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Background and Objective: Severe asthma is a heterogeneous disease with subtype classification according to dominant airway infiltrates, including eosinophilic (Type 2 high), or non‐eosinophilic asthma. Non‐eosinophilic asthma is further divided into paucigranulocytic or neutrophilic asthma characterized by elevated neutrophils, and mixed Type 1 and Type 17 cytokines in the airways. Severe non‐eosinophilic asthma has few effective treatments and many patients do not qualify for biologic therapies. The cystic fibrosis transmembrane conductance regulator (CFTR) is dysregulated in multiple respiratory diseases including cystic fibrosis and chronic obstructive pulmonary disease and has proven a valuable therapeutic target. We hypothesized that the CFTR may also play a role in non‐eosinophilic asthma. Methods: Patient‐derived human bronchial epithelial cells (hBECs) were isolated and differentiated at the air‐liquid interface. Single cell RNA‐sequencing (scRNAseq) was used to identify epithelial cell subtypes and transcriptional activity. Ion transport was investigated with Ussing chambers and immunofluorescent quantification of ionocyte abundance in human airway epithelial cells and murine models of asthma. Results: We identified that hBECs from patients with non‐eosinophilic asthma had reduced CFTR function, and did not differentiate into CFTR‐expressing ionocytes compared to those from eosinophilic asthma or healthy donors. Similarly, ionocytes were also diminished in the airways of a murine model of neutrophilic‐dominant but not eosinophilic asthma. Treatment of hBECs from healthy donors with a neutrophilic asthma‐like inflammatory cytokine mixture led to a reduction in ionocytes. Conclusion: Inflammation‐induced loss of CFTR‐expressing ionocytes in airway cells from non‐eosinophilic asthma may represent a key feature of disease pathogenesis and a novel drug target. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) can be fatal and is a well-defined risk factor for the development of chronic kidney disease. Group 2 innate lymphoid cells (ILC2s) are innate producers of type-2 cytokines and are critical regulators of homeostasis in peripheral organs. However, our knowledge of their function in the kidney is relatively limited. Recent evidence suggests that increasing ILC2 numbers by systemic administration of recombinant interleukin (IL)-25 or IL-33 protects against renal injury. Whilst ILC2s can be induced to protect against ischemic- or chemical-induced AKI, the impact of ILC2 deficiency or depletion on the severity of renal injury is unknown. Firstly, the phenotype and location of ILC2s in the kidney was assessed under homeostatic conditions. Kidney ILC2s constitutively expressed high levels of IL-5 and were located in close proximity to the renal vasculature. To test the functional role of ILC2s in the kidney, an experimental model of renal ischemia-reperfusion injury (IRI) was used and the severity of injury was assessed in wild-type, ILC2-reduced, ILC2-deficient, and ILC2-depleted mice. Surprisingly, there were no differences in histopathology, collagen deposition or mRNA expression of injury-associated (Lcn2), inflammatory (Cxcl1, Cxcl2, and Tnf) or extracellular matrix (Col1a1, Fn1) factors following IRI in the absence of ILC2s. These data suggest the absence of ILC2s does not alter the severity of renal injury, suggesting possible redundancy. Therefore, other mechanisms of type 2-mediated immune cell activation likely compensate in the absence of ILC2s. Hence, a loss of ILC2s is unlikely to increase susceptibility to, or severity of AKI.

Although aging and lung injury are linked to the development of idiopathic pulmonary fibrosis (IPF), the underlying pathognomonic processes predisposing to fibrotic lesions remain largely unknown. A deficiency in the ability of type 2 alveolar epithelial cell (AEC2) progenitors to regenerate and repair the epithelia has been proposed as a critical factor. In this issue of the JCI, Liang et al. identify a deficiency in the zinc transporter SLC39A8 (ZIP8) in AEC2s and in the subsequent activation of the sirtuin SIRT1 that predisposes to decreased AEC2 renewal capacity and enhanced lung fibrosis in both IPF and aging lungs. Interestingly, the authors demonstrate the efficacy of modulating dietary zinc levels, suggesting the need for clinical trials to evaluate the therapeutic potential of dietary supplementation and the development of pharmacological modulation of the Zn/ZIP8/SIRT1 axis for treatment., Idiopathic pulmonary fibrosis Most lung diseases are pathologically characterized by fibrosis, which is typically restricted to the airway walls. However, in idiopathic pulmonary fibrosis (IPF), the normal honeycomb structure of [...]

Asthma Asthma is a chronic inflammatory disorder of the airways with mixed lymphocytic and myelogenous (e.g., granulocytes/ monocytes) infiltrates (1). Although the inflammatory response is complex, many patients with asthma [...], Allergic asthma is a chronic inflammatory airway disease characterized by dysregulated type 2 immune responses, including degranulating airway eosinophils that induce tissue damage and airway hyperresponsiveness (AHR). The type 2 cytokines interleukin 5 (IL-5) and IL-13 and the eosinophil-specific chemokine CCL11/CCL24/CCL26 axis recruit, activate, and regulate eosinophils in the airways. In this issue of the JCI, Karcz et al. identified a mechanism involving the nucleotide sugar UDP-glucose (UDP-G) and the purinergic receptor [P2Y.sub.14]R in amplifying eosinophil accumulation in the lung. During type 2 inflammation, UDP-G activates [P2Y.sub.14]R on eosinophils, inducing the cells to move and migrate into the lung. Pharmacologically or genetically inhibiting [P2Y.sub.14]R on eosinophils attenuated eosinophil infiltration and AHR. Future experiments, including identifying additional type 2 factors regulating [P2Y.sub.14]R expression on lung eosinophils, are necessary to ascertain the impact of targeting [P2Y.sub.14]R as an alternative or adjunctive therapy to current type 2 biologics for the treatment of asthma.

The dopaminergic system is implicated in depressive disorders and research has also shown that dopamine constricts lexical/semantic networks by reducing spreading activation. Hence, depression, which is linked to reductions of dopamine, may be associated with increased spreading activation. However, research has generally found no effects of depression on spreading activation, using semantic priming paradigms. We used a different paradigm to investigate the relationship between depression and spreading activation, one based on word frequencies. Our sample included 97 undergraduates who completed the BDI-II and the Controlled Oral Word Association test as well as the Animal Naming test. The results indicated that the group scoring within the depressed ranged evidenced greater spreading activation as compared to those who scored within the normal range on the BDI-II. The implications of these results as they relate to creativity in depression is discussed. (Contains 2 figures.)

Lesion studies demonstrate that the right temporal-parietal region (RTP) is important for mediating spatial attention. The RTP is also involved in emotional experiences that can be evoked by art. Normal people vary in their ability to allocate spatial attention, thus, people who can better allocate attention might also be more influenced by the emotional messages of the paintings (evocative impact). Seventeen healthy participants bisected an unlabeled 100 mm line and their performance on this task was used to create two groups, individuals who were more (mALB) and less accurate (lALB). These participants also judged 10 paintings on five qualities, Evocative Impact, Aesthetics, Novelty, Technique, and Closure by marking a 100 mm line from 1 (low degree) to 10 (high degree). An ANOVA indicated differences in accuracy on the line bisection (LB) between the two groups. Additional ANOVAs, using the quality ratings as the dependent measure, revealed that the mALB group scored the Evocative Impact greater than the lALB group. These results suggest that the differences in attentional bias between the two groups, as indicated by their LB performance, might influence their evocative impact or reactions and also be a "barometer" of other RTP functions, including emotional processing.

Background/Hypothesis: The degree of attention directed to a stimulus and the presence of anisometric representations can alter the perception of the magnitude of a stimulus. We wanted to learn if normal right-handed subjects' estimates of distance traveled are influenced by the right-left direction or hemispace of movements. Methods: We had blindfolded participants estimate the distance their arm was moved in a rightward or leftward direction, in right and left hemispace. Since we wanted subjects to estimate the distance traveled rather than compute the distance between the start and finish points, the subjects' arms were passively moved in sinusoidal trajectories at a constant speed. Results: Subjects estimated leftward movements as longer than rightward movements, but there was no effect of hemispace. Comments/Conclusions: People often attend more to novel than routine conditions and therefore participants might have overestimated the distance associated with leftward versus rightward movement because right-handed people more frequently move their right hand in a rightward direction and learn to read and write using rightward movements. Thus, leftward movements might be more novel and more attended than rightward movements and this enhanced directional attention might have influenced estimates of magnitude (distance).

The cerebral regulation of cardiovascular functioning varies along both a lateral and a longitudinal axis. The parasympathetic and sympathetic nervous systems are lateralized to the left and right cerebral hemispheres, respectively. Further, the frontal lobes are known to be inhibitory in nature, whereas the temporal lobes are excitatory. However, no systematic investigation has been conducted to determine the nature and strength of the relationship between the left and right frontal and temporal lobes in regulating cardiovascular activity. The present investigation sought to examine these relationships by testing the hypothesis that negative correlations would be found between baseline heart rate and blood pressure and asymmetry of alpha magnitude across the frontal lobes. Further, positive correlations were hypothesized to exist across the temporal lobes. A total of 20 women were asked to relax with their eyes closed while heart rate and blood pressure as well as quantitative electroencephalography data were obtained. The results indicated that, as hypothesized, significant negative correlations existed across the frontal lobes and significant positive correlations existed across the temporal lobes. The results provide further support for a division of responsibility between the left and right frontal and temporal lobes in the regulation of heart rate and blood pressure.