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BackgroundPlatelet-activating factor acetylhydrolase 1B1 (LIS1), a critical mediator of neuronal migration in developing brain, is expressed throughout life. However, relatively little is known about LIS1 function in the mature brain. We previously demonstrated that LIS1 involvement in the formation and turnover of synaptic protrusions and synapses of young brain after neuronal migration is complete. Here we examine the requirement for LIS1 to maintain hippocampal circuit function in adulthood.MethodsEffects of conditional Lis1 inactivation in excitatory pyramidal neurons, starting in juvenile mouse brain, were probed using high-resolution approaches combining mouse genetics, designer receptor exclusively activated by designer drug technology to specifically manipulate CA1 pyramidal neuron excitatory activity, electrophysiology, hippocampus-selective behavioral testing, and magnetic resonance imaging tractography to examine the connectivity of LIS1-deficient neurons.ResultsWe found progressive excitatory and inhibitory postsynaptic dysfunction as soon as 10 days after conditional inactivation of Lis1 targeting CA1 pyramidal neurons. Surprisingly, by postnatal day 60 it also caused CA1 histological disorganization, with a selective decline in parvalbumin-expressing interneurons and further reduction in inhibitory neurotransmission. Accompanying these changes were behavioral and cognitive deficits that could be rescued by either designer receptor exclusively activated by designer drug-directed specific increases in CA1 excitatory transmission or pharmacological enhancement of gamma-aminobutyric acid transmission. Lagging behind electrophysiological changes was a progressive, selective decline in neural connectivity, affecting hippocampal efferent pathways documented by magnetic resonance imaging tractography.ConclusionsLIS1 supports synaptic function and plasticity of mature CA1 neurons. Postjuvenile loss of LIS1 disrupts the structure and cellular composition of the hippocampus, its connectivity with other brain regions, and cognition dependent on hippocampal circuits.

Activating mutations in genes encoding phosphatidylinositol 3-kinase (PI3K)-AKT pathway components cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH, OMIM 603387). Here we report that individuals with MPPH lacking upstream PI3K-AKT pathway mutations carry de novo mutations in CCND2 (encoding cyclin D2) that are clustered around a residue that can be phosphorylated by glycogen synthase kinase 3β (GSK-3β). Mutant CCND2 was resistant to proteasomal degradation in vitro compared to wild-type CCND2. The PI3K-AKT pathway modulates GSK-3β activity, and cells from individuals with PIK3CA, PIK3R2 or AKT3 mutations showed similar CCND2 accumulation. CCND2 was expressed at higher levels in brains of mouse embryos expressing activated AKT3. In utero electroporation of mutant CCND2 into embryonic mouse brains produced more proliferating transfected progenitors and a smaller fraction of progenitors exiting the cell cycle compared to cells electroporated with wild-type CCND2. These observations suggest that cyclin D2 stabilization, caused by CCND2 mutation or PI3K-AKT activation, is a unifying mechanism in PI3K-AKT-related megalencephaly syndromes.

The authors have embarked on an extensive analysis of the open court principle, access to justice concerns, and how these have been impacted by the Manitoba courts' pandemic response measures. Due to the length of this analysis, it is divided into two parts, to be published as separate articles in the same Issue: Part A ("Setting the Stage") and Part B ("Drawing the Curtains in the House of Justice"). These papers are intended to be read in conjunction. In Part B, the authors apply the observations and recommendations of the federal Action Committee on Court Operations in Response to the Pandemic, discussed in Part A, to the pandemic-response approach taken in Manitoba to evaluate whether the measures achieved the access movement's objectives. Particular attention is paid to outcomes for individuals charged with murder, who are guaranteed the right to a jury trial under the Charter of Rights and Freedoms. The authors examine the various Practice Directions and Notices that were issued by the leaders of the court system to identify the subtle disregard for the Charter rights of these individuals. Informed by various reports, the authors offer four recommendations to improve the state's response to the pandemic, including on a prospective basis. [ABSTRACT FROM AUTHOR]

The authors have embarked on an extensive analysis of the open court principle, access to justice concerns, and how these have been impacted by the Manitoba courts' pandemic response measures. Due to the length of this analysis, it is divided into two parts, to be published as separate articles in the same Issue: Part A ("Setting the Stage") and Part B ("Drawing the Curtains in the House of Justice"). Importantly, these papers are to be read in conjunction. Part A provides a vital and extensive background, outlining the modern history of the open court principle and the importance of ensuring access to justice. [ABSTRACT FROM AUTHOR]

The Canadian federal government has fallen short of its reconciliatory objectives with Indigenous peoples and preventing anthropogenic climate change. In recognizing these issues, the Government of Canada implemented several policy initiatives to realign industrial production and consumption at the national level, as well as to grow Indigenous participation in capitalist production as a means of approaching a form of self-government. As part of this policy agenda, the state targets Indigenous communities as leaders who hold the potential to implement more sustainable methods of energy production to encourage them to become Canada's environmental stewards. However, we contend that such policy initiatives also erode the socio-legal and environmental obligations owed to Indigenous peoples by the Canadian federal government. To articulate the impact of these policies on the interests of Indigenous communities, we explore certain efforts of the Canadian state, through the lens of neoliberal settler colonialism, to identify its striking consistency with past approaches of dislocating colonized populations and reclaiming power bases that are still within settler state control. We recommend the arrest of the Canadian settler state's modern approach to eroding its obligations to Indigenous peoples, while also proposing further measures be taken to recognize and strengthen Indigenous and environmental rights. [ABSTRACT FROM AUTHOR]

Canadian law enforcement agencies are applying algorithmic technologies to identify individuals at the regional, provincial, and federal levels. These technologies connect templated facial images to an array of informational fragments that are collected from databases scattered between the public and private sectors. While that is the case, these surveillance technologies continue to be authorized under SCC jurisprudence, as opposed to legislation enacted by Parliament. Algorithmic technologies collate and analyze disparate information from public and private databases to identify patterns, which are then used to generate formulas to 'predict' future trends. Kate Robertson and colleagues explain that implementation of APTs by Canadian police services holds serious deleterious potential for the Charter rights of Canadians, with consequences that disproportionately affect people of colour. Be that as it may, the most malevolent consequence of applying APTs may be their application of generalized formulas to generate recommendations used to intercept individuals based on biased and inaccurate information. Although not authorized by statute, surveillance technologies continue to be permissible under common law authorities. Richard Jochelson explains the inappropriate nature of this approach, arguing in the alternative that the court's traditional role calls for application of the Oakes test to determine if state surveillant practices fall within its constitutional limits. Considering APT's serious implications for Charter protected rights, this paper calls on legislators to implement dedicated legislation to govern the use of surveillant technologies in law enforcement, with a particular focus on regulating the use of APTs. Failure to do so risks an unprecedented expansion of prejudicial policing practices, which may act to crystallize the existing biases in law enforcement practices into objective 'scientific' outputs that may hold serious deleterious potential for Canada's most vulnerable populations. [ABSTRACT FROM AUTHOR]

Interest has been growing in the behavioral animation of autonomous actors in virtual worlds. However, authoring complicated interactions between multiple actors in a way that balances control flexibility and automation remains a considerable challenge. A proposed behavior-authoring framework gives users complete control over the domain of the system: the state space, action space, and cost of executing actions. To specialize actors, the framework uses effect and cost modifiers, which modify existing action definitions, and constraints, which prune action choices in a state-dependent manner. The framework groups actors with common or conflicting goals to form a composite domain, and a multiagent planner generates complicated interactions between multiple actors. The Web extra is a video that shows how multiactor simulations should aim to strike a happy medium between the automation of generation and the flexibility of specification. [ABSTRACT FROM PUBLISHER]