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Necrotising enterocolitis (NEC) is a devastating gastrointestinal disease of prematurity that typically develops after the administration of infant formula, suggesting a link between nutritional components and disease development. One of the most significant complications that develops in patients with NEC is severe lung injury. We have previously shown that the administration of a nutritional formula that is enriched in pre-digested Triacylglyceride that do not require lipase action can significantly reduce the severity of NEC in a mouse model. We now hypothesise that this 'pre-digested fat (PDF) system' may reduce NEC-associated lung injury. In support of this hypothesis, we now show that rearing newborn mice on a nutritional formula based on the 'PDF system' promotes lung development, as evidenced by increased tight junctions and surfactant protein expression. Mice that were administered this 'PDF system' were significantly less vulnerable to the development of NEC-induced lung inflammation, and the administration of the 'PDF system' conferred lung protection. In seeking to define the mechanisms involved, the administration of the 'PDF system' significantly enhanced lung maturation and reduced the production of reactive oxygen species (ROS). These findings suggest that the PDF system protects the development of NEC-induced lung injury through effects on lung maturation and reduced ROS in the lung and also increases lung maturation in non-NEC mice. [ABSTRACT FROM AUTHOR]

The topic of adaptive event‐triggered control for multi‐input‐multi‐output nonlinear systems with asymmetric state constraints is considered in this article. First, by introducing unified barrier functions method, the initial system is transformed to a non‐constraints system, which brings that the requirement of feasibility conditions could be eliminated and the constraint functions could be relaxed effectively. Then, an adaptive tracking controller is designed by combining some excellent technology, where command filter is utilized to overcome the explosion of complexity, neural network is introduced to approximate unknown nonlinear function, and event‐triggered mechanism is proposed to save communication resources. The designed control scheme can make the outputs of the system to track the target trajectories within a small bounded error range, all signals in the closed‐loop system are bounded, and all states do not escape the state constraints. Finally, practical and comparative examples are given to verify the effectiveness of the method. [ABSTRACT FROM AUTHOR]

Summary: Mixed starter of pure mould and yeast was designed to circument the problem of flavour characteristics in rice wine. The result underlined that the mixed starter (Q7) made by simultaneous inoculation of Rhizopus oryzae, Saccharomyces cerevisiae, Wickerhamomyces anomalus and Candida glabrata had the highest contents of α‐amylase (8.02 ± 0.96 U/g) and sensory scoring (92.05 ± 2.24), presenting relatively strong flower‐aroma, wine‐aroma, Qu‐aroma and rice‐aroma. Meanwhile, the total concentration of flavour compounds in rice wine (RQ, 125.828 mg L−1) obtained from rice fermentation using Q7 were better than the commercially available rice wine (SS, 125.828 mg L−1). The E‐nose analysis showed that the flavour components in RQ differed dramatically from SS. The E‐tongue results indicated that the sourness, sweetness and umami aftertaste were greatly higher in RQ, and the bitterness and astringency are lower compared with SS. This study provided a method to improve the flavour and quality of rice wine. [ABSTRACT FROM AUTHOR]

NEC takes its Toll: Toll-like receptor-4 (TLR4) has been implicated in the pathophysiology of necrotizing enterocolitis (NEC). However, how TLR4 activation contributes to NEC remains to be elucidated. Here, Kovler et al. focused on enteric glia and showed that TLR4 activation induced glial loss in NEC. The mechanism involves BDNF expression in enteric glia, and the authors showed that exogenous BDNF administration reduced TLR4 activation and prevented cell loss. Treating the mice with a compound able to increase BDNF release from glial cells had therapeutic effects in mice. Necrotizing enterocolitis (NEC) is a devastating disease of premature infants, whose pathogenesis remains incompletely understood, although activation of the Gram-negative bacterial receptor Toll-like receptor 4 (TLR4) on the intestinal epithelium plays a critical role. Patients with NEC typically display gastrointestinal dysmotility before systemic disease is manifest, suggesting that dysmotility could drive NEC development. Both intestinal motility and inflammation are governed by the enteric nervous system, a network of enteric neurons and glia. We hypothesized here that enteric glia loss in the premature intestine could lead to dysmotility, exaggerated TLR4 signaling, and NEC development. We found that intestinal motility is reduced early in NEC in mice, preceding the onset of intestinal inflammation, whereas pharmacologic restoration of intestinal motility reduced NEC severity. Ileal samples from mouse, piglet, and human NEC revealed enteric glia depletion, and glia-deficient mice (Plp1ΔDTR, Sox10ΔDTR, and BdnfΔDTR) showed increased NEC severity compared with wild-type mice. Mice lacking TLR4 on enteric glia (Sox10-Tlr4ko) did not show NEC-induced enteric glia depletion and were protected from NEC. Mechanistically, brain-derived neurotrophic factor (BDNF) from enteric glia restrained TLR4 signaling on the intestine to prevent NEC. BDNF was reduced in mouse and human NEC, and BDNF administration reduced both TLR4 signaling and NEC severity in enteric glia–deficient mice. Last, we identified an agent (J11) that enhanced enteric glial BDNF release, inhibited intestinal TLR4, restored motility, and prevented NEC in mice. Thus, enteric glia loss might contribute to NEC through intestinal dysmotility and increased TLR4 activation, suggesting enteric glia therapies for this disorder. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is a disease of premature infants characterized by acute intestinal necrosis. Current dogma suggests that NEC develops in response to post-natal dietary and bacterial factors, and so a potential role for in utero factors in NEC remains unexplored. We now show that during pregnancy, administration of a diet rich in the aryl hydrocarbon receptor (AHR) ligand indole-3-carbinole (I3C), or of breast milk, activates AHR and prevents NEC in newborn mice by reducing Toll-like receptor 4 (TLR4) signaling in the newborn gut. Protection from NEC requires activation of AHR in the intestinal epithelium which is reduced in mouse and human NEC, and is independent of leukocyte activation. Finally, we identify an AHR ligand ("A18") that limits TLR4 signaling in mouse and human intestine, and prevents NEC in mice when administered during pregnancy. In summary, AHR signaling is critical in NEC development, and maternally-delivered, AHR-based therapies may alleviate NEC. Necrotizing enterocolitis (NEC) is a disease of prematurity requiring Toll-like receptor 4 (TLR4) activation on the gut epithelium. Here the authors show that the aryl hydrocarbon receptor (AHR) mediates NEC pathogenesis via effects on TLR4, and that supplementing the diet with AHR ligands during pregnancy or postnatally prevents NEC. [ABSTRACT FROM AUTHOR]

Elucidating the gut-brain connection in necrotizing enterocolitis: Necrotizing enterocolitis (NEC) is a devastating disease of premature infants characterized by acute intestinal necrosis and long-term neurological dysfunction, through mechanisms that are poorly understood. In new work, Zhou et al. study a neonatal mouse model of NEC, human brain autopsy specimens from infants with and without NEC, and human and mouse brain organoids. They report that CD4+ T lymphocytes, partially of intestinal origin, damage the developing brain of neonatal mice in the setting of NEC through the release of IFN-γ. These findings suggest that early management of intestinal injury, or control of the lymphocyte response, could improve neurological impairment in children with NEC. Necrotizing enterocolitis (NEC) causes acute intestinal necrosis in premature infants and is associated with severe neurological impairment. In NEC, Toll-like receptor 4 is activated in the intestinal epithelium, and NEC-associated brain injury is characterized by microglial activation and white matter loss through mechanisms that remain unclear. We now show that the brains of mice and humans with NEC contained CD4+ T lymphocytes that were required for the development of brain injury. Inhibition of T lymphocyte influx into the brains of neonatal mice with NEC reduced inflammation and prevented myelin loss. Adoptive intracerebroventricular delivery of gut T lymphocytes from mice with NEC into Rag1−/− recipient mice lacking CD4+ T cells resulted in brain injury. Brain organoids derived from mice with or without NEC and from human neuronal progenitor cells revealed that IFN-γ release by CD4+ T lymphocytes induced microglial activation and myelin loss in the organoids. IFN-γ knockdown in CD4+ T cells derived from mice with NEC abrogated the induction of NEC-associated brain injury after adoptive transfer to naïve Rag1−/− recipient mice. T cell receptor sequencing revealed that NEC mouse brain-derived T lymphocytes shared homology with gut T lymphocytes from NEC mice. Intraperitoneal injection of NEC gut-derived CD4+ T lymphocytes into naïve Rag1−/− recipient mice induced brain injury, suggesting that gut-derived T lymphocytes could mediate neuroinflammation in NEC. These findings indicate that NEC-associated brain injury may be induced by gut-derived IFN-γ–releasing CD4+ T cells, suggesting that early management of intestinal inflammation in children with NEC could improve neurological outcomes. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis–induced brain injury in mice can be prevented with an oral nanotherapeutic that targets microglia. The gut-brain conNECtion: Necrotizing enterocolitis (NEC) is a gastrointestinal disorder affecting premature infants. Newborns with NEC often develop cognitive impairments. The mechanisms leading to cognitive disabilities remain unclear. Niño et al. show that increased oxidative stress in the brain triggered NEC-associated cognitive impairments in mice. The release of the proinflammatory molecule high-mobility group box 1 from the injured intestine activated Toll-like receptor 4 on microglial cells in the brain, resulting in accumulation of reactive oxygen species. Oral administration of microglia-targeting antioxidants prevented cognitive impairments in a mouse model of NEC. The results suggest that reducing microglial activation might be a strategy to protect patients from cognitive impairments associated with NEC. Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease of the premature infant. One of the most important long-term complications observed in children who survive NEC early in life is the development of profound neurological impairments. However, the pathways leading to NEC-associated neurological impairments remain unknown, thus limiting the development of prevention strategies. We have recently shown that NEC development is dependent on the expression of the lipopolysaccharide receptor Toll-like receptor 4 (TLR4) on the intestinal epithelium, whose activation by bacteria in the newborn gut leads to mucosal inflammation. Here, we hypothesized that damage-induced production of TLR4 endogenous ligands in the intestine might lead to activation of microglial cells in the brain and promote cognitive impairments. We identified a gut-brain signaling axis in an NEC mouse model in which activation of intestinal TLR4 signaling led to release of high-mobility group box 1 in the intestine that, in turn, promoted microglial activation in the brain and neurological dysfunction. We further demonstrated that an orally administered dendrimer-based nanotherapeutic approach to targeting activated microglia could prevent NEC-associated neurological dysfunction in neonatal mice. These findings shed light on the molecular pathways leading to the development of NEC-associated brain injury, provide a rationale for early removal of diseased intestine in NEC, and indicate the potential of targeted therapies that protect the developing brain in the treatment of NEC in early childhood. [ABSTRACT FROM AUTHOR]