Search

Variants in the AUTS2 gene are associated with a broad spectrum of neurological conditions characterized by intellectual disability, microcephaly, and congenital brain malformations. Here, we use a human cerebral organoid (CO) model to investigate the pathophysiology of a heterozygous de novo missense AUTS2 variant identified in a patient with multiple neurological impairments including primary microcephaly and profound intellectual disability. Proband COs exhibit reduced growth, deficits in neural progenitor cell (NPC) proliferation and disrupted NPC polarity within ventricular zone-like regions compared to control COs. We used CRISPR-Cas9-mediated gene editing to correct this variant and demonstrate rescue of impaired organoid growth and NPC proliferative deficits. Single-cell RNA sequencing revealed a marked reduction of G1/S transition gene expression and alterations in WNT-β-Catenin signaling within proband NPCs, uncovering a novel role for AUTS2 in NPCs during human cortical development. Collectively, these results underscore the value of COs to uncover molecular mechanisms underlying AUTS2 syndrome.

Summary Cerebral organoids (COs) are rapidly accelerating the rate of translational neuroscience based on their potential to model complex features of the developing human brain. Several studies have examined the electrophysiological and neural network features of COs; however, no study has comprehensively investigated the developmental trajectory of electrophysiological properties in whole-brain COs and correlated these properties with developmentally linked morphological and cellular features. Here, we profiled the neuroelectrical activities of COs over the span of 5 months with a multi-electrode array platform and observed the emergence and maturation of several electrophysiologic properties, including rapid firing rates and network bursting events. To complement these analyses, we characterized the complex molecular and cellular development that gives rise to these mature neuroelectrical properties with immunohistochemical and single-cell transcriptomic analyses. This integrated approach highlights the value of COs as an emerging model system of human brain development and neurological disease., Highlights • CO electrophysiology can be quantified with a multi-electrode array method • CO electrophysiological trajectories correlate with molecular and cellular development • The neurotrophin/TRK signaling pathway is active in COs by 5 months in culture, Cerebral organoids (COs) have a unique advantage in modeling human-specific features of early brain development. Here, we profile their neuroelectrical activities with an MEA platform over time and correlate these activities with their increasingly complex molecular and cellular features. This integrated approach highlights the value of COs as an emerging model system of human brain development and neurological disease.

Alzheimer’s disease (AD) is pathologically characterized by amyloid beta (Aβ) plaques, neurofibrillary tangles (tau aggregates), and alterations in microglia, astrocytes and oligodendrocytes. The mesial temporal lobe is a vulnerable brain region in early AD; however, little is known about the transcriptome-scale gene expression in this region and its relation to AD pathology. Here we use the 10x Genomics Visium platform in combination with co-immunofluorescence staining of AD-associated pathological markers to define the spatial topography of gene expression in the middle temporal gyrus (MTG) from both early AD and age- and gender-matched control cases. We identify unique marker genes for six cortical layers and the adjacent white matter as well as gene expression patterns and alterations that showcase unique gene signatures and pathways associated with a range of AD pathology. Also, gene co-expression analyses of differentially expressed genes (DEGs) between AD and controls reveal four unique gene modules, which significantly change their co-expression patterns in the presence of variations of AD pathology. Furthermore, we validate the changes of key representative DEGs that are associated with AD pathology in neurons, microglia, astrocytes and oligodendrocytes using single-molecule fluorescent in situ hybridization. In summary, we provide a rich resource for the spatial transcriptomic profile of the human MTG, which will contribute to our understanding of the complex architecture and AD pathology of this vulnerable brain region.

Human central nervous system (CNS) regeneration is considered the holy grail of neuroscience research, and is one of the most pressing and difficult questions in biology and science. Despite more than 20 years of work in the field of neural stem cells (NSCs), the area remains in its infancy as our understanding of the fundamental mechanisms that can be leveraged to improve CNS regeneration in neurological diseases is still growing. Here, we focus on the recent lessons from lower organism CNS regeneration genetics and how such findings are starting to illuminate our understanding of NSC signaling pathways in humans. These findings will allow us to improve upon our knowledge of endogenous NSC function, the utility of exogenous NSCs, and the limitations of NSCs as therapeutic vehicles for providing relief from devastating human neurological diseases. We also discuss the limitations of activating NSC signaling for CNS repair in humans, especially the potential for tumor formation. Finally, we will review the recent advances in new culture techniques, including patient-derived cells and cerebral organoids to model the genetic regulation of signaling pathways controlling the function of NSCs during injury and disease states.

Human middle temporal gyrus (MTG) is a vulnerable brain region in early Alzheimer's disease (AD); however, little is known about the molecular mechanisms underlying this regional vulnerability. Here we use the 10x Visium platform to define the spatial topography of gene expression in the MTG from both early AD and control cases. We identify differentially expressed genes (DEGs) and enriched pathways that may contribute to the layer-specific vulnerability of AD pathology. Also, gene co-expression analyses reveal four gene modules, which significantly change their co-expression patterns in the presence of variations of AD pathology. Furthermore, we validate the changes of key representative DEGs that are associated with AD pathology using single-molecule fluorescent in situ hybridization. In summary, we provide a rich resource for the spatial transcriptomic profile of the human MTG, which will contribute to our understanding of the complex architecture and AD pathology of this vulnerable brain region.

In an effort to reduce repeat sexual offending, some Australian jurisdictions have introduced legislation providing for the restriction of a sex offender’s liberty in anticipation of future predicted crimes. The operation of preventive detention legislation relies centrally upon forensic clinician assessments of risk for future sexual offending. This legislation has raised important research questions related to the validity of the laws’ assumptions on sexual recidivism and risk prediction, the characteristics of sex offenders submitted to post-sentence orders, and clinicians’ standard of practice of risk assessment in this legal context. This thesis conducted a series of theoretical and empirical investigations linked to these research areas. The first study consisted of a psycho-legal analysis whereby the assumptions underpinning the laws’ provisions were evaluated in light of the empirical evidence on risk prediction, sex offender recidivism, and sex offender rehabilitation. Together, the findings revealed that many of the laws’ assumptions are invalid; this has implications for the efficacy of the legislation to protect the community from sexual offending. The second study empirically examined the demographic, developmental, clinical, and criminal characteristics of a sample of 50 sex offenders under post-sentence orders in Western Australia, New South Wales, and Victoria. Data was obtained from court-ordered clinical risk assessment reports. The findings described a group of demonstrably dangerous men who exhibited an early onset of sexual offending and complex psychiatric presentations, with a high prevalence of sexual deviance and antisociality. Their developmental histories were characterised by early exposure to multiple vulnerability factors such as abuse, illicit substance use, and social dislocation. Their complex and varied needs require a comprehensive treatment approach. The early onset of their offending suggests that well resourced early intervention services, such as those offered by mental health professionals, can play a critically important role in any effort to alter offending trajectories such as those exhibited in this sample. The third study empirically evaluated the standard of risk assessment practice amongst experts retained in preventive detention proceedings. Eighty-six court-ordered forensic evaluation reports prepared by 23 mental health professionals were obtained and analysed. Overall, the findings were mixed. Positively, valid structured risk assessment tools were commonly utilised. Also, there was good agreement between experts on the final risk assessment outcome, suggesting a consensus in relevant areas relating to risk assessment. However, a number of concerning results were also found (e.g., some evaluators adopted invalid risk assessment methodologies; others incorrectly applied and interpreted otherwise valid risk tools). Taken together, the findings suggest that the standard of practice of risk assessment must be raised. Recommendations for best practice were proposed.

The earliest characterisation of Australian sex offenders subjected to post‐sentence legislation is presented. Demographic, developmental, clinical, and criminal characteristics were obtained for s...

Australian governments have introduced legislation to detain or supervise sex offenders whose sentences have expired but who are still considered to be dangerous. In the enactment of these controversial laws, governments largely overlooked a significant body of empirical knowledge on sexual offending and risk prediction. Consequently, these schemes are based on unexamined assumptions. Accordingly, an evaluation of the compatibility between these assumptions and the available science is warranted. To this end, the article will submit the central provisions of the legislation to a psycho-legal analysis whereby the assumptions underpinning the laws will be weighed against the empirical evidence. The article reveals that there is considerable disconnect between the laws' assumptions and the existing literature on sexual offending and risk prediction, such that the evidence suggests that the legislation will not achieve its aims in any meaningful and sustainable way. Future criminal justice policy in the area of sex offending needs to be collaboratively developed between policymakers and the relevant scientific communities and experts. It must be founded on cost-effective and empirically defensible approaches based on what we understand, rather than what we fear, about sex offenders.

We present a lady in whom late post-partum eclampsia (LPE) was overlooked. The diagnosis was delayed and only made when MRI brain demonstrated posterior reversible encephalopathy syndrome (PRES(. There is a need for greater awareness of both LPE and PRES. We summarise the recent literature and emphasise the importance of recognising the conditions on clinical grounds so that treatment can be started without delay.