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Monoclonal antibodies that target amyloid-beta (Aβ) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody with highest affinity for aggregated Aβ that has been tested for the treatment of Alzheimer's disease. We conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer's disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116. A total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, -0.31; 95% confidence interval [CI], -0.66 to 0.05; P = 0.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, -0.19; 95% CI, -0.55 to 0.17; P = 0.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was -66.44 and -56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the two trials. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of Aβ42 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%. Among persons with early Alzheimer's disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline. (Funded by F. Hoffmann-La Roche; GRADUATE I and II ClinicalTrials.gov numbers, NCT03444870 and NCT03443973, respectively.).

This study examines how participants in routines view and balance pressures for consistency in the face of ongoing change. We address this question through a qualitative case-based inquiry into the ostensive aspects of the core operational routine in six waste management organizations. We find that organizational members simultaneously establish and maintain two ostensive patterns—one of targeted consistency and another of flexibility in internal coordination—by leveraging artifacts and connections. Organizations, however, could not establish similar patterns among their customers, who, lacking connections with other routine participants, expected consistency and performed their part less flexibly. These observations lead us to develop a theoretical model that identifies the processes through which simultaneous ostensive patterns of consistency and flexibility are established and sustained among organizational members, as well as the challenges that arise from multiplicity of ostensive patterns among routine participants with different roles and connections. The model advances the dynamic perspective on routines by articulating how artifacts and connections support the balancing of pressures for consistency and for change in routine functioning.

‘Brains’ may be considered to be computation engines, with neurons and synapses analogized to electronic components wired into networks that process information, learn and evolve. Alternatively, ‘brains’ are cognitive systems, which contain elements of intentionality, purposefulness and creativity that do not fit comfortably into a brain-as-computer metaphor. I address the question of how we may think most constructively about brains in their various forms—solid, liquid or fluid—and whether there is a coherent theory that unites them all. In this essay, I explore cognitive systems in the context of new understanding of life's distinctive nature, in particular the core concept of homeostasis, and how this new understanding lays a sound conceptual foundation for an expansive theory of brains. This article is part of the theme issue ‘Liquid brains, solid brains: How distributed cognitive architectures process information'.

The search for general common principles that unify disciplines is a longstanding challenge for interdisciplinary research. Architecture has always been an interdisciplinary pursuit, combining engineering, art and culture. The rise of biomimetic architecture adds to the interdisciplinary span. We discuss the similarities and differences among human and animal societies in how architecture influences their collective behaviour. We argue that the emergence of a fully biomimetic architecture involves breaking down what we call ‘pernicious dualities’ that have permeated our discourse for decades, artificial divisions between species, between organism and environment, between genotype and phenotype, and in the case of architecture, the supposed duality between the built environment and its builders. We suggest that niche construction theory may serve as a starting point for unifying our thinking across disciplines, taxa and spatial scales. This article is part of the theme issue ‘Interdisciplinary approaches for uncovering the impacts of architecture on collective behaviour’.

A fundamental question in corporate strategy is how headquarters in multibusiness firms can create value above and beyond the burden of its own overhead. The leading theories from Chandler and Williamson hold that this is possible through resource allocation across businesses. Yet, there are multibusiness firms for whom reallocation opportunities are limited—e.g., chains. Accordingly, we propose, model, and test an alternative theory, one in which headquarters facilitates market-like dynamics between businesses that fuel innovation and growth. Whereas Chandler’s and Williamson’s theories involve the visible hand of managers, ours involves an invisible hand of managers. We construct an interacting agent model of the theory, which yields three propositions relating multibusiness structure to firm growth. We test those propositions in the banking industry and obtain results consistent with the model’s predictions. In particular, knowledge growth increases in the number of units and heterogeneity in their knowledge, and increases then decreases in their geographic distance. Interestingly, once we account for these structural elements, scale and hierarchy both suppress innovation. Thus, neither Williamson’s nor Chandler’s theories hold in our setting (consistent with the argument motivating the need for an additional theory).

Termite colonies construct towering, complex mounds, in a classic example of distributed agents coordinating their activity via interaction with a shared environment. The traditional explanation for how this coordination occurs focuses on the idea of a ‘cement pheromone’, a chemical signal left with deposited soil that triggers further deposition. Recent research has called this idea into question, pointing to a more complicated behavioural response to cues perceived with multiple senses. In this work, we explored the role of topological cues in affecting early construction activity in Macrotermes . We created artificial surfaces with a known range of curvatures, coated them with nest soil, placed groups of major workers on them and evaluated soil displacement as a function of location at the end of 1 h. Each point on the surface has a given curvature, inclination and absolute height; to disambiguate these factors, we conducted experiments with the surface in different orientations. Soil displacement activity is consistently correlated with surface curvature, and not with inclination nor height. Early exploration activity is also correlated with curvature, to a lesser degree. Topographical cues provide a long-term physical memory of building activity in a manner that ephemeral pheromone labelling cannot. Elucidating the roles of these and other cues for group coordination may help provide organizing principles for swarm robotics and other artificial systems. This article is part of the theme issue ‘Liquid brains, solid brains: How distributed cognitive architectures process information’.

Termites construct complex mounds that are orders of magnitude larger than any individual and fulfil a variety of functional roles. Yet the processes through which these mounds are built, and by which the insects organize their efforts, remain poorly understood. The traditional understanding focuses on stigmergy, a form of indirect communication in which actions that change the environment provide cues that influence future work. Termite construction has long been thought to be organized via a putative ‘cement pheromone’: a chemical added to deposited soil that stimulates further deposition in the same area, thus creating a positive feedback loop whereby coherent structures are built up. To investigate the detailed mechanisms and behaviours through which termites self-organize the early stages of mound construction, we tracked the motion and behaviour of major workers from two Macrotermes species in experimental arenas. Rather than a construction process focused on accumulation of depositions, as models based on cement pheromone would suggest, our results indicated that the primary organizing mechanisms were based on excavation. Digging activity was focused on a small number of excavation sites, which in turn provided templates for soil deposition. This behaviour was mediated by a mechanism of aggregation, with termites being more likely to join in the work at an excavation site as the number of termites presently working at that site increased. Statistical analyses showed that this aggregation mechanism was a response to active digging, distinct from and unrelated to putative chemical cues that stimulate deposition. Agent-based simulations quantitatively supported the interpretation that the early stage of de novo construction is primarily organized by excavation and aggregation activity rather than by stigmergic deposition.

Spondyloarthropathies are characterized by a distinct pattern of inflammation at distinct anatomical sites and are associated with elevated expression of interleukin 23 (IL-23). Daniel Cua and his colleagues identify an IL-23–responsive CD4 − CD8 − T cell population located within entheses. Systemic overexpression of IL-23 activates these cells and recapitulates aspects of the human disease in mice, and neutralization of IL-17 and IL-22 decreases pathology, suggesting new therapeutic targets for these disorders. The spondyloarthropathies are a group of rheumatic diseases that are associated with inflammation at anatomically distal sites, particularly the tendon-bone attachments (entheses) and the aortic root. Serum concentrations of interleukin-23 (IL-23) are elevated and polymorphisms in the IL-23 receptor are associated with ankyosing spondylitis, however, it remains unclear whether IL-23 acts locally at the enthesis or distally on circulating cell populations. We show here that IL-23 is essential in enthesitis and acts on previously unidentified IL-23 receptor (IL-23R) + , RAR-related orphan receptor γt (ROR-γt) + CD3 + CD4 − CD8 − , stem cell antigen 1 (Sca1) + entheseal resident T cells. These cells allow entheses to respond to IL-23 in vitro —in the absence of further cellular recruitment—and to elaborate inflammatory mediators including IL-6, IL-17, IL-22 and chemokine (C-X-C motif) ligand 1 (CXCL1). Notably, the in vivo expression of IL-23 is sufficient to phenocopy the human disease, with the specific and characteristic development of enthesitis and entheseal new bone formation in the initial complete absence of synovitis. As in the human condition, inflammation also develops in vivo at the aortic root and valve, which are structurally similar to entheses. The presence of these entheseal resident cells and their production of IL-22, which activates signal transducer and activator of transcription 3 (STAT3)-dependent osteoblast-mediated bone remodeling, explains why dysregulation of IL-23 results in inflammation at this precise anatomical site.

Rationale α v integrins, key regulators of transforming growth factor-β activation and fibrogenesis in in vivo models of pulmonary fibrosis, are expressed on abnormal epithelial cells (α v β 6 ) and fibroblasts (α v β 1 ) in fibrotic lungs. Objectives We evaluated multiple α v integrin inhibition strategies to assess which most effectively reduced fibrogenesis in explanted lung tissue from patients with idiopathic pulmonary fibrosis. Methods Selective α v β 6 and α v β 1 , dual α v β 6 /α v β 1 , and multi-α v integrin inhibitors were characterized for potency, selectivity, and functional activity by ligand binding, cell adhesion, and transforming growth factor-β cell activation assays. Precision-cut lung slices generated from lung explants from patients with idiopathic pulmonary fibrosis or bleomycin-challenged mouse lungs were treated with integrin inhibitors or standard-of-care drugs (nintedanib or pirfenidone) and analyzed for changes in fibrotic gene expression or TGF-β signaling. Bleomycin-challenged mice treated with dual α v β 6 /α v β 1 integrin inhibitor, PLN-74809, were assessed for changes in pulmonary collagen deposition and Smad3 phosphorylation. Measurements and main results Inhibition of integrins α v β 6 and α v β 1 was additive in reducing type I collagen gene expression in explanted lung tissue slices from patients with idiopathic pulmonary fibrosis. These data were replicated in fibrotic mouse lung tissue, with no added benefit observed from inhibition of additional α v integrins. Antifibrotic efficacy of dual α v β 6 /α v β 1 integrin inhibitor PLN-74809 was confirmed in vivo, where dose-dependent inhibition of pulmonary Smad3 phosphorylation and collagen deposition was observed. PLN-74809 also, more potently, reduced collagen gene expression in fibrotic human and mouse lung slices than clinically relevant concentrations of nintedanib or pirfenidone. Conclusions In the fibrotic lung, dual inhibition of integrins α v β 6 and α v β 1 offers the optimal approach for blocking fibrogenesis resulting from integrin-mediated activation of transforming growth factor-β.