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Brace yourself for a fun challenge: build a photorealistic 3D renderer from scratch! In just a couple of weeks, build a ray tracer that renders beautiful scenes with shadows, reflections, refraction effects, and subjects composed of various graphics primitives: spheres, cubes, cylinders, triangles, and more. With each chapter, implement another piece of the puzzle and move the renderer forward. Use whichever language and environment you prefer, and do it entirely test-first, so you know it's correct.

While many digital mental health interventions (DMHIs) have been found to be efficacious, patient engagement with DMHIs has increasingly emerged as a concern for implementation in real-world clinical settings. To address engagement, we must first understand what standard engagement levels are in the context of randomized controlled trials (RCTs) and how these compare with other treatments. This scoping review aims to examine the state of reporting on intervention engagement in RCTs of mobile app-based interventions intended to treat symptoms of depression. We sought to identify what engagement metrics are and are not routinely reported as well as what the metrics that are reported reflect about standard engagement levels. We conducted a systematic search of 7 databases to identify studies meeting our eligibility criteria, namely, RCTs that evaluated use of a mobile app-based intervention in adults, for which depressive symptoms were a primary outcome of interest. We then extracted 2 kinds of information from each article: intervention details and indices of DMHI engagement. A 5-element framework of minimum necessary DMHI engagement reporting was derived by our team and guided our data extraction. This framework included (1) recommended app use as communicated to participants at enrollment and, when reported, app adherence criteria; (2) rate of intervention uptake among those assigned to the intervention; (3) level of app use metrics reported, specifically number of uses and time spent using the app; (4) duration of app use metrics (ie, weekly use patterns); and (5) number of intervention completers. Database searching yielded 2083 unique records. Of these, 22 studies were eligible for inclusion. Only 64% (14/22) of studies included in this review specified rate of intervention uptake. Level of use metrics was only reported in 59% (13/22) of the studies reviewed. Approximately one-quarter of the studies (5/22, 23%) reported duration of use metrics. Only half (11/22, 50%) of the studies reported the number of participants who completed the app-based components of the intervention as intended or other metrics related to completion. Findings in those studies reporting metrics related to intervention completion indicated that between 14.4% and 93.0% of participants randomized to a DMHI condition completed the intervention as intended or according to a specified adherence criteria. Findings suggest that engagement was underreported and widely varied. It was not uncommon to see completion rates at or below 50% (11/22) of those participants randomized to a treatment condition or to simply see completion rates not reported at all. This variability in reporting suggests a failure to establish sufficient reporting standards and limits the conclusions that can be drawn about level of engagement with DMHIs. Based on these findings, the 5-element framework applied in this review may be useful as a minimum necessary standard for DMHI engagement reporting.

Intestinal goblet cells maintain the protective epithelial barrier through mucus secretion and yet sample lumenal substances for immune processing through formation of goblet cell associated antigen passages (GAPs). The cellular biology of GAPs and how these divergent processes are balanced and regulated by goblet cells remains unknown. Using high-resolution light and electron microscopy, we found that in mice, GAPs were formed by an acetylcholine (ACh)-dependent endocytic event remarkable for delivery of fluid-phase cargo retrograde into the trans-golgi network and across the cell by transcytosis – in addition to the expected transport of fluid-phase cargo by endosomes to multi-vesicular bodies and lysosomes. While ACh also induced goblet cells to secrete mucins, ACh-induced GAP formation and mucin secretion were functionally independent and mediated by different receptors and signaling pathways, enabling goblet cells to differentially regulate these processes to accommodate the dynamically changing demands of the mucosal environment for barrier maintenance and sampling of lumenal substances. Cells in the gut need to be protected against the many harmful microbes which inhabit this environment. Yet the immune system also needs to ‘keep an eye’ on intestinal contents to maintain tolerance to innocuous substances, such as those from the diet. The ‘goblet cells’ that are part of the gut lining do both: they create a mucus barrier that stops germs from invading the body, but they also can pass on molecules from the intestine to immune cells deep in the tissue to promote tolerance. This is achieved through a ‘GAP’ mechanism. A chemical messenger called acetylcholine can trigger both mucus release and the GAP process in goblet cells. Gustafsson et al. investigated how the cells could take on these two seemingly opposing roles in response to the same signal. A fluorescent molecule was introduced into the intestines of mice, and monitored as it pass through the goblet cells. This revealed how the GAP process took place: the cells were able to capture molecules from the intestines, wrap them in internal sack-like vesicles and then transport them across the entire cell. To explore the role of acetylcholine, Gustafsson et al. blocked the receptors that detect the messenger at the surface of goblet cells. Different receptors and therefore different cascades of molecular events were found to control mucus secretion and GAP formation; this explains how the two processes can be performed in parallel and independently from each other. Understanding how cells relay molecules to the immune system is relevant to other tissues in contact with the environment, such as the eyes, the airways, or the inside of the genital and urinary tracts. Understanding, and then ultimately harnessing this mechanism could help design of new ways to deliver drugs to the immune system and alter immune outcomes.

Pancreatic β cells, responsible for secreting insulin into the bloodstream and maintaining glucose homeostasis, are organized in the islets of Langerhans as clusters of electrically coupled cells. Gap junctions, connecting neighboring cells, coordinate the behavior of the islet, leading to the synchronized oscillations in the intracellular calcium and insulin secretion in healthy islets. Recent experimental work has shown that silencing special hub cells can lead to a disruption in the coordinated behavior, calling into question the democratic paradigm of islet insulin secretion with more or less equal input from each β cell. Islets were shown to have scale-free functional connectivity and a hub cell whose silencing would lead to a loss of functional connectivity and activity in the islet. A mechanistic model representing the electrical and calcium dynamics of β cells during insulin secretion was applied to a network of cells connected by gap junctions to test the hypothesis of hub cells. Functional connectivity networks were built from the simulated calcium traces, with some networks classified as scale-free, confirming experimental results. Potential hub cells were identified using previously defined centrality measures, but silencing them was unable to desynchronize the islet. Instead, switch cells, which were able to turn off the activity of the islet but were not highly functionally connected, were found via systematically silencing each cell in the network.

Current mouse models of nonalcoholic steatohepatitis are limited, making identification and preclinical testing of new treatments challenging. Housing mice at thermoneutrality leads to less stress, a stronger immune response and better modeling of this condition. Nonalcoholic fatty liver disease (NAFLD), a common prelude to cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. Defining the molecular mechanisms underlying the pathogenesis of NAFLD has been hampered by a lack of animal models that closely recapitulate the severe end of the disease spectrum in humans, including bridging hepatic fibrosis. Here we demonstrate that a novel experimental model employing thermoneutral housing, as opposed to standard housing, resulted in lower stress-driven production of corticosterone, augmented mouse proinflammatory immune responses and markedly exacerbated high-fat diet (HFD)-induced NAFLD pathogenesis. Disease exacerbation at thermoneutrality was conserved across multiple mouse strains and was associated with augmented intestinal permeability, an altered microbiome and activation of inflammatory pathways that are associated with the disease in humans. Depletion of Gram-negative microbiota, hematopoietic cell deletion of Toll-like receptor 4 (TLR4) and inactivation of the IL-17 axis resulted in altered immune responsiveness and protection from thermoneutral-housing-driven NAFLD amplification. Finally, female mice, typically resistant to HFD-induced obesity and NAFLD, develop full disease characteristics at thermoneutrality. Thus, thermoneutral housing provides a sex-independent model of exacerbated NAFLD in mice and represents a novel approach for interrogation of the cellular and molecular mechanisms underlying disease pathogenesis.

Anaphylaxis is an acute life-threatening allergic reaction and a concern at a global level; therefore, further progress in understanding the underlying mechanisms and more effective strategies for diagnosis, prevention and management are needed. We sought to identify the global architecture of blood transcriptomic features of anaphylaxis by integrating expression data from human patients and mouse model of anaphylaxis. Bulk RNA-sequencings of peripheral whole blood were performed in: i) 14 emergency department (ED) patients with acute anaphylaxis, predominantly to venom, ii) 11 patients with peanut allergy undergoing double-blind, placebo-controlled food challenge (DBPCFC) to peanut, iii) murine model of IgE-mediated anaphylaxis. Integrative characterisation of differential gene expression, immune cell-type-specific gene expression profiles, and functional and pathway analysis was undertaken. 1023 genes were commonly and significantly dysregulated during anaphylaxis in ED and DBPCFC patients; of those genes, 29 were also dysregulated in the mouse model. Cell-type-specific gene expression profiles showed a rapid downregulation of blood basophil and upregulation of neutrophil signature in ED and DBPCFC patients and the mouse model, but no consistent and/or significant differences were found for other blood cells. Functional and pathway analysis demonstrated that human and mouse blood transcriptomic signatures of anaphylaxis follow trajectories of upregulation of cell movement, migration and neuroinflammatory signalling, and downregulation of lipid activating nuclear receptors signalling. Our study highlights the matched and extensive blood transcriptomic changes and suggests the involvement of discrete cellular components and upregulation of migration and neuroinflammatory pathways during anaphylaxis.

High‐resolution numerical simulations of the northern Gulf of Mexico region using the Hybrid Coordinate Ocean Model (HYCOM) were employed to investigate the dynamical processes controlling the fate of the Mississippi River plume, in particular the conditions that favor cross‐marginal transport. The study focuses on the effects of topography, wind‐driven and eddy‐driven circulation on the offshore removal of plume waters. A realistically forced simulation (nested in a data‐assimilative regional Gulf of Mexico HYCOM model) reveals that the offshore removal is a frequent plume pathway. Eastward wind‐driven currents promote large freshwater transport toward the shelf break and the DeSoto Canyon, where eddies with diameters ranging from 50 to 130 km interact with the buoyant plume and effectively entrain the riverine waters. Our estimates show that the offshore removal by eddies can be as large as the wind‐driven shelf transport. The proximity of eddies to the shelf break is a sufficient condition for offshore removal, and shelf‐to‐offshore interaction is facilitated by the steep bottom topography near the delta. Strong eddy‐plume interactions were observed when the Loop Current System impinged against the shelf break, causing the formation of coherent, narrow low‐salinity bands that extended toward the gulf interior. The offshore pathways depend on the position of the eddies near the shelf edge, their life span and the formation of eddy pairs that generate coherent cross‐shelf flows. This study elucidates the dynamics that initiate a unique cross‐marginal removal mechanism of riverine low‐salinity, nutrient‐rich waters, allowing their export along connectivity pathways, induced by a large‐scale current system. Key Points The offshore removal is a frequent pathway of the Mississippi River plume Strong eddy‐plume interactions happen when the LC system approaches the shelf Offshore pathway is dependent on the eddy dynamics

Hypothalamic retinal input is traditionally considered distinct from the subcortical pathways supporting vision, specialised to adjust physiology and behaviour alongside variations in ambient illumination. Investigations of retinohypothalamic function have overwhelming focussed on the suprachiasmatic nucleus circadian clock, however. Here we employ multielectrode recording, viral tracing and chemogenetic manipulation in mice to show that another retinohypothalamic target, the anterior lateral hypothalamic area (LHA), displays diverse visual processing capabilities, supporting regulation of more complex visually-guided behaviours. Hence, while some visually responsive LHA cells track irradiance, a majority are highly selective for spatiotemporal contrast or motion signals. We further provide evidence for a retinotopic order to LHA visual responses, show that retinorecipient LHA neurons provide excitatory projections to behavioural control centres including the septal complex and habenula, and that LHA retinal inputs modulate behavioural responses to light flashes and ‘looming’ stimuli. Collectively, these data establish the LHA as a locus for regulation of visually-guided behaviours and environmental threat responses. The accepted function of hypothalamic retinal input is regulation of daily rhythms in physiology and behaviour. Here authors show it also supports detection of form and motion and regulates visually-guided behaviours, via the lateral hypothalamus.