Neuroecological links of the exposome and One Health.

This NeuroView assesses the interplay among exposome, One Health, and brain capital in health and disease. Physical and social exposomes affect brain health, and green brain skills are required for environmental health strategies. Ibanez et al. address current gaps and strategies needed in research, policy, and technology, offering a road map for stakeholders.

Navigating a stable transition to the age of intelligence: A mental wealth perspective.

In the grand narrative of technological evolution, we are transitioning from the "Age of Information" to the "Age of Intelligence." Rapid advancements in generative artificial intelligence (AI) are set to reshape society, revolutionize industries, and change the nature of work, challenging our traditional understanding of the dynamics of the economy and its relationship with human productivity and societal prosperity. As we brace for this transformative shift, promising advancements in healthcare, education, productivity, and more, there are concerns of large-scale job loss, mental health repercussions, and risks to social stability and democracy. This paper proposes the concept of Mental Wealth as an action framework that supports nations to proactively position themselves for a smooth transition to the Age of Intelligence while fostering economic and societal prosperity.

The influence of economic policies on social environments and mental health.

Despite increased advocacy and investments in mental health systems globally, there has been limited progress in reducing mental disorder prevalence. In this paper, we argue that meaningful advancements in population mental health necessitate addressing the fundamental sources of shared distress. Using a systems perspective, economic structures and policies are identified as the potential cause of causes of mental ill-health. Neoliberal ideologies, prioritizing economic optimization and continuous growth, contribute to the promotion of individualism, job insecurity, increasing demands on workers, parental stress, social disconnection and a broad range of manifestations well-recognized to erode mental health. We emphasize the need for mental health researchers and advocates to increasingly engage with the economic policy discourse to draw attention to mental health and well-being implications. We call for a shift towards a well-being economy to better align commercial interests with collective well-being and social prosperity. The involvement of individuals with lived mental ill-health experiences, practitioners and researchers is needed to mobilize communities for change and influence economic policies to safeguard well-being. Additionally, we call for the establishment of national mental wealth observatories to inform coordinated health, social and economic policies and realize the transition to a more sustainable well-being economy that offers promise for progress on population mental health outcomes.

Malgré une meilleure sensibilisation et des investissements accrus dans les systèmes de santé mentale à travers le monde, les progrès en matière de réduction du degré de prévalence des troubles mentaux demeurent très limités. Dans le présent document, nous estimons que, pour réaliser des avancées au niveau de la santé mentale des populations, il est impératif de s'attaquer aux sources de cette détresse collective. En adoptant une perspective systémique, force est de constater que les politiques et structures économiques constituent les causes potentielles d'une mauvaise santé mentale. Les idéologies néolibérales, qui privilégient l'optimisation économique et la croissance ininterrompue, contribuent à promouvoir l'individualisme, l'insécurité professionnelle, la pression pesant sur les travailleurs, le stress parental, l'isolement social et un large éventail de facteurs associés à une dégradation de la santé mentale. Nous insistons sur la nécessité de faire appel à des chercheurs et défenseurs actifs dans ce domaine, afin de jouer un rôle dans la politique économique en attirant l'attention sur les implications pour le bien-être et la santé mentale. Nous plaidons pour une transition vers une économie du bien-être visant à rapprocher les intérêts commerciaux de la prospérité sociale et collective. L'intervention de personnes ayant été confrontées à des troubles mentaux, de praticiens et de chercheurs est nécessaire pour mobiliser les communautés en faveur d'un changement et influencer les politiques économiques pour préserver le bien-être. Par ailleurs, nous militons pour la création d'observatoires nationaux de la santé mentale qui serviront à orienter des politiques économiques, sociales et sanitaires coordonnées, mais aussi à favoriser l'évolution vers une économie du bien-être plus durable, laissant entrevoir une amélioration de la santé mentale au sein de la population.

A pesar del aumento de la promoción y las inversiones en sistemas de salud mental en todo el mundo, los avances en la reducción de la prevalencia de los trastornos mentales han sido limitados. En este documento, sostenemos que para lograr avances significativos en la salud mental de la población es necesario abordar las fuentes fundamentales de la angustia compartida. Mediante una perspectiva sistémica, las estructuras y políticas económicas se identifican como la posible causa de los problemas de salud mental. Las ideologías neoliberales, que priorizan la optimización económica y el crecimiento continuo, contribuyen al fomento del individualismo, la inseguridad laboral, el aumento de las exigencias a los trabajadores, el estrés parental, la desconexión social y una gran variedad de manifestaciones bien reconocidas que perjudican la salud mental. Insistimos en la necesidad de que los investigadores y los defensores de la salud mental se impliquen cada vez más en el discurso de la política económica para atraer la atención sobre las implicaciones para la salud mental y el bienestar. Pedimos un cambio hacia una economía del bienestar para alinear mejor los intereses comerciales con el bienestar colectivo y la prosperidad social. Para movilizar a las comunidades en favor del cambio e influir en las políticas económicas con el fin de salvaguardar el bienestar, es necesaria la participación de personas que han padecido enfermedades mentales, profesionales e investigadores. Además, pedimos la creación de observatorios nacionales de bienestar mental que sirvan de base a las políticas sanitarias, sociales y económicas coordinadas y permitan la transición a una economía del bienestar más sostenible, que ofrezca perspectivas de progreso en los resultados de salud mental de la población.

The Brain Economy: Advancing Brain Science to Better Understand the Modern Economy.

The coming years are likely to be turbulent due to a myriad of factors or polycrisis, including an escalation in climate extremes, emerging public health threats, weak productivity, increases in global economic instability and further weakening in the integrity of global democracy. These formidable challenges are not exogenous to the economy but are in some cases generated by the system itself. They can be overcome, but only with far-reaching changes to global economics. Our current socio-economic paradigm is insufficient for addressing these complex challenges, let alone sustaining human development, well-being and happiness. To support the flourishing of the global population in the age of polycrisis, we need a novel, person-centred and collective paradigm. The brain economy leverages insights from neuroscience to provide a novel way of centralising the human contribution to the economy, how the economy in turn shapes our lives and positive feedbacks between the two. The brain economy is primarily based on Brain Capital, an economic asset integrating brain health and brain skills, the social, emotional, and the diversity of cognitive brain resources of individuals and communities. People with healthy brains are essential to navigate increasingly complex systems. Policies and investments that improve brain health and hence citizens' cognitive functions and boost brain performance can increase productivity, stimulate greater creativity and economic dynamism, utilise often underdeveloped intellectual resources, afford social cohesion, and create a more resilient, adaptable and sustainability-engaged population.

A perfused multi-well bioreactor platform to assess tumor organoid response to a chemotherapeutic gradient.

There is an urgent need to develop new therapies for colorectal cancer that has metastasized to the liver and, more fundamentally, to develop improved preclinical platforms of colorectal cancer liver metastases (CRCLM) to screen therapies for efficacy. To this end, we developed a multi-well perfusable bioreactor capable of monitoring CRCLM patient-derived organoid response to a chemotherapeutic gradient. CRCLM patient-derived organoids were cultured in the multi-well bioreactor for 7 days and the subsequently established gradient in 5-fluorouracil (5-FU) concentration resulted in a lower IC50 in the region near the perfusion channel versus the region far from the channel. We compared behaviour of organoids in this platform to two commonly used PDO culture models: organoids in media and organoids in a static (no perfusion) hydrogel. The bioreactor IC50 values were significantly higher than IC50 values for organoids cultured in media whereas only the IC50 for organoids far from the channel were significantly different than organoids cultured in the static hydrogel condition. Using finite element simulations, we showed that the total dose delivered, calculated using area under the curve (AUC) was similar between platforms, however normalized viability was lower for the organoid in media condition than in the static gel and bioreactor. Our results highlight the utility of our multi-well bioreactor for studying organoid response to chemical gradients and demonstrate that comparing drug response across these different platforms is nontrivial.

Investing in Late-Life Brain Capital.

Within many societies and cultures around the world, older adults are too often undervalued and underappreciated. This exacerbates many key challenges that older adults may face. It also undermines the many positive aspects of late life that are of tremendous value at both an individual and societal level. We propose a new approach to elevate health and well-being in late life by optimizing late-life Brain Capital. This form of capital prioritizes brain skills and brain health in a brain economy, which the challenges and opportunities of the 21st-century demands. This approach incorporates investing in late-life Brain Capital, developing initiatives focused on building late-life Brain Capital.

Adaptation, Transformation and Resilience in Healthcare Comment on "Government Actions and Their Relation to Resilience in Healthcare During the COVID-19 Pandemic in New South Wales, Australia and Ontario, Canada".

Adaptive capacity is a critical component of building resilience in healthcare (RiH). Adaptive capacity comprises the ability of a system to cope with and adapt to disturbances. However, "shocks," such as the current coronavirus disease 2019 (COVID-19) pandemic, can potentially exceed critical adaptation thresholds and lead to systemic collapse. To effectively manage healthcare systems during periods of crises, both adaptive and transformative changes are necessary. This commentary discusses adaptation and transformation as two complementary, integral components of resilience and applies them to healthcare. We treat resilience as an emergent property of complex systems that accounts for multiple, often disparately distinct regimes in which multiple processes (eg, adaptation, recovery) are subsumed and operate. We argue that Convergence Mental Health and other transdisciplinary paradigms such as Brain Capital and One Health can facilitate resilience planning and management in healthcare systems.

Extracellular matrix modulates T cell clearance of malignant cells in vitro.

Despite the success of T cell checkpoint therapies, breast cancers rarely express these immunotherapy markers and are believed to be largely "immune cold" with limited inflammation and immune activation. The reason for this limited immune activation remains poorly understood. We sought to determine whether extracellular matrix substrate could contribute to this limited immune activation. Specifically, we asked whether extracellular matrix could alter T cell cytotoxicity against malignant mammary gland carcinoma cells (MCC) in a setup designed to promote maximal T cell efficacy (i.e., rich media with abundant IL2, high ratio of T cells to MCC). We observed that T cell clearance of MCC varied from 0% in collagen 4 or 6 conditions to almost 100% in fibronectin or vitronectin. Transcriptomics revealed that T cell function was defective in MCC/T cell cocultures on collagen 4 (Col4), potentially corresponding to greater expression of cytokines MCC cultured in this environment. In contrast, transcriptomics revealed an effective, exhausted phenotype on vitronectin. The observation that Col4 induces T cell suppression suggests that targeting tumor-ECM interactions may permit new approaches for utilizing immunotherapy in tumors which do not provoke a strong immune response.

Nanolipoprotein-Mediated Her2 Protein Transfection Induces Malignant Transformation in Human Breast Acinar Cultures.

Her2 overexpression is associated with an aggressive form of breast cancer and malignant transformation. We demonstrate in this work that nanolipoprotein particles (NLPs) synthesized in a cell-free manner can be used to transfer Her2 protein into the membrane of nonmalignant cells in 3D culture in a nontoxic and facile manner. With NLP-mediated Her2 protein delivery, we observed an increased probability of nonmalignant cells forming apolar nongrowth-arrested tumor-like structures. The NLP delivery system alone or Her2-NLPs plus the Her2 inhibitor trastuzumab showed no effect on the acinar organization rate, indicating that Her2 signaling is key to this process. Transcriptomics revealed essentially no effect of empty NLPs compared to untreated cells, whereas Her2-NLPs versus either untreated or empty-NLP-treated cells revealed upregulation of several factors associated with breast cancer. Pathway analysis also suggested that known nodes downstream of Her2 were activated in response to Her2-NLP treatment. This demonstrates that Her2 protein delivery with NLPs is sufficient for the malignant transformation of nonmalignant cells. Thus, this system offers a new model for studying cell surface receptor signaling without genomic modification or transformation techniques.

Building brain capital.

Brains are indispensable drivers of human progress. Why not invest more heavily in them? We seek to place Brain Capital at the center of a new narrative to fuel economic and societal recovery and resilience.

Projection Microstereolithographic Microbial Bioprinting for Engineered Biofilms.

Microbes are critical drivers of all ecosystems and many biogeochemical processes, yet little is known about how the three-dimensional (3D) organization of these dynamic organisms contributes to their overall function. To probe how biofilm structure affects microbial activity, we developed a technique for patterning microbes in 3D geometries using projection stereolithography to bioprint microbes within hydrogel architectures. Bacteria were printed and monitored for biomass accumulation, demonstrating postprint viability of cells using this technique. We verified our ability to integrate biological and geometric complexity by fabricating a printed biofilm with two E. coli strains expressing different fluorescence. Finally, we examined the target application of microbial absorption of metal ions to investigate geometric effects on both the metal sequestration efficiency and the uranium sensing capability of patterned engineered Caulobacter crescentus strains. This work represents the first demonstration of the stereolithographic printing of microbials and presents opportunities for future work of engineered biofilms and other complex 3D structured cultures.

Investigating the Interaction Between Circulating Tumor Cells and Local Hydrodynamics via Experiment and Simulations.

INTRODUCTION: The biological and mechanical properties of circulating tumor cells (CTCs) in combination with the hemodynamics affect the preference of metastatic sites in the vasculature. Despite the extensive literature on the effects of biological properties on cell adhesion, the effects of hydrodynamic forces on primary attachment remains an active area of research. Using simulations in conjunction with experimentation, we provide new insight into the interplay of CTCs dynamics and local hydrodynamics. METHODS: A flow experiment of CTC attachment was performed within a bioprinted, double branching endothelialized vessel. Simulations of fluid flow and CTC transport in the reconstructed and idealized bifurcated vessel were respectively performed by HARVEY, our in-house massively parallel computational fluid dynamics solver. HARVEY is based on the lattice Boltzmann and finite element methods to model the fluid and cells dynamics. The immersed boundary method is employed for resolving the fluid-structure interaction. RESULTS: CTC attachment was quantified experimentally at all regions of the complex vessel. The results demonstrate a clear preference for CTCs to attach at the branch points. To elucidate the effect of the vessel topology on the location of attachment, a fluid-only simulation was performed assessing the differences in the hydrodynamics along the vessel. CTC transport in idealized bifurcated vessels was subsequently studied to examine the effects of cell deformability on the local hydrodynamics patterns and, thus, the preference of attachment sites. CONCLUSIONS: The current work provides evidence on the correlation of the hydrodynamics forces arising from the vessel topology and CTC properties on the attachment regions.

Three-dimensional bioprinting of aneurysm-bearing tissue structure for endovascular deployment of embolization coils.

Various types of embolization devices have been developed for the treatment of cerebral aneurysms. However, it is challenging to properly evaluate device performance and train medical personnel for device deployment without the aid of functionally relevant models. Currentin vitroaneurysm models suffer from a lack of key functional and morphological features of brain vasculature that limit their applicability for these purposes. These features include the physiologically relevant mechanical properties and the dynamic cellular environment of blood vessels subjected to constant fluid flow. Herein, we developed three-dimensionally (3D) printed aneurysm-bearing vascularized tissue structures using gelatin-fibrin hydrogel of which the inner vessel walls were seeded with human cerebral microvascular endothelial cells (hCMECs). The hCMECs readily exhibited cellular attachment, spreading, and confluency all around the vessel walls, including the aneurysm walls. Additionally, thein vitroplatform was directly amenable to flow measurements via particle image velocimetry, enabling the direct assessment of the vascular flow dynamics for comparison to a 3D computational fluid dynamics model. Detachable coils were delivered into the printed aneurysm sac through the vessel using a microcatheter and static blood plasma clotting was monitored inside the aneurysm sac and around the coils. This biomimeticin vitroaneurysm model is a promising method for examining the biocompatibility and hemostatic efficiency of embolization devices and for providing hemodynamic information which would aid in predicting aneurysm rupture or healing response after treatment.

Bouncing forward: a resilience approach to dealing with COVID-19 and future systemic shocks.

Policy questions are often framed in popular discussion as situations where pulling the right levers will get the economy and society back on track after shocks and crises. This approach ignores how systems interact and how their systemic properties shape socioeconomic outcomes, leading to an over-emphasis on a limited set of characteristics, notably efficiency. We argue that this emphasis on efficiency in the operation, management and outcomes of various economic and social systems is not a conscious collective choice, but rather the response of the whole system to the incentives that individual components face. This has brought much of the world to rely upon complex, nested, and interconnected systems to deliver goods and services around the globe. While this approach has many benefits, the Covid-19 crisis shows how it has also reduced the resilience of key systems to shocks, and allowed failures to cascade from one system to others. This paper reviews the impact of COVID-19 on socioeconomic systems, discusses the notion of resilience, and provides specific recommendations on both integrating resilience analytics for recovery from the current crisis as well as on building resilient infrastructure to address future systemic challenges.