially larger or thicker temporal and fusiform regions; smaller or thinner inferior frontal lobe and midline structures; larger callosal subregion volume; and smaller cerebellum. Most differences are replicated in an independent cohort of 75 toddlers. These brain alterations improve accuracy for predicting language outcome at 6-month follow-up beyond intake clinical and demographic variables. Temporal, fusiform, and inferior frontal alterations are related to autism symptom severity and cognitive impairments at early intake ages. Among autistic toddlers, brain alterations in social, language and face processing areas enhance the prediction of the child's future language ability.

Embryonic origin of two ASD subtypes of social symptom severity: the larger the brain cortical organoid size, the more severe the social symptoms.

BACKGROUND: Social affective and communication symptoms are central to autism spectrum disorder (ASD), yet their severity differs across toddlers: Some toddlers with ASD display improving abilities across early ages and develop good social and language skills, while others with "profound" autism have persistently low social, language and cognitive skills and require lifelong care. The biological origins of these opposite ASD social severity subtypes and developmental trajectories are not known. METHODS: Because ASD involves early brain overgrowth and excess neurons, we measured size and growth in 4910 embryonic-stage brain cortical organoids (BCOs) from a total of 10 toddlers with ASD and 6 controls (averaging 196 individual BCOs measured/subject). In a 2021 batch, we measured BCOs from 10 ASD and 5 controls. In a 2022 batch, we  tested replicability of BCO size and growth effects by generating and measuring an independent batch of BCOs from 6 ASD and 4 control subjects. BCO size was analyzed within the context of our large, one-of-a-kind social symptom, social attention, social brain and social and language psychometric normative datasets ranging from N = 266 to N = 1902 toddlers. BCO growth rates were examined by measuring size changes between 1- and 2-months of organoid development. Neurogenesis markers at 2-months were examined at the cellular level. At the molecular level, we measured activity and expression of Ndel1; Ndel1 is a prime target for cell cycle-activated kinases; known to regulate cell cycle, proliferation, neurogenesis, and growth; and known to be involved in neuropsychiatric conditions. RESULTS: At the BCO level, analyses showed BCO size was significantly enlarged by 39% and 41% in ASD in the 2021 and 2022 batches. The larger the embryonic BCO size, the more severe the ASD social symptoms. Correlations between BCO size and social symptoms were r = 0.719 in the 2021 batch and r = 0. 873 in the replication 2022 batch. ASD BCOs grew at an accelerated rate nearly 3 times faster than controls. At the cell level, the two largest ASD BCOs had accelerated neurogenesis. At the molecular level, Ndel1 activity was highly correlated with the growth rate and size of BCOs. Two BCO subtypes were found in ASD toddlers: Those in one subtype had very enlarged BCO size with accelerated rate of growth and neurogenesis; a profound autism clinical phenotype displaying severe social symptoms, reduced social attention, reduced cognitive, very low language and social IQ; and substantially altered growth in specific cortical social, language and sensory regions. Those in a second subtype had milder BCO enlargement and milder social, attention, cognitive, language and cortical differences. LIMITATIONS: Larger samples of ASD toddler-derived BCO and clinical phenotypes may reveal additional ASD embryonic subtypes. CONCLUSIONS: By embryogenesis, the biological bases of two subtypes of ASD social and brain development-profound autism and mild autism-are already present and measurable and involve dysregulated cell proliferation and accelerated neurogenesis and growth. The larger the embryonic BCO size in ASD, the more severe the toddler's social symptoms and the more reduced the social attention, language ability, and IQ, and the more atypical the growth of social and language brain regions.