Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis.

Organelle transporters define metabolic compartmentalization, and how this metabolite transport process can be modulated is poorly explored. Here, we discovered that human SLC25A39, a mitochondrial transporter critical for mitochondrial glutathione uptake, is a short-lived protein under dual regulation at the protein level. Co-immunoprecipitation mass spectrometry and CRISPR knockout (KO) in mammalian cells identified that mitochondrial m-AAA protease AFG3L2 is responsible for degrading SLC25A39 through the matrix loop 1. SLC25A39 senses mitochondrial iron-sulfur cluster using four matrix cysteine residues and inhibits its degradation. SLC25A39 protein regulation is robust in developing and mature neurons. This dual transporter regulation, by protein quality control and metabolic sensing, allows modulating mitochondrial glutathione level in response to iron homeostasis, opening avenues for exploring regulation of metabolic compartmentalization. Neuronal SLC25A39 regulation connects mitochondrial protein quality control, glutathione, and iron homeostasis, which were previously unrelated biochemical features in neurodegeneration.

A physicochemical model of odor sampling.

We present a general physicochemical sampling model for olfaction, based on established pharmacological laws, in which arbitrary combinations of odorant ligands and receptors can be generated and their individual and collective effects on odor representations and olfactory performance measured. Individual odor ligands exhibit receptor-specific affinities and efficacies; that is, they may bind strongly or weakly to a given receptor, and can act as strong agonists, weak agonists, partial agonists, or antagonists. Ligands interacting with common receptors compete with one another for dwell time; these competitive interactions appropriately simulate the degeneracy that fundamentally defines the capacities and limitations of odorant sampling. The outcome of these competing ligand-receptor interactions yields a pattern of receptor activation levels, thereafter mapped to glomerular presynaptic activation levels based on the convergence of sensory neuron axons. The metric of greatest interest is the mean discrimination sensitivity, a measure of how effectively the olfactory system at this level is able to recognize a small change in the physicochemical quality of a stimulus. This model presents several significant outcomes, both expected and surprising. First, adding additional receptors reliably improves the system's discrimination sensitivity. Second, in contrast, adding additional ligands to an odorscene initially can improve discrimination sensitivity, but eventually will reduce it as the number of ligands increases. Third, the presence of antagonistic ligand-receptor interactions produced clear benefits for sensory system performance, generating higher absolute discrimination sensitivities and increasing the numbers of competing ligands that could be present before discrimination sensitivity began to be impaired. Finally, the model correctly reflects and explains the modest reduction in odor discrimination sensitivity exhibited by transgenic mice in which the specificity of glomerular targeting by primary olfactory neurons is partially disrupted.

What drives consumer activism during trade disputes? Experimental evidence from Canada.

What drives consumer activism during trade disputes? We investigate this important and timely question using a survey experiment in the context of the recent Canada-US trade dispute. We find that Canadians are more likely to express willingness to take punitive actions in the form of boycotting during a trade conflict when they learn that Americans are taking such actions (retaliation), when many fellow citizens are taking such actions (peer pressure), and when they are rallied by their government (elite cue). Among the three conditions, peer pressure has the largest effect. These findings contribute to our understanding of the microfoundations of consumer activism during international trade disputes. They also have important policy implications in a world where both protectionism and populism are rising.

Standing by: The spatial organization of coercive institutions in China.

How do authoritarian states organize their coercive institutions over space? We argue that autocrats maximize the utility of their limited coercive resources by clustering them with perceived threats in society, i.e., segments of the population that are ideologically distant and have mobilizational potential. We test this proposition using a dataset that covers the universe of police stations (N = 147,428) and religious sites (N = 115,394) in China. We find that police stations are more likely to be located within walking distance of foreign religious sites (churches) than other sites (temples), even after controlling for the estimated population within 1 km of each site and a set of key site attributes. This finding is robust to using alternative model specifications, different variable measurements, and multiple data sources. Moving beyond the clustering pattern, we also address the temporal order issue and show that the Chinese state has allocated more new coercive resources around existing foreign religious sites than native sites, i.e., after these sites are already in place. This study enriches our understanding of how autocrats rule and further opens up an emerging new methodological avenue for research on authoritarian politics.

Does a Question Prompt List Improve Perceived Involvement in Care in Orthopaedic Surgery Compared with the AskShareKnow Questions? A Pragmatic Randomized Controlled Trial.

BACKGROUND: Most conditions in orthopaedic surgery are preference-sensitive, where treatment choices are based on the patient's values and preferences. One set of tools increasingly used to help align treatment choices with patient preferences are question prompt lists (QPLs), which are comprehensive lists of potential questions that patients can ask their physicians during their encounters. Whether or not a comprehensive orthopaedic-specific question prompt list would increase patient-perceived involvement in care more effectively than might three generic questions (the AskShareKnow questions) remains unknown; learning the answer would be useful, since a three-question list is easier to use compared with the much lengthier QPLs. QUESTION/PURPOSE: Does an orthopaedic-specific question prompt list increase patient-perceived involvement in care compared with the three generic AskShareKnow questions? METHODS: We performed a pragmatic randomized controlled trial of all new patients visiting a multispecialty orthopaedic clinic. A pragmatic design was used to mimic normal clinical care that compared two clinically acceptable interventions. New patients with common orthopaedic conditions were enrolled between August 2019 and November 2019 and were randomized to receive either the intervention QPL handout (orthopaedic-specific QPL with 45 total questions, developed with similar content and length to prior QPLs used in hand surgery, oncology, and palliative care) or a control handout (the AskShareKnow model questions, which are: "What are my options? What are the benefits and harms of those options? How likely are each of those benefits and harms to happen to me?") before their visits. A total of 156 patients were enrolled, with 78 in each group. There were no demographic differences between the study and control groups in terms of key variables. After the visit, patients completed the Perceived Involvement in Care Scale (PICS), a validated instrument designed to evaluate patient-perceived involvement in their care, which served as the primary outcome measure. This instrument is scored from 0 to 13, with higher scores indicating higher perceived involvement. RESULTS: There was no difference in mean PICS scores between the intervention and control groups (QPL 8.3 ± 2.3, control 8.5 ± 2.3, mean difference 0.2 [95% CI -0.53 to 0.93 ]; p = 0.71. CONCLUSION: In patients undergoing orthopaedic surgery, a QPL does not increase patient-perceived involvement in care compared with providing patients the three AskShareKnow questions. Implementation of the three AskShareKnow questions can be a more efficient way to improve patient-perceived involvement in their care compared with a lengthy QPL. LEVEL OF EVIDENCE: Level II, therapeutic study.

Eugene--a domain specific language for specifying and constraining synthetic biological parts, devices, and systems.

BACKGROUND: Synthetic biological systems are currently created by an ad-hoc, iterative process of specification, design, and assembly. These systems would greatly benefit from a more formalized and rigorous specification of the desired system components as well as constraints on their composition. Therefore, the creation of robust and efficient design flows and tools is imperative. We present a human readable language (Eugene) that allows for the specification of synthetic biological designs based on biological parts, as well as provides a very expressive constraint system to drive the automatic creation of composite Parts (Devices) from a collection of individual Parts. RESULTS: We illustrate Eugene's capabilities in three different areas: Device specification, design space exploration, and assembly and simulation integration. These results highlight Eugene's ability to create combinatorial design spaces and prune these spaces for simulation or physical assembly. Eugene creates functional designs quickly and cost-effectively. CONCLUSIONS: Eugene is intended for forward engineering of DNA-based devices, and through its data types and execution semantics, reflects the desired abstraction hierarchy in synthetic biology. Eugene provides a powerful constraint system which can be used to drive the creation of new devices at runtime. It accomplishes all of this while being part of a larger tool chain which includes support for design, simulation, and physical device assembly.

The Eugene language for synthetic biology.

Synthetic biological systems are currently created by an ad hoc, iterative process of design, simulation, and assembly. These systems would greatly benefit from the introduction of a more formalized and rigorous specification of the desired system components as well as constraints on their composition. In order to do so, the creation of robust and efficient design flows and tools is imperative. We present a human readable language (Eugene) which allows for both the specification of synthetic biological designs based on biological parts as well as providing a very expressive constraint system to drive the creation of composite devices from collection of parts. This chapter provides an overview of the language primitives as well as instructions on installation and use of Eugene v0.03b.