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Mitochondria are an essential source of ATP for cellular function, but when damaged, mitochondria generate a plethora of stress signals, which lead to cellular dysfunction and eventually programmed cell death. Thus, a major component of maintaining cellular homeostasis is the recognition and removal of dysfunctional mitochondria through autophagy-mediated degradation, i.e., mitophagy. Mitophagy further constitutes a developmental program, and undergoes a high degree of crosstalk with apoptosis. Reduced mitochondrial quality control is linked to disease pathogenesis, suggesting the importance of process elucidation as a clinical target. Recent work has revealed multiple mitophagy programs that operate independently or undergo crosstalk, and require modulated autophagy receptor activities at outer membranes of mitochondria. Here, we review these mitophagy programs, focusing on pathway mechanisms which recognize and target mitochondria for sequestration by autophagosomes, as well as mechanisms controlling pathway activities. Furthermore, we provide an introduction to the currently available methods for detecting mitophagy.

Biology has evolved a variety of agents capable of permeabilizing and disrupting lipid membranes, from amyloid aggregates, to antimicrobial peptides, to venom compounds. While often associated with disease or toxicity, these agents are also central to many biosensing and therapeutic technologies. Here, we introduce a class of synthetic, DNA-based particles capable of disrupting lipid membranes. The particles have finely programmable size, and self-assemble from all-DNA and cholesterol-DNA nanostructures, the latter forming a membrane-adhesive core and the former a protective hydrophilic corona. We show that the corona can be selectively displaced with a molecular cue, exposing the ‘sticky’ core. Unprotected particles adhere to synthetic lipid vesicles, which in turn enhances membrane permeability and leads to vesicle collapse. Furthermore, particle-particle coalescence leads to the formation of gel-like DNA aggregates that envelop surviving vesicles. This response is reminiscent of pathogen immobilisation through immune cells secretion of DNA networks, as we demonstrate by trapping E. coli bacteria. Lipid membrane disruption is often associated with disease but is also essential to a range of biosensing and therapeutic techniques. Here, the authors report on the development of DNA-based particles that, upon exposure to an external cue, can aggregate, disrupt lipid membranes, and arrest the motion of bacteria.

We present multi-integration of transcriptome-wide association studies and colocalization (Multi-INTACT), an algorithm that models multiple “gene products” (e.g., encoded RNA transcript and protein levels) to implicate causal genes and relevant gene products. In simulations, Multi-INTACT achieves higher power than existing methods, maintains calibrated false discovery rates, and detects the true causal gene product(s). We apply Multi-INTACT to GWAS on 1408 metabolites, integrating the GTEx expression and UK Biobank protein QTL datasets. Multi-INTACT infers 52 to 109% more metabolite causal genes than protein-alone or expression-alone analyses and indicates both gene products are relevant for most gene nominations.

Light has become an essential tool to make and manipulate living systems in the increasingly intertwined fields of cell biology and materials science. With the ever-expanding interdisciplinary nature of current scientific research and the ongoing hunt for orthogonal, high-precision stimuli for biomaterial synthesis and modification, light has emerged as the gold standard with its low cytotoxicity and high bioorthogonality, enabling the modulation of properties in both 3D space and time (that is, 4D). Not only can light govern when and where changes occur, dosage modulation permits control over the extent of material customization, providing a route to engineered constructs approaching the 4D complexity of native tissue. Recent technological innovations span advances in stereolithography, digital light processing, volumetric bioprinting, multiphoton lithography and grayscale fabrication. Material chemistries have matched pace with the technologies: novel photochemistries permit the building of dynamic materials with complex mechanical and biochemical functionalities, such as on-demand protein activation, rapid gel formation/degradation and immobilization/release of signalling factors. Herein, we discuss the union of rapid light-based manufacturing and photoresponsive chemistries and highlight future opportunities using photochemistry in the design and user-defined customization of hydrogel biomaterials. We anticipate that these areas will continue to evolve in tandem and be influenced by new insights from traditionally disparate disciplines (such as protein engineering and inorganic chemistry), facilitating further discoveries in cellular development and disease progression, as well as orchestrating advanced tissue construction.Photochemistry enables biomaterials to be made and modified with high spatiotemporal and dose-dependent precision. In this Review, the authors investigate the recent and parallel developments in light-based chemistries and manufacturing technologies and discuss their combined applications in probing and directing 4D cell fate.

Adaptive decision making in humans depends on feedback between monitoring , which assesses mental states, and control , by which cognitive processes are modified. We investigated the extent to which monitoring and control interact iteratively in monkeys. Monkeys classified images as birds, fish, flowers, or people. At the beginning of each trial, to-be-classified images were not visible. Monkeys touched the image area to incrementally brighten the image, referred to as the brighten response . The amount by which brightness increased with each brighten response was unpredictable, and the monkeys could choose to classify the images at any time during a trial. We hypothesized that if monkeys monitored the status of their classification decision then they would seek information depending on the amount of information available. In Experiment 1, monkeys rarely used the brighten response when images were bright initially, and they used the brighten response more when earlier uses in a given trial yielded smaller amounts of information. In Experiment 2, monkeys made more brighten responses when the presented image did not belong in any of the trained categories, suggesting monkeys were sensitive to the fact that they could not reach a classification decision despite the image brightening. In Experiment 3, we found that the probability that monkeys used the brighten response correlated with their ability to correctly classify when the brighten response was not available. These findings add to the literature documenting the metacognitive skills of nonhuman primates by demonstrating an iterative feedback loop between cognitive monitoring and cognitive control that allows for adaptive information-seeking behavior.

How fast and how long (and to what magnitude) does a change in housing prices in one region affect its neighbors? In this paper, I apply a time series technique for measuring impulse response functions from local projections to a spatial autoregressive model of housing prices. For a dynamic panel of California counties, the data reveal that the diffusion of regional housing prices across space lasts up to two and half years. This result, and the econometric techniques employed, should be of interest not only to housing and regional economists, but to a variety of applied econometricians as well.

Wake steering is a form of wind farm control in which turbines use yaw offsets to affect wakes in order to yield an increase in total energy production. In this first phase of a study of wake steering at a commercial wind farm, two turbines implement a schedule of offsets. Results exploring the observed performance of wake steering are presented and some first lessons learned. For two closely spaced turbines, an approximate 14 % increase in energy was measured on the downstream turbine over a 10∘ sector, with a 4 % increase in energy production of the combined upstream–downstream turbine pair. Finally, the influence of atmospheric stability over the results is explored.

Recent evidence implicates a gut-first pathogenesis in the enteric nervous system (ENS) within a portion of PD patients, yet in vitro investigations have primarily focused on the central nervous system. Here, the preformed fibril (PFF) PD model is applied with co-administered groups of butyrate and lipopolysaccharide to model the effects of the local gut microbiome. Significant PFF uptake and retention occur in isolated rat enteric neurons compared to untreated controls resulting in increasing immunostained aggregate conformation-specific, alpha-synuclein (a-Syn) average intensity between 6 µg PFF and untreated controls. Cortical neurons significantly retain PFFs with an increase in aggregated a-Syn average intensity within all dosages. Differences in growth cone morphology but not dynamics in PFF-treated ENS cultures occur. Electrophysiological recordings via a microelectrode array (MEA) indicate no overall difference in spontaneous spike rate. However, only untreated controls respond to PD-relevant dopamine stimulus, while 1 µg PFF and control populations respond to stimulus with ENS-abundant acetylcholine. Finally, no differences in substance P levels—correlated with PD and neurodegeneration—are observed. Overall, these findings suggest the ENS retains PFF dosage absent acute loss in function, however, does experience changes in growth cone morphology and dopamine-stimulated activity.

This paper presents the results of a field campaign investigating the performance of wake steering applied at a section of a commercial wind farm. It is the second phase of the study for which the first phase was reported in . The authors implemented wake steering on two turbine pairs, and compared results with the latest FLORIS (FLOw Redirection and Induction in Steady State) model of wake steering, showing good agreement in overall energy increase. Further, although not the original intention of the study, we also used the results to detect the secondary steering phenomenon. Results show an overall reduction in wake losses of approximately 6.6 % for the regions of operation, which corresponds to achieving roughly half of the static optimal result.

Mitochondria are semi-autonomous organelles that supply energy for cellular biochemistry through oxidative phosphorylation. Within a cell, hundreds of mobile mitochondria undergo fusion and fission events to form a dynamic network. These morphological and mobility dynamics are essential for maintaining mitochondrial functional homeostasis, and alterations both impact and reflect cellular stress states. Mitochondrial homeostasis is further dependent on production (biogenesis) and the removal of damaged mitochondria by selective autophagy (mitophagy). While mitochondrial function, dynamics, biogenesis and mitophagy are highly-integrated processes, it is not fully understood how systemic control in the cell is established to maintain homeostasis, or respond to bioenergetic demands. Here we used agent-based modeling (ABM) to integrate molecular and imaging knowledge sets, and simulate population dynamics of mitochondria and their response to environmental energy demand. Using high-dimensional parameter searches we integrated experimentally-measured rates of mitochondrial biogenesis and mitophagy, and using sensitivity analysis we identified parameter influences on population homeostasis. By studying the dynamics of cellular subpopulations with distinct mitochondrial masses, our approach uncovered system properties of mitochondrial populations: (1) mitochondrial fusion and fission activities rapidly establish mitochondrial sub-population homeostasis, and total cellular levels of mitochondria alter fusion and fission activities and subpopulation distributions; (2) restricting the directionality of mitochondrial mobility does not alter morphology subpopulation distributions, but increases network transmission dynamics; and (3) maintaining mitochondrial mass homeostasis and responding to bioenergetic stress requires the integration of mitochondrial dynamics with the cellular bioenergetic state. Finally, (4) our model suggests sources of, and stress conditions amplifying, cell-to-cell variability of mitochondrial morphology and energetic stress states. Overall, our modeling approach integrates biochemical and imaging knowledge, and presents a novel open-modeling approach to investigate how spatial and temporal mitochondrial dynamics contribute to functional homeostasis, and how subcellular organelle heterogeneity contributes to the emergence of cell heterogeneity.