BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.

Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.

Sparse and stereotyped encoding implicates a core glomerulus for ant alarm behavior.

Ants communicate via large arrays of pheromones and possess expanded, highly complex olfactory systems, with antennal lobes in the brain comprising up to ∼500 glomeruli. This expansion implies that odors could activate hundreds of glomeruli, which would pose challenges for higher-order processing. To study this problem, we generated transgenic ants expressing the genetically encoded calcium indicator GCaMP in olfactory sensory neurons. Using two-photon imaging, we mapped complete glomerular responses to four ant alarm pheromones. Alarm pheromones robustly activated ≤6 glomeruli, and activity maps for the three pheromones inducing panic alarm in our study species converged on a single glomerulus. These results demonstrate that, rather than using broadly tuned combinatorial encoding, ants employ precise, narrowly tuned, and stereotyped representations of alarm pheromones. The identification of a central sensory hub glomerulus for alarm behavior suggests that a simple neural architecture is sufficient to translate pheromone perception into behavioral outputs.

Sounds emitted by plants under stress are airborne and informative.

Stressed plants show altered phenotypes, including changes in color, smell, and shape. Yet, airborne sounds emitted by stressed plants have not been investigated before. Here we show that stressed plants emit airborne sounds that can be recorded from a distance and classified. We recorded ultrasonic sounds emitted by tomato and tobacco plants inside an acoustic chamber, and in a greenhouse, while monitoring the plant's physiological parameters. We developed machine learning models that succeeded in identifying the condition of the plants, including dehydration level and injury, based solely on the emitted sounds. These informative sounds may also be detectable by other organisms. This work opens avenues for understanding plants and their interactions with the environment and may have significant impact on agriculture.

Mitochondria as Cellular and Organismal Signaling Hubs.

Mitochondria are traditionally known as the powerhouse of the cell, but their functions extend far beyond energy production. They are vital in cellular and organismal pathways that direct metabolism, stress responses, immunity, and cellular fate. To accomplish these tasks, mitochondria have established networks of both intra- and extracellular communication. Intracellularly, these communication routes comprise direct contacts between mitochondria and other subcellular components as well as indirect vesicle transport of ions, metabolites, and other intracellular messengers. Extracellularly, mitochondria can induce stress responses or other cellular changes that secrete mitochondrial cytokine (mitokine) factors that can travel between tissues as well as respond to immune challenges from extracellular sources. Here we provide a current perspective on the major routes of communication for mitochondrial signaling, including their mechanisms and physiological impact. We also review the major diseases and age-related disorders associated with defects in these signaling pathways. An understanding of how mitochondrial signaling controls cellular homeostasis will bring greater insight into how dysfunctional mitochondria affect health in disease and aging.

A Quantitative Multivariate Model of Human Dendritic Cell-T Helper Cell Communication.

Cell-cell communication involves a large number of molecular signals that function as words of a complex language whose grammar remains mostly unknown. Here, we describe an integrative approach involving (1) protein-level measurement of multiple communication signals coupled to output responses in receiving cells and (2) mathematical modeling to uncover input-output relationships and interactions between signals. Using human dendritic cell (DC)-T helper (Th) cell communication as a model, we measured 36 DC-derived signals and 17 Th cytokines broadly covering Th diversity in 428 observations. We developed a data-driven, computationally validated model capturing 56 already described and 290 potentially novel mechanisms of Th cell specification. By predicting context-dependent behaviors, we demonstrate a new function for IL-12p70 as an inducer of Th17 in an IL-1 signaling context. This work provides a unique resource to decipher the complex combinatorial rules governing DC-Th cell communication and guide their manipulation for vaccine design and immunotherapies.

Engineering a Model Cell for Rational Tuning of GPCR Signaling.

G protein-coupled receptor (GPCR) signaling is the primary method eukaryotes use to respond to specific cues in their environment. However, the relationship between stimulus and response for each GPCR is difficult to predict due to diversity in natural signal transduction architecture and expression. Using genome engineering in yeast, we constructed an insulated, modular GPCR signal transduction system to study how the response to stimuli can be predictably tuned using synthetic tools. We delineated the contributions of a minimal set of key components via computational and experimental refactoring, identifying simple design principles for rationally tuning the dose response. Using five different GPCRs, we demonstrate how this enables cells and consortia to be engineered to respond to desired concentrations of peptides, metabolites, and hormones relevant to human health. This work enables rational tuning of cell sensing while providing a framework to guide reprogramming of GPCR-based signaling in other systems.

Secretin-Activated Brown Fat Mediates Prandial Thermogenesis to Induce Satiation.

The molecular mediator and functional significance of meal-associated brown fat (BAT) thermogenesis remains elusive. Here, we identified the gut hormone secretin as a non-sympathetic BAT activator mediating prandial thermogenesis, which consequentially induces satiation, thereby establishing a gut-secretin-BAT-brain axis in mammals with a physiological role of prandial thermogenesis in the control of satiation. Mechanistically, meal-associated rise in circulating secretin activates BAT thermogenesis by stimulating lipolysis upon binding to secretin receptors in brown adipocytes, which is sensed in the brain and promotes satiation. Chronic infusion of a modified human secretin transiently elevates energy expenditure in diet-induced obese mice. Clinical trials with human subjects showed that thermogenesis after a single-meal ingestion correlated with postprandial secretin levels and that secretin infusions increased glucose uptake in BAT. Collectively, our findings highlight the largely unappreciated function of BAT in the control of satiation and qualify BAT as an even more attractive target for treating obesity.

LlamaTags: A Versatile Tool to Image Transcription Factor Dynamics in Live Embryos.

Embryonic cell fates are defined by transcription factors that are rapidly deployed, yet attempts to visualize these factors in vivo often fail because of slow fluorescent protein maturation. Here, we pioneer a protein tag, LlamaTag, which circumvents this maturation limit by binding mature fluorescent proteins, making it possible to visualize transcription factor concentration dynamics in live embryos. Implementing this approach in the fruit fly Drosophila melanogaster, we discovered stochastic bursts in the concentration of transcription factors that are correlated with bursts in transcription. We further used LlamaTags to show that the concentration of protein in a given nucleus heavily depends on transcription of that gene in neighboring nuclei; we speculate that this inter-nuclear signaling is an important mechanism for coordinating gene expression to delineate straight and sharp boundaries of gene expression. Thus, LlamaTags now make it possible to visualize the flow of information along the central dogma in live embryos.

The Upsides and Downsides of Organelle Interconnectivity.

Interconnectivity and feedback control are hallmarks of biological systems. This includes communication between organelles, which allows them to function and adapt to changing cellular environments. While the specific mechanisms for all communications remain opaque, unraveling the wiring of organelle networks is critical to understand how biological systems are built and why they might collapse, as occurs in aging. A comprehensive understanding of all the routes involved in inter-organelle communication is still lacking, but important themes are beginning to emerge, primarily in budding yeast. These routes are reviewed here in the context of sub-system proteostasis and complex adaptive systems theory.

orco Mutagenesis Causes Loss of Antennal Lobe Glomeruli and Impaired Social Behavior in Ants.

Life inside ant colonies is orchestrated with diverse pheromones, but it is not clear how ants perceive these social signals. It has been proposed that pheromone perception in ants evolved via expansions in the numbers of odorant receptors (ORs) and antennal lobe glomeruli. Here, we generate the first mutant lines in the clonal raider ant, Ooceraea biroi, by disrupting orco, a gene required for the function of all ORs. We find that orco mutants exhibit severe deficiencies in social behavior and fitness, suggesting they are unable to perceive pheromones. Surprisingly, unlike in Drosophila melanogaster, orco mutant ants also lack most of the ∼500 antennal lobe glomeruli found in wild-type ants. These results illustrate that ORs are essential for ant social organization and raise the possibility that, similar to mammals, receptor function is required for the development and/or maintenance of the highly complex olfactory processing areas in the ant brain. VIDEO ABSTRACT.

Transcriptional Architecture of Synaptic Communication Delineates GABAergic Neuron Identity.

Understanding the organizational logic of neural circuits requires deciphering the biological basis of neuronal diversity and identity, but there is no consensus on how neuron types should be defined. We analyzed single-cell transcriptomes of a set of anatomically and physiologically characterized cortical GABAergic neurons and conducted a computational genomic screen for transcriptional profiles that distinguish them from one another. We discovered that cardinal GABAergic neuron types are delineated by a transcriptional architecture that encodes their synaptic communication patterns. This architecture comprises 6 categories of ∼40 gene families, including cell-adhesion molecules, transmitter-modulator receptors, ion channels, signaling proteins, neuropeptides and vesicular release components, and transcription factors. Combinatorial expression of select members across families shapes a multi-layered molecular scaffold along the cell membrane that may customize synaptic connectivity patterns and input-output signaling properties. This molecular genetic framework of neuronal identity integrates cell phenotypes along multiple axes and provides a foundation for discovering and classifying neuron types.

A Theoretical Framework for Human and Nonhuman Vocal Interaction.

Vocal communication is a critical feature of social interaction across species; however, the relation between such behavior in humans and nonhumans remains unclear. To enable comparative investigation of this topic, we review the literature pertinent to interactive language use and identify the superset of cognitive operations involved in generating communicative action. We posit these functions comprise three intersecting multistep pathways: (a) the Content Pathway, which selects the movements constituting a response; (b) the Timing Pathway, which temporally structures responses; and (c) the Affect Pathway, which modulates response parameters according to internal state. These processing streams form the basis of the Convergent Pathways for Interaction framework, which provides a conceptual model for investigating the cognitive and neural computations underlying vocal communication across species.

Acquiring tissue for advanced lung cancer diagnosis and comprehensive biomarker testing: A National Lung Cancer Roundtable best-practice guide.

Advances in biomarker-driven therapies for patients with nonsmall cell lung cancer (NSCLC) both provide opportunities to improve the treatment (and thus outcomes) for patients and pose new challenges for equitable care delivery. Over the last decade, the continuing development of new biomarker-driven therapies and evolving indications for their use have intensified the importance of interdisciplinary communication and coordination for patients with or suspected to have lung cancer. Multidisciplinary teams are challenged with completing comprehensive and timely biomarker testing and navigating the constantly evolving evidence base for a complex and time-sensitive disease. This guide provides context for the current state of comprehensive biomarker testing for NSCLC, reviews how biomarker testing integrates within the diagnostic continuum for patients, and illustrates best practices and common pitfalls that influence the success and timeliness of biomarker testing using a series of case scenarios.

Structural diversity of the SARS-CoV-2 Omicron spike.

Aided by extensive spike protein mutation, the SARS-CoV-2 Omicron variant overtook the previously dominant Delta variant. Spike conformation plays an essential role in SARS-CoV-2 evolution via changes in receptor-binding domain (RBD) and neutralizing antibody epitope presentation, affecting virus transmissibility and immune evasion. Here, we determine cryo-EM structures of the Omicron and Delta spikes to understand the conformational impacts of mutations in each. The Omicron spike structure revealed an unusually tightly packed RBD organization with long range impacts that were not observed in the Delta spike. Binding and crystallography revealed increased flexibility at the functionally critical fusion peptide site in the Omicron spike. These results reveal a highly evolved Omicron spike architecture with possible impacts on its high levels of immune evasion and transmissibility.

Promoter and enhancer RNAs regulate chromatin reorganization and activation of miR-10b/HOXD locus, and neoplastic transformation in glioma.

miR-10b is silenced in normal neuroglial cells of the brain but commonly activated in glioma, where it assumes an essential tumor-promoting role. We demonstrate that the entire miR-10b-hosting HOXD locus is activated in glioma via the cis-acting mechanism involving 3D chromatin reorganization and CTCF-cohesin-mediated looping. This mechanism requires two interacting lncRNAs, HOXD-AS2 and LINC01116, one associated with HOXD3/HOXD4/miR-10b promoter and another with the remote enhancer. Knockdown of either lncRNA in glioma cells alters CTCF and cohesin binding, abolishes chromatin looping, inhibits the expression of all genes within HOXD locus, and leads to glioma cell death. Conversely, in cortical astrocytes, enhancer activation is sufficient for HOXD/miR-10b locus reorganization, gene derepression, and neoplastic cell transformation. LINC01116 RNA is essential for this process. Our results demonstrate the interplay of two lncRNAs in the chromatin folding and concordant regulation of miR-10b and multiple HOXD genes normally silenced in astrocytes and triggering the neoplastic glial transformation.

Clinician communication strategies associated with increased uptake of the human papillomavirus (HPV) vaccine: A systematic review.

Human papillomavirus (HPV) is currently linked to almost 35,000 new cases of cancer in women and men each year in the United States. Gardasil-9 (Merck & Company), the only HPV vaccine now available in the United States, is nearly 100% effective at preventing precancers caused by oncogenic HPV types. In the United States, however, only about one half of adolescents are up to date with HPV vaccination. It is well known that health care clinicians' recommendations play a significant role in parents' decisions regarding HPV vaccination. A growing body of literature examines specific communication strategies for promoting uptake of the HPV vaccine. A comprehensive review of the evidence for each of these strategies is needed. The authors searched the PubMed, EMBASE, Cochrane Central Register of Controlled Trials, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, and Web of Science Complete databases for original articles with a defined clinician communication strategy and an outcome of HPV vaccine uptake or intention to vaccinate (PROSPERO registry no. CRD42020107602). In total, 46 studies were included. The authors identified two main strategies with strong evidence supporting their positive impact on vaccine uptake: strong recommendation and presumptive recommendation. Determinations about a causal relationship were limited by the small numbers of randomized controlled trials. There is also opportunity for more research to determine the effects of motivational interviewing and cancer-prevention messaging.

Interorganelle communication, aging, and neurodegeneration.

Our cells are comprised of billions of proteins, lipids, and other small molecules packed into their respective subcellular organelles, with the daunting task of maintaining cellular homeostasis over a lifetime. However, it is becoming increasingly evident that organelles do not act as autonomous discrete units but rather as interconnected hubs that engage in extensive communication through membrane contacts. In the last few years, our understanding of how these contacts coordinate organelle function has redefined our view of the cell. This review aims to present novel findings on the cellular interorganelle communication network and how its dysfunction may contribute to aging and neurodegeneration. The consequences of disturbed interorganellar communication are intimately linked with age-related pathologies. Given that both aging and neurodegenerative diseases are characterized by the concomitant failure of multiple cellular pathways, coordination of organelle communication and function could represent an emerging regulatory mechanism critical for long-term cellular homeostasis. We anticipate that defining the relationships between interorganelle communication, aging, and neurodegeneration will open new avenues for therapeutics.

Genetic basis of chemical communication in eusocial insects.

Social behavior is one of the most fascinating and complex behaviors in humans and animals. A fundamental process of social behavior is communication among individuals. It relies on the capability of the nervous system to sense, process, and interpret various signals (e.g., pheromones) and respond with appropriate decisions and actions. Eusocial insects, including ants, some bees, some wasps, and termites, display intriguing cooperative social behavior. Recent advances in genetic and genomic studies have revealed key genes that are involved in pheromone synthesis, chemosensory perception, and physiological and behavioral responses to varied pheromones. In this review, we highlight the genes and pathways that regulate queen pheromone-mediated social communication, discuss the evolutionary changes in genetic systems, and outline prospects of functional studies in sociobiology.

CellVis2: a conference on visualizing the molecular cell.

In January 2024, a targeted conference, 'CellVis2', was held at Scripps Research in La Jolla, USA, the second in a series designed to explore the promise, practices, roadblocks, and prospects of creating, visualizing, sharing, and communicating physical representations of entire biological cells at scales down to the atom.

Glucocorticoid receptor signaling: intricacies and therapeutic opportunities.

The glucocorticoid receptor (GR) is a major nuclear receptor (NR) drug target for the treatment of inflammatory disorders and several cancers. Despite the effectiveness of GR ligands, their systemic action triggers a plethora of side effects, limiting long-term use. Here, we discuss new concepts of and insights into GR mechanisms of action to assist in the identification of routes toward enhanced therapeutic benefits. We zoom in on the communication between different GR domains and how this is influenced by different ligands. We detail findings on the interaction between GR and chromatin, and highlight how condensate formation and coregulator confinement can perturb GR transcriptional responses. Last, we discuss the potential of novel ligands and the therapeutic exploitation of crosstalk with other NRs.