Cellular geometry and epithelial-mesenchymal plasticity intersect with PIEZO1 in breast cancer cells.

Differences in shape can be a distinguishing feature between different cell types, but the shape of a cell can also be dynamic. Changes in cell shape are critical when cancer cells escape from the primary tumor and undergo major morphological changes that allow them to squeeze between endothelial cells, enter the vasculature, and metastasize to other areas of the body. A shift from rounded to spindly cellular geometry is a consequence of epithelial-mesenchymal plasticity, which is also associated with changes in gene expression, increased invasiveness, and therapeutic resistance. However, the consequences and functional impacts of cell shape changes and the mechanisms through which they occur are still poorly understood. Here, we demonstrate that altering the morphology of a cell produces a remodeling of calcium influx via the ion channel PIEZO1 and identify PIEZO1 as an inducer of features of epithelial-to-mesenchymal plasticity. Combining automated epifluorescence microscopy and a genetically encoded calcium indicator, we demonstrate that activation of the PIEZO1 force channel with the PIEZO1 agonist, YODA 1, induces features of epithelial-to-mesenchymal plasticity in breast cancer cells. These findings suggest that PIEZO1 is a critical point of convergence between shape-induced changes in cellular signaling and epithelial-mesenchymal plasticity in breast cancer cells.

Mapping clinical interactions in an Australian tertiary hospital emergency department for patients presenting with risk of suicide or self-harm: Network modeling from observational data.

BACKGROUND: Reliable assessment of suicide and self-harm risk in emergency medicine is critical for effective intervention and treatment of patients affected by mental health disorders. Teams of clinicians face the challenge of rapidly integrating medical history, wide-ranging psychosocial factors, and real-time patient observations to inform diagnosis, treatment, and referral decisions. Patient outcomes therefore depend on the reliable flow of information through networks of clinical staff and information systems. This study aimed to develop a quantitative data-driven research framework for the analysis of information flow in emergency healthcare settings to evaluate clinical practice and operational models for emergency psychiatric care. METHODS AND FINDINGS: We deployed 2 observers in a tertiary hospital emergency department during 2018 for a total of 118.5 h to record clinical interactions along patient trajectories for presentations with risk of self-harm or suicide (n = 272 interactions for n = 43 patient trajectories). The study population was reflective of a naturalistic sample of patients presenting to a tertiary emergency department in a metropolitan Australian city. Using the observational data, we constructed a clinical interaction network to model the flow of clinical information at a systems level. Community detection via modularity maximization revealed communities in the network closely aligned with the underlying clinical team structure. The Psychiatric Liaison Nurse (PLN) was identified as the most important agent in the network as quantified by node degree, closeness centrality, and betweenness centrality. Betweenness centrality of the PLN was significantly higher than expected by chance (>95th percentile compared with randomly shuffled networks) and removing the PLN from the network reduced both the global efficiency of the model and the closeness centrality of all doctors. This indicated a potential vulnerability in the system that could negatively impact patient care if the function of the PLN was compromised. We developed an algorithmic strategy to mitigate this risk by targeted strengthening of links between clinical teams using greedy cumulative addition of network edges in the model. Finally, we identified specific interactions along patient trajectories which were most likely to precipitate a psychiatric referral using a machine learning model trained on features from dynamically constructed clinical interaction networks. The main limitation of this study is the use of nonclinical information only (i.e., modeling is based on timing of interactions and agents involved, but not the content or quantity of information transferred during interactions). CONCLUSIONS: This study demonstrates a data-driven research framework, new to the best of our knowledge, to assess and reinforce important information pathways that guide clinical decision processes and provide complementary insights for improving clinical practice and operational models in emergency medicine for patients at risk of suicide or self-harm. Our findings suggest that PLNs can play a crucial role in clinical communication, but overreliance on PLNs may pose risks to reliable information flow. Operational models that utilize PLNs may be made more robust to these risks by improving interdisciplinary communication between doctors. Our research framework could also be applied more broadly to investigate service delivery in different healthcare settings or for other medical specialties, patient groups, or demographics.

Cortical activity emerges in region-specific patterns during early brain development.

The development of precise neural circuits in the brain requires spontaneous patterns of neural activity prior to functional maturation. In the rodent cerebral cortex, patchwork and wave patterns of activity develop in somatosensory and visual regions, respectively, and are present at birth. However, whether such activity patterns occur in noneutherian mammals, as well as when and how they arise during development, remain open questions relevant for understanding brain formation in health and disease. Since the onset of patterned cortical activity is challenging to study prenatally in eutherians, here we offer an approach in a minimally invasive manner using marsupial dunnarts, whose cortex forms postnatally. We discovered similar patchwork and travelling waves in the dunnart somatosensory and visual cortices at stage 27 (equivalent to newborn mice) and examined earlier stages of development to determine the onset of these patterns and how they first emerge. We observed that these patterns of activity emerge in a region-specific and sequential manner, becoming evident as early as stage 24 in somatosensory and stage 25 in visual cortices (equivalent to embryonic day 16 and 17, respectively, in mice), as cortical layers establish and thalamic axons innervate the cortex. In addition to sculpting synaptic connections of existing circuits, evolutionarily conserved patterns of neural activity could therefore help regulate other early events in cortical development.

Cortical activity emerges in region-specific patterns during early brain development.

The development of precise neural circuits in the brain requires spontaneous patterns of neural activity prior to functional maturation. In the rodent cerebral cortex patchwork and wave patterns of activity develop in somatosensory and visual regions, respectively, and are present at birth. However, whether such activity patterns occur in non-eutherian mammals, as well as when and how they arise during development remain open questions relevant to understand brain formation in health and disease. Since the onset of patterned cortical activity is challenging to study prenatally in eutherians, here we offer a new approach in a minimally invasive manner using marsupial dunnarts, whose cortex forms postnatally. We discovered similar patchwork and travelling waves in the dunnart somatosensory and visual cortices at stage 27 (equivalent to newborn mice), and examined progressively earlier stages of development to determine their onset and how they first emerge. We observed that these patterns of activity emerge in a region-specific and sequential manner, becoming evident as early as stage 24 in somatosensory and stage 25 in visual cortices (equivalent to embryonic day 16 and 17, respectively, in mice), as cortical layers establish and thalamic axons innervate the cortex. In addition to sculpting synaptic connections of existing circuits, evolutionarily conserved patterns of neural activity could therefore help regulate early events in cortical development. Significance Statement: Region-specific patterns of neural activity are present at birth in rodents and are thought to refine synaptic connections during critical periods of cerebral cortex development. Marsupials are born much more immature than rodents, allowing the investigation of how these patterns arise in vivo. We discovered that cortical activity patterns are remarkably similar in marsupial dunnarts and rodents, and that they emerge very early, before cortical neurogenesis is complete. Moreover, they arise from the outset in different patterns specific to somatosensory and visual areas (i.e., patchworks and waves) indicating they may also play evolutionarily conserved roles in cortical regionalization during development.

fmr1 Mutation Alters the Early Development of Sensory Coding and Hunting and Social Behaviors in Larval Zebrafish.

Autism spectrum disorders (ASDs) are developmental in origin; however, little is known about how they affect the early development of behavior and sensory coding. The most common inherited form of autism is Fragile X syndrome (FXS), caused by a mutation in FMR1 Mutation of fmr1 in zebrafish causes anxiety-like behavior, hyperactivity, and hypersensitivity in auditory and visual processing. Here, we show that zebrafish fmr1-/- mutant larvae of either sex also display changes in hunting behavior, tectal coding, and social interaction. During hunting, they were less successful at catching prey and displayed altered behavioral sequences. In the tectum, representations of prey-like stimuli were more diffuse and had higher dimensionality. In a social behavioral assay, they spent more time observing a conspecific but responded more slowly to social cues. However, when given a choice of rearing environment fmr1-/- larvae preferred one with reduced visual stimulation, and rearing them in this environment reduced genotype-specific effects on tectal excitability. Together, these results shed new light on how fmr1-/- changes the early development of neural systems and behavior in a vertebrate.SIGNIFICANCE STATEMENT Autism spectrum disorders (ASDs) are caused by changes in early neural development. Animal models of ASDs offer the opportunity to study these developmental processes in greater detail than in humans. Here, we found that a zebrafish mutant for a gene which in humans causes one type of ASD showed early alterations in hunting behavior, social behavior, and how visual stimuli are represented in the brain. However, we also found that mutant fish preferred reduced visual stimulation, and rearing them in this environment reduced alterations in neural activity patterns. These results suggest interesting new directions for using zebrafish as a model to study the development of brain and behavior in ASDs, and how the impact of ASDs could potentially be reduced.

Unsupervised quantification of naturalistic animal behaviors for gaining insight into the brain.

Neural computation has evolved to optimize the behaviors that enable our survival. Although much previous work in neuroscience has focused on constrained task behaviors, recent advances in computer vision are fueling a trend toward the study of naturalistic behaviors. Automated tracking of fine-scale behaviors is generating rich datasets for animal models including rodents, fruit flies, zebrafish, and worms. However, extracting meaning from these large and complex data often requires sophisticated computational techniques. Here we review the latest methods and modeling approaches providing new insights into the brain from behavior. We focus on unsupervised methods for identifying stereotyped behaviors and for resolving details of the structure and dynamics of behavioral sequences.