In conclusion, our findings suggested that DIO attenuates DSS-induced colitis in mice by means of modulating imbalanced gut microbiota and increases in SCFA generation.Background The reversibility of bronchial obstruction is needed to diagnose asthma. Bronchodilation (BD) testing is, therefore, used in asthma work-up. This study explored the benefit of performing BD testing in asthmatic children without bronchial obstruction. Methods The study included 60 subjects with asthma and normal lung function, 13 (21.7%) females and 47 (78.3%) males; the mean age was 11.5 years, 26 were adolescents, and 34 were children. Lung function, symptoms, use of asthma medications, type 2 inflammation, and asthma control were assessed in all subjects. Results Eleven (18%) subjects positively responded to BD testing. Fifty-five percent of subjects were uncontrolled based on Global Initiative for Asthma (GINA) criteria. The multivariate analysis identified 2 factors associated with a positive response to BD testing FEV1 [odds ratio (OR) = 0.91) and ACT (OR = 0.79). Conclusions This study showed that BD testing could give additional helpful information in clinical practice. In addition, uncontrolled asthma, based on GINA criteria, was prevalent in children with normal lung function.Background Evidence has demonstrated that adding intermittent inhaled corticosteroids (ICS) to treatment with short-acting b2-agonists (SABAs) in children 5 years of age and younger who experience intermittent viral-induced wheezing (VIW) reduces the risk of severe exacerbations. However, there is concern about whether the extra benefit offered by this drug outweighs the additional cost. This study aimed to evaluate the cost-effectiveness of intermittent ICS in children 5 years of age and younger who experience intermittent VIW. Methods We constructed a probabilistic Markov model to estimate the cost and quality-adjusted life-years (QALYs) of intermittent ICS compared with SABA reliever therapy in preschoolers with viral-triggered wheezing in Colombia. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at a willingness-to-pay value of $5,180. Results In an analysis of the Markov cohort model, we estimated a gain of 0.2 QALYs per patient per year on intermittent ICS compared with SABA and a reduction of cost per patient of USD $37 per year. This position of dominance negated the need to calculate an incremental cost-effectiveness ratio. Deterministic and probabilistic sensitivity analyses, our base case results were robust to variations of all assumptions and parameters. Conclusion Adding intermittent ICS to treatment with SABAs in children 5 years of age and younger who experience intermittent VIW was found to be cost effective. These results could improve the use of health care resources, especially in settings with limited economic resources.Background Specific granule deficiency (SGD) is a rare immunodeficiency associated with CCAT/enhancer-binding protein epsilon (CEBPE) gene variants. It can cause severe recurrent infections and is lethal without successful stem cell transplantation. Few cases with SGD of both type 1 and type 2 have been described in the literature. In this study, we present the first report of a case with a novel homozygous c.511 C > T (p.Gln171Ter) mutation in the SMARCD2 gene of SGD type 2, which was successfully treated with bone marrow transplantation. Case A male infant presented to our neonatal intensive care unit on the second day of life with an icteric appearance and mild hypotonia. He was evaluated for immunodeficiency as the cause of delayed cord separation and refractory neutropenia. At 6 weeks of age, SGD type 2 with a new variant was diagnosed and successfully treated by bone marrow transplantation. Conclusion SGD is an immunodeficiency disease that is quite rare. However, we believe that SGD diagnosis and associated new variants can be detected more frequently with the widespread use of all whole-exome sequencing techniques.Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease. Tumors are poorly immunogenic and immunosuppressive, preventing T cell activation in the tumor microenvironment. Here, we present a microbial-based immunotherapeutic treatment for selective delivery of an immunogenic tetanus toxoid protein (TT856-1313) into PDAC tumor cells by attenuated Listeria monocytogenes. This treatment reactivated preexisting TT-specific memory T cells to kill infected tumor cells in mice. Treatment of KrasG12D,p53R172H, Pdx1-Cre (KPC) mice with Listeria-TT resulted in TT accumulation inside tumor cells, attraction of TT-specific memory CD4 T cells to the tumor microenvironment, and production of perforin and granzyme B in tumors. Low doses of gemcitabine (GEM) increased immune effects of Listeria-TT, turning immunologically cold into hot tumors in mice. In vivo depletion of T cells from Listeria-TT + GEM-treated mice demonstrated a CD4 T cell-mediated reduction in tumor burden. CD4 T cells from TT-vaccinated mice were able to kill TT-expressing Panc-02 tumor cells in vitro. In addition, peritumoral lymph node-like structures were observed in close contact with pancreatic tumors in KPC mice treated with Listeria-TT or Listeria-TT + GEM. These structures displayed CD4 and CD8 T cells producing perforin and granzyme B. Whereas CD4 T cells efficiently infiltrated the KPC tumors, CD8 T cells did not. Listeria-TT + GEM treatment of KPC mice with advanced PDAC reduced tumor burden by 80% and metastases by 87% after treatment and increased survival by 40% compared to nontreated mice. These results suggest that Listeria-delivered recall antigens could be an alternative to neoantigen-mediated cancer immunotherapy.Increased dietary intake of niacin has been correlated with reduced risk of Alzheimer’s disease (AD). Niacin serves as a high-affinity ligand for the receptor HCAR2 (GPR109A). In the brain, HCAR2 is expressed selectively by microglia and is robustly induced by amyloid pathology in AD. The genetic inactivation of Hcar2 in 5xFAD mice, a model of AD, results in impairment of the microglial response to amyloid deposition, including deficits in gene expression, proliferation, envelopment of amyloid plaques, and uptake of amyloid-β (Aβ), ultimately leading to exacerbation of amyloid burden, neuronal loss, and cognitive deficits. In contrast, activation of HCAR2 with an FDA-approved formulation of niacin (Niaspan) in 5xFAD mice leads to reduced plaque burden and neuronal dystrophy, attenuation of neuronal loss, and rescue of working memory deficits. These data provide direct evidence that HCAR2 is required for an efficient and neuroprotective response of microglia to amyloid pathology. Administration of Niaspan potentiates the HCAR2-mediated microglial protective response and consequently attenuates amyloid-induced pathology, suggesting that its use may be a promising therapeutic approach to AD that specifically targets the neuroimmune response.Fibrosis is a central pathway that drives progression of multiple chronic diseases, yet few safe and effective clinical antifibrotic therapies exist. In most fibrotic disorders, transforming growth factor-β (TGF-β)-driven scarring is an important pathologic feature and a key contributor to disease progression. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are two closely related transcription cofactors that are important for coordinating fibrogenesis after organ injury, but how they are activated in response to tissue injury has, so far, remained unclear. Here, we describe NUAK family kinase 1 (NUAK1) as a TGF-β-inducible profibrotic kinase that is up-regulated in multiple fibrotic organs in mice and humans. Mechanistically, we show that TGF-β induces a rapid increase in NUAK1 in fibroblasts. NUAK1, in turn, can promote profibrotic YAP and TGF-β/SMAD signaling, ultimately leading to organ scarring. Moreover, activated YAP and TAZ can induce further NUAK1 expression, creating a profibrotic positive feedback loop that enables persistent fibrosis. Using mouse models of kidney, lung, and liver fibrosis, we demonstrate that this fibrogenic signaling loop can be interrupted via fibroblast-specific loss of NUAK1 expression, leading to marked attenuation of fibrosis. Pharmacologic NUAK1 inhibition also reduced scarring, either when initiated immediately after injury or when initiated after fibrosis was already established. Together, our data suggest that NUAK1 plays a critical, previously unrecognized role in fibrogenesis and represents an attractive target for strategies that aim to slow fibrotic disease progression.Inflammation has profound but poorly understood effects on metabolism, especially in the context of obesity and nonalcoholic fatty liver disease (NAFLD). Here, we report that hepatic interferon regulatory factor 3 (IRF3) is a direct transcriptional regulator of glucose homeostasis through induction of Ppp2r1b, a component of serine/threonine phosphatase PP2A, and subsequent suppression of glucose production. Global ablation of IRF3 in mice on a high-fat diet protected against both steatosis and dysglycemia, whereas hepatocyte-specific loss of IRF3 affects only dysglycemia. Integration of the IRF3-dependent transcriptome and cistrome in mouse hepatocytes identifies Ppp2r1b as a direct IRF3 target responsible for mediating its metabolic actions on glucose homeostasis. IRF3-mediated induction of Ppp2r1b amplified PP2A activity, with subsequent dephosphorylation of AMPKα and AKT. Furthermore, suppression of hepatic Irf3 expression with antisense oligonucleotides reversed obesity-induced insulin resistance and restored glucose homeostasis in obese mice. Obese humans with NAFLD displayed enhanced activation of liver IRF3, with reversion after bariatric surgery. Hepatic PPP2R1B expression correlated with HgbA1C and was elevated in obese humans with impaired fasting glucose. We therefore identify the hepatic IRF3-PPP2R1B axis as a causal link between obesity-induced inflammation and dysglycemia and suggest an approach for limiting the metabolic dysfunction accompanying obesity-associated NAFLD.Octopus, clingfish, and larva use soft cups to attach to surfaces under water. Recently, various bioinspired cups have been engineered. However, the mechanisms of their attachment and detachment remain elusive. Using a novel microcup, fabricated by two-photon lithography, coupled with in situ pressure sensor and observation cameras, we reveal the detailed nature of its attachment/detachment under water. It involves elasticity-enhanced hydrodynamics generating „self-sealing” and high suction at the cup-substrate interface, converting water into „glue.” Detachment is mediated by seal breaking. Three distinct mechanisms of breaking are identified, including elastic buckling of the cup rim. A mathematical model describes the interplay between the attachment/detachment process, geometry, elasto-hydrodynamics, and cup retraction speed. If the speed is too slow, then the octopus cannot attach; if the tide is too gentle for the larva, then water cannot serve as a glue. The concept of „water glue” can innovate underwater transport and manufacturing strategies.