The impact of misinformation presented during jury deliberation on juror memory and decision-making.

When deliberating, jurors may introduce misinformation that may influence other jurors' memory and decision-making. In two studies, we explored the impact of misinformation exposure during jury deliberation. Participants in both studies read a transcript of an alleged sexual assault. In Study 1 (N = 275), participants encountered either consistent pro-prosecution misinformation, consistent pro-defense misinformation, or contradictory misinformation (pro-prosecution and pro-defense). In Study 2 (N = 339), prior to encountering either pro-prosecution or pro-defense misinformation while reading a jury deliberation transcript, participants either received or did not receive a judicial instruction about misinformation exposure during deliberation. Participants in both studies completed legal decision-making variables (e.g., defendant guilt rating) before and after deliberation, and their memory was assessed for misinformation acceptance via recall and source memory tasks. In Study 1, misinformation type did not influence legal decision-making, but pro-prosecution misinformation was more likely to be misattributed as trial evidence than pro-defense or contradictory misinformation. In Study 2, pro-defense misinformation was more likely to be misattributed to the trial than pro-prosecution misinformation, and rape myths moderated this. Furthermore, exposure to pro-defense misinformation skewed legal decision-making towards the defense's case. However, the judicial instruction about misinformation exposure did not influence memory or decision-making. Together, these findings suggest that misinformation in jury deliberations may distort memory for trial evidence and bias decision-making, highlighting the need to develop effective safeguards for reducing the impact of misinformation in trial contexts.

A survey of what legal populations believe and know about inattentional blindness and visual detection.

Inattentional blindness refers to when people fail to notice obvious and unexpected events when their attention is elsewhere. Existing research suggests that inattentional blindness is a poorly understood concept that violates the beliefs that are commonly held by the public about vision and attention. Given that legal cases may involve individuals who may have experienced inattentional blindness, it is important to understand the beliefs legal populations and members of the community have about inattentional blindness, and their general familiarity and experience with the concept. Australian police officers (n = 94) and lawyers (n = 98), along with psychology students (n = 99) and community members (n = 100) completed a survey where they: a) stated whether an individual would have noticed an event in six legal vignettes, b) rated whether factors would make an individual more, less, or just as likely to notice an unexpected event, c) reported their familiarity with and personal experiences of inattentional blindness, and d) indicated whether they believed individuals could make themselves more likely to notice unexpected events. Respondents in all populations frequently responded "yes" to detecting the unexpected event in most legal vignettes. They also held misconceptions about some factors (expertise and threat) that would influence the noticing of unexpected events. Additionally, personal experiences with inattentional blindness were commonly reported. Finally, respondents provided strategies for what individuals can do to make themselves more likely to notice of unexpected events, despite a lack of evidence to support them. Overall, these findings provide direction for where education and training could be targeted to address misconceptions about inattentional blindness held by legal populations, which may lead to improved decision-making in legal settings.

Does experiencing inattentional blindness for crime influence eyewitness recall?

Witnesses may not notice crimes occurring when their attention is elsewhere, which may affect their memory. In this study, 174 participants completed an attention-demanding task while viewing a video containing an assault. Whether participants noticed the assault or experienced inattentional blindness for it was assessed. Then, participants were exposed to post-event information (containing misinformation) before completing a cued-recall task under one of three recall instructions (free, forced, or no instruction). Most participants experienced inattentional blindness for the assault (65.5%), which had a negative effect on recall, regardless of recall instruction. Specifically, participants who experienced inattentional blindness were less confident, complete, and accurate, and were more likely to report misinformation, than participants who noticed the crime. Witnesses who experienced inattentional blindness reported that they relied purely on post-event information to answer some questions. The findings suggest that caution should be taken when interviewing witnesses who have not paid attention to a crime.

Stopping crime? The effect of crime re-enactments on eyewitness memory.

Crime re-enactments broadcast on television encourage witnesses to provide information regarding unsolved crimes. However, given that eyewitness memory can be altered through exposure to post-event information, it is possible that crime re-enactments may influence the memory of eyewitnesses. The current studies examined the effects of crime re-enactments on eyewitness memory. In two experiments (Experiment 1 with a distractor task, Experiment 2 without a distractor task), participants were shown one of three versions of a crime video that differed in their ambiguity. One week later half of the participants viewed a crime re-enactment. All participants then completed a guided free- and cued-recall task regarding the original event. Across both studies, exposure to the re-enactment did not improve eyewitness memory; instead, participants who viewed the re-enactment were more likely to accept the misinformation in the re-enactment. The findings shed light on potential issues with using crime re-enactments to elicit eyewitness accounts.

Disease-associated missense variants in ZBTB18 disrupt DNA binding and impair the development of neurons within the embryonic cerebral cortex.

The activities of DNA-binding transcription factors, such as the multi-zinc-finger protein ZBTB18 (also known as RP58, or ZNF238), are essential to coordinate mammalian neurodevelopment, including the birth and radial migration of newborn neurons within the fetal brain. In humans, the majority of disease-associated missense mutations in ZBTB18 lie within the DNA-binding zinc-finger domain and are associated with brain developmental disorder, yet the molecular mechanisms explaining their role in disease remain unclear. To address this, we developed in silico models of ZBTB18, bound to DNA, and discovered that half of the missense variants map to residues (Asn461, Arg464, Glu486) predicted to be essential to sequence-specific DNA contact, whereas others map to residues (Leu434, Tyr447, Arg495) with limited contributions to DNA binding. We studied pathogenic variants to residues with close (N461S) and limited (R495G) DNA contact and found that each bound DNA promiscuously, displayed altered transcriptional regulatory activity in vitro, and influenced the radial migration of newborn neurons in vivo in different ways. Taken together, our results suggest that altered transcriptional regulation could represent an important pathological mechanism for ZBTB18 missense variants in brain developmental disease.

MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib.

BACKGROUND: Metastatic disease is largely resistant to therapy and accounts for almost all cancer deaths. Myeloid cell leukemia-1 (MCL-1) is an important regulator of cell survival and chemo-resistance in a wide range of malignancies, and thus its inhibition may prove to be therapeutically useful. METHODS: To examine whether targeting MCL-1 may provide an effective treatment for breast cancer, we constructed inducible models of BIMs2A expression (a specific MCL-1 inhibitor) in MDA-MB-468 (MDA-MB-468-2A) and MDA-MB-231 (MDA-MB-231-2A) cells. RESULTS: MCL-1 inhibition caused apoptosis of basal-like MDA-MB-468-2A cells grown as monolayers, and sensitized them to the BCL-2/BCL-XL inhibitor ABT-263, demonstrating that MCL-1 regulated cell survival. In MDA-MB-231-2A cells, grown in an organotypic model, induction of BIMs2A produced an almost complete suppression of invasion. Apoptosis was induced in such a small proportion of these cells that it could not account for the large decrease in invasion, suggesting that MCL-1 was operating via a previously undetected mechanism. MCL-1 antagonism also suppressed local invasion and distant metastasis to the lung in mouse mammary intraductal xenografts. Kinomic profiling revealed that MCL-1 antagonism modulated Src family kinases and their targets, which suggested that MCL-1 might act as an upstream modulator of invasion via this pathway. Inhibition of MCL-1 in combination with dasatinib suppressed invasion in 3D models of invasion and inhibited the establishment of tumors in vivo. CONCLUSION: These data provide the first evidence that MCL-1 drives breast cancer cell invasion and suggests that MCL-1 antagonists could be used alone or in combination with drugs targeting Src kinases such as dasatinib to suppress metastasis.

The HSA21 gene EURL/C21ORF91 controls neurogenesis within the cerebral cortex and is implicated in the pathogenesis of Down Syndrome.

Copy number variations to chromosome 21 (HSA21) cause intellectual disability and Down Syndrome, but our understanding of the HSA21 genetic factors which contribute to fetal brain development remains incomplete. Here, we focussed on the neurodevelopmental functions for EURL (also known as C21ORF91, Refseq Gene ID:54149), a protein-coding gene at the centromeric boundary of the Down Syndrome Critical Region (DSCR) of HSA21. We report that EURL is expressed during human and mouse cerebral cortex development, and we report that alterations to EURL mRNA levels within the human brain underlie Down Syndrome. Our gene perturbation studies in mice demonstrate that disruptions to Eurl impair progenitor proliferation and neuronal differentiation. Also, we find that disruptions to Eurl impair the long-term positioning and dendritic spine densities of cortical projection neurons. We provide evidence that EURL interacts with the coiled-coil domain-containing protein CCDC85B so as to modulate ß-catenin levels in cells. Further, we utilised a fluorescent reporter (8xTOPFLASHd2EGFP) to demonstrate that disruptions to Eurl alter ß-catenin signalling in vitro as well as in vivo. Together, these studies highlight EURL as an important new player in neuronal development that is likely to impact on the neuropathogenesis of HSA21-related disorders including Down Syndrome.

De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation.

Disruptions to neuronal mRNA translation are hypothesized to underlie human neurodevelopmental syndromes. Notably, the mRNA translation re-initiation factor DENR is a regulator of eukaryotic translation and cell growth, but its mammalian functions are unknown. Here, we report that Denr influences the migration of murine cerebral cortical neurons in vivo with its binding partner Mcts1, whereas perturbations to Denr impair the long-term positioning, dendritic arborization, and dendritic spine characteristics of postnatal projection neurons. We characterized de novo missense mutations in DENR (p.C37Y and p.P121L) detected in two unrelated human subjects diagnosed with brain developmental disorder to find that each variant impairs the function of DENR in mRNA translation re-initiation and disrupts the migration and terminal branching of cortical neurons in different ways. Thus, our findings link human brain disorders to impaired mRNA translation re-initiation through perturbations in DENR (OMIM: 604550) function in neurons.

Bacurd1/Kctd13 and Bacurd2/Tnfaip1 are interacting partners to Rnd proteins which influence the long-term positioning and dendritic maturation of cerebral cortical neurons.

BACKGROUND: The development of neural circuits within the embryonic cerebral cortex relies on the timely production of neurons, their positioning within the embryonic cerebral cortex as well as their terminal differentiation and dendritic spine connectivity. The RhoA GTPases Rnd2 and Rnd3 are important for neurogenesis and cell migration within the embryonic cortex (Nat Commun 4:1635, 2013), and we recently identified the BTB/POZ domain-containing Adaptor for Cul3-mediated RhoA Degradation family member Bacurd2 (also known as Tnfaip1) as an interacting partner to Rnd2 for the migration of embryonic mouse cortical neurons (Neural Dev 10:9, 2015). FINDINGS: We have extended this work and report that Bacurd1/Kctd13 and Bacurd2/Tnfaip1 are interacting partners to Rnd2 and Rnd3 in vitro. Given that these genes are expressed during cortical development, we performed a series of in utero electroporation studies in mice and found that disruptions to Bacurd1/Kctd13 or Bacurd2/Tnfaip1 expression impair the long-term positioning of E14.5-born cortical neurons within the postnatal (P17) mouse cerebral cortex. We also find that forced expression of Bacurd1/Kctd13 and Bacurd2/Tnfaip1 alters the branching and dendritic spine properties of layer II/III projection neurons. CONCLUSIONS: We identify Bacurd1/Kctd13 and Bacurd2/Tnfaip1 as interacting partners to Rnd proteins which influence the development of cortical neurons. Their neurodevelopmental functions are likely to be relevant to human brain development and disease.

Infantile neurodegenerative disorder associated with mutations in TBCD, an essential gene in the tubulin heterodimer assembly pathway.

Mutation in a growing spectrum of genes is known to either cause or contribute to primary or secondary microcephaly. In primary microcephaly the genetic determinants frequently involve mutations that contribute to or modulate the microtubule cytoskeleton by causing perturbations of neuronal proliferation and migration. Here we describe four patients from two unrelated families each with an infantile neurodegenerative disorder characterized by loss of developmental milestones at 9­24 months of age followed by seizures, dystonia and acquired microcephaly. The patients harboured homozygous missense mutations (A475T and A586V) in TBCD, a gene encoding one of five tubulin-specific chaperones (termed TBCA-E) that function in concert as a nanomachine required for the de novo assembly of the α/ß tubulin heterodimer. The latter is the subunit from which microtubule polymers are assembled. We found a reduced intracellular abundance of TBCD in patient fibroblasts to about 10% (in the case of A475T) or 40% (in the case of A586V) compared to age-matched wild type controls. Functional analyses of the mutant proteins revealed a partially compromised ability to participate in the heterodimer assembly pathway. We show via in utero shRNA-mediated suppression that a balanced supply of tbcd is critical for cortical cell proliferation and radial migration in the developing mouse brain. We conclude that TBCD is a novel functional contributor to the mammalian cerebral cortex development, and that the pathological mechanism resulting from the mutations we describe is likely to involve compromised interactions with one or more TBCD-interacting effectors that influence the dynamics and behaviour of the neuronal cytoskeleton.