Catecholamine-induced lipolysis, the first step in generation of energy substrates through hydrolysis of triglycerides (TGs) 1, declines with age 2,3. The defect in mobilization of free fatty acids (FFA) in elderly is accompanied with increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. While catecholamine signaling in adipocytes is normal in elderly, how lipolysis is impaired in aging remains unknown 2,4. Here we uncover that the adipose tissue macrophages (ATMs) regulate age-related reduction in adipocyte lipolysis by lowering the bioavailability of norepinephrine (NE). Unexpectedly, unbiased whole transcriptome analyses of adipose macrophages revealed that aging upregulates genes controlling catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in aging restored catecholamine-induced lipolysis through downregulation of growth differentiation factor-3 (GDF3) and monoamine oxidase-a (MAOA) that is known to degrade NE. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing MAOA and caspase-1. Furthermore, inhibition of MAOA reversed age-related reduction in adipose tissue NE concentration and restored lipolysis with increased levels of key lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-innate signaling between sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.

There is growing interest in evidence‐based conservation, yet there are no widely accepted standard definitions of evidence, let alone guidance on how to use it in the context of conservation and natural resource management practice. In this paper, we first draw on insights of evidence‐based practice from different disciplines to define evidence as being the “relevant information used to assess one or more hypotheses related to a question of interest.” We then construct a typology of different kinds of information, hypotheses, and evidence and show how these different types can be used in different steps of conservation practice. In particular, we distinguish between specific evidence used to assess project hypotheses and generic evidence used to assess generic hypotheses. We next build on this typology to develop a decision tree to support practitioners in how to appropriately use available specific and generic evidence in a given conservation situation. Finally, we conclude with a discussion of how to better promote and enable evidence‐based conservation in both projects and across the discipline of conservation. Our hope is that by understanding and using evidence better, conservation can both become more effective and attract increased support from society.

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Group 3 innate lymphoid cells (ILC3s) expressing the transcription factor (TF) RORγt are important for the defense and homeostasis of host intestinal tissues. The zinc finger TF Ikaros encoded by Ikzf1 is essential for RORγt+ fetal lymphoid tissue inducer (LTi) cell development and lymphoid organogenesis, but its role in postnatal ILC3s is unknown. Here, we showed that small intestinal ILC3s had the lowest expression of Ikaros compared to ILC precursors and other ILC subsets. Ikaros inhibited ILC3s in a cell-intrinsic manner through zinc finger-dependent inhibition of transcriptional activity of the aryl hydrocarbon receptor, a key regulator of ILC3 maintenance and function. Ablation of Ikzf1 in RORγt+ ILC3s resulted in increased expansion and cytokine production of intestinal ILC3s and protection against infection and colitis. Therefore, in contrast to its requirement for LTi development, Ikaros inhibits postnatal ILC3 development and function to regulate gut immune responses at steady state and in disease.

Proper immune responses are needed for controlling pathogen infection at mucosal surfaces. IL-22-producing CD4+ T cells play an important role in controlling bacterial infection in the gut; however, transcriptional regulation of these cells remains elusive. Here, we show that mice with targeted deletion of the fourth DNA-binding zinc finger of the transcription factor Ikaros had increased IL-22- but not IL-17-producing CD4+ T cells in the gut. Adoptive transfer of CD4+ T cells from these Ikaros mutant mice conferred enhanced mucosal immunity against Citrobacter rodentium infection. Despite an intact in vivo thymic-derived Treg compartment in these Ikaros mutant mice, TGF-β, a cytokine well known for induction of Tregs, failed to induce Foxp3 expression in Ikaros mutant CD4+ T cells in vitro but instead promoted IL-22. Aberrant upregulation of IL-21 in CD4+ T cells expressing mutant Ikaros was at least in part responsible for the enhanced IL-22 expression in a Stat3-dependent manner. Genetic analysis using compound mutations further demonstrated that the aryl hydrocarbon receptor (Ahr), but not RORγt, was required for aberrant IL-22 expression by Ikaros mutant CD4+ T cells, whereas forced expression of Foxp3 was sufficient to inhibit this aberrant cytokine production. Together, our data has uncovered new functions for Ikaros in maintaining mucosal immune homeostasis by restricting IL-22 production by CD4+ T cells.

Urothelial carcinoma (UC) is characterized by expression of a plethora of cell surface antigens, thus offering opportunities for specific therapeutic targeting with use of antibody-drug conjugates (ADCs). ADCs are structured from two major constituents, a monoclonal antibody (mAb) against a specific target and a cytotoxic drug connected via a linker molecule. Several ADCs are developed against different UC surface markers, but the ones at most advanced stages of development include sacituzumab govitecan (IMMU-132), enfortumab vedotin (ASG-22CE/ASG-22ME), ASG-15ME for advanced UC, and oportuzumab monatox (VB4-845) for early UC. Several new targets are identified and utilized for novel or existing ADC testing. The most promising ones include human epidermal growth factor receptor 2 (HER2) and members of the fibroblast growth factor receptor axis (FGF/FGFR). Positive preclinical and early clinical results are reported in many cases, thus the next step involves further improving efficacy and reducing toxicity as well as testing combination strategies with approved agents.

This editorial introduces a new series in this journal featuring generic theories of change (ToCs) for key conservation strategies. We hope these ToCs can both help practitioners learn about each strategy as well as enable the collection of standardized data across specific implementations of each strategy in different conditions. These data will, in turn, inform increasingly more systematic assessments of the strategy, thus contributing to the evidence base of strategy effectiveness.

Background: While sodium is attractive at low and aversive at high concentrations in most studied species, including Caenorhabditis elegans, the molecular mechanisms behind transduction remain poorly understood. Additionally, past studies with C. elegans provide evidence that the nematode's innate behavior can be altered by previous experiences. Here we investigated the molecular aspects of both innate and conditioned responses to salts. Transmembrane channel-like 1 (tmc-1) has been suggested to encode a sodium-sensitive channel required for sodium chemosensation in C. elegans, but its specific role remains unclear. Results: We report that TMC-1 is necessary for sodium attraction, but not aversion in the nematode. We show that TMC-1 contributes to the nematode's lithium induced attraction behavior, but not potassium or magnesium attraction thus clarifying the specificity of the response. In addition, we show that sodium conditioned aversion is dependent on TMC-1 and disrupts not only sodium induced attraction, but also lithium. Conclusions: These findings represent the first time a role for TMC-1 has been described in sodium and lithium attraction in vivo, as well as in sodium conditioned aversion. Together this clarifies TMC-1's importance in sodium hedonics and offer molecular insight into salt chemotaxis learning.