The polarization of adipose tissue-resident macrophages toward the alternatively activated, anti-inflammatory M2 phenotype is believed to improve insulin sensitivity. However, the mechanisms controlling tissue macrophage activation remain unclear. Here we show that adipocytes are a source of Th2 cytokines, including IL-13 and to a lesser extent IL-4, which induce macrophage PPARdelta/beta (Ppard/b) expression through a STAT6 binding site on its promoter to activate alternative activation. Coculture studies indicate that Ppard ablation renders macrophages incapable of transition to the M2 phenotype, which in turns causes inflammation and metabolic derangement in adipocytes. Remarkably, a similar regulatory mechanism by hepatocyte-derived Th2 cytokines and macrophage PPARdelta is found to control hepatic lipid metabolism. The physiological relevance of this paracrine pathway is demonstrated in myeloid-specific PPARdelta(-/-) mice, which develop insulin resistance and show increased adipocyte lipolysis and severe hepatosteatosis. These findings provide a molecular basis to modulate tissue-resident macrophage activation and insulin sensitivity.

Natural variability in abundance of signaling regulators can lead to divergence in cell fate, even within genetically identical cells sharing a common differentiation state. To leverage this observation, we introduce cell-to-cell variability analysis (CCVA), an experimental and computational methodology to quantify the correlation between variability in signaling regulator abundance and variation in sensitivity to stimuli. Here, we apply CCVA to investigate the unexpected effects of the interleukin 2 (IL-2) receptor α chain (IL-2Rα) on the sensitivity to common-gamma chain (γc) cytokines in primary T lymphocytes. Our work demonstrates that increased IL-2Rα abundance decreases the concentration of IL-2 but increases the concentrations of IL-7 and IL-15 required for a half-maximal activation (EC50) of downstream signal transducer and activator of transcription 5 (STAT5), without affecting the EC50 of other γc cytokines. To probe the mechanism of IL-2Rα's effect on γc family cytokine EC50s, we introduce a Bayesian-inference computational framework that models the formation of receptor signaling complexes using prior biophysical measurements. Using this framework, we demonstrate that a model in which IL-2Rα drives γc depletion through pre-assembly of complete IL-2 receptors is consistent with both CCVA data and prior measurements. The combination of CCVA and computational modeling yields quantitative understanding of the crosstalk of γc cytokine signaling in T lymphocytes.

Objective In our study, the aim was to identify the serum uric acid levels, a marker of oxidative stress, according to migraine subtypes (aura/without aura and episodic/chronic migraine). Method The study included 300 migraine patients and 150 healthy controls for a total of 450 individuals. Migraine and subtypes were diagnosed according to International Classification of Headache Disorders-2013 criteria. Patients were evaluated during attendance at the neurology clinic. Results Our patient group was 77.0% female and disease duration was 9.2 ± 7.2 years. Our control group comprised 77.3% females. The age intervals in the patient and control groups were 36.4 ± 10.4 years and 36.0 ± 8.1 years. There was no statistically significant difference between our control and patient groups in terms of age and gender (p = .937 and p = .655). The serum UA, ferritin, and urea levels in our patient group were found to be significantly low compared to the healthy control group (p < .001). The serum UA levels in the migraine and control groups were 3.7 ± 0.7 and 4.6 ± 0.7 mg/dL, respectively (p < .001). There were no statistically significant differences observed between serum uric acid levels and other blood parameters between aura/without aura and episodic/chronic migraine subtypes (p > .05). Conclusion Our study supports the hypothesis that the oxidative stress marker of serum uric acid levels may be associated with migraine diagnosis, concluding that serum uric acid levels were not significant for migraine subtypes.

Background: Although cure rates in pediatric acute lymphoblastic leukemia (ALL) are quite high with combined chemotherapy regimens, complete response (CR) and long-term survival rates in adults are 80–90 and 30–40%, respectively. Currently, combined chemotherapy regimens, such as Hyper-CVAD and PETHEMA, are used in patients with adult ALL. However, there has been no study comparing the results of Hyper-CVAD and PETHEMA ALL-93. Methods: In this retrospective single-center study, we evaluated the results of Hyper-CVAD and PETHEMA ALL-93 in 51 ALL patients treated between September 2008 and March 2017 at the Department of Hematology, Faculty of Medicine, Karadeniz Technical University. Results: Thirty-eight patients were treated with Hyper-CVAD and 13 with PETHEMA ALL-93. CR was obtained in 90 and 100% of patients, respectively. Survival estimates were comparable between Hyper-CVAD and PE­THEMA ALL-93, with a median overall survival (OS) and a median disease-free survival (DFS) of 17.5 and 12.1 months, respectively, for Hyper-CVAD and of 18.6 and 12.9 months, respectively, for PETHEMA ALL-93. The 2-year OS rates for Hyper-CVAD and PETHEMA ALL-93 were 30 and 40%, respectively, and the 2-year DFS rates were 28 and 44%, respectively. PETHEMA ALL-93 resulted in more hepatotoxicity, hypofibrinogenemia, aspergillus infection, and skin rash than Hyper-CVAD. Conclusions: Although Hyper-CVAD and PE­THEMA ALL-93 showed similar effects, Hyper-CVAD was tolerated better. Age and comorbidities should be taken into account before a chemotherapy regimen is determined for patients with ALL.

The single-cell resolution of flow cytometry provides a quantitative measurement of the heterogeneity of protein expression within clonal populations of cells. As the biological significance of this variability is becoming more widely appreciated, there is a need for new tools and methodology to analyze and leverage the effects of endogenous variation. These tools can provide alternatives to genetic methods, such as siRNA knockdown or germline knockout, that are commonly used to manipulate protein expression. We introduce such a new tool, named ScatterSlice, that enables rapid quantification of the correlation between heterogeneity in cellular responses (measured by staining of phospho-proteins) and varied expression of signaling molecules. We demonstrate its application to the validation of biochemical models of cellular responses to IL-2, IL-7, and IL-15 in living, unperturbed cells. In addition, we demonstrate that heterogeneous distribution of receptor subunits within a population of lymphocytes results in gradations of sensitivity to each cytokine. Finally, using experimental measurements of error and uncertainty in combination with biochemical models, we demonstrate the robustness of this analysis to experimental noise, and consider both limits and extensions to its use.