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A major barrier to the impact of genomic diagnosis in patients with congenital malformations is the lack of understanding regarding how sequence variants contribute to disease pathogenesis and whether this information could be used to generate patient-specific therapies. Congenital diaphragmatic hernia (CDH) is among the most common and severe of all structural malformations; however, its underlying mechanisms are unclear. We identified loss-of-function sequence variants in the epigenomic regulator gene SIN3A in two patients with complex CDH. Tissue-specific deletion of Sin3a in mice resulted in defects in diaphragm development, lung hypoplasia, and pulmonary hypertension, the cardinal features of CDH and major causes of CDH-associated mortality. Loss of SIN3A in the lung mesenchyme resulted in reduced cellular differentiation, impaired cell proliferation, and increased DNA damage. Treatment of embryonic Sin3a mutant mice with anacardic acid, an inhibitor of histone acetyltransferase, reduced DNA damage, increased cell proliferation and differentiation, improved lung and pulmonary vascular development, and reduced pulmonary hypertension. These findings demonstrate that restoring the balance of histone acetylation can improve lung development in the Sin3a mouse model of CDH.

Corn (Zea mays L.) stover demand as a forage or for an emerging bioeconomy has increased the importance of determining the long‐term effects of stover removal on grain yield and soil properties. Study objectives were to evaluate grain yield, soil organic carbon (SOC), and total soil N (0–150 cm) in a 20‐year, irrigated, continuous corn study, located in eastern Nebraska, under conventional tillage (CT) and no‐till (NT) with variable corn stover removal rates (none, medium, and high). After 20 years, grain yield was up to 6.0% greater under NT with stover removal compared with NT and no stover removal, while yield was similar for CT in all stover removal treatments. Grain yield was similar between NT with stover removal and CT in all stover removal treatments. High stover removal rates resulted in greater SOC loss at the surface soil layers (0–15 cm and 0–30 cm) after 20 years compared with no or medium stover removal. Corn stover retention under NT resulted in the same cumulative SOC stock loss as CT or stover removal. All management practices resulted in cumulative (0–120 cm) SOC stock loss (8% decrease) that occurred in the last 10 years of the study. Total soil nitrogen stocks were maintained or increased after 20 years at the surface soil layers (0–15 cm and 0–30 cm) and were similar between NT and CT. In an irrigated continuous corn system, neither NT nor stover retention was able to maintain cumulative SOC stocks over time. Core Ideas: Corn yield increased under no‐till with stover removal but not under conventional tillage.Corn yield was similar in conventional tillage under no, medium, and high stover removal rates.High residue removal rates decreased SOC stocks at the soil surface (0–30 cm) under both no‐till and conventional tillage.All management practices resulted in a net loss of cumulative SOC stocks. [ABSTRACT FROM AUTHOR]

Intestinal permeability (IP) plays an important role in the pathophysiology of nonalcoholic fatty liver disease (NAFLD). We assessed site-specific (gastroduodenum, small intestine, colon and whole gut) IP in NAFLD patients and healthy controls (HC) and its association with the degree of hepatic steatosis, hepatic fibrosis and dietary composition in these NAFLD patients. In vivo site-specific IP was analysed with a validated multi-sugar test in NAFLD patients and HC. Furthermore, in NAFLD patients, hepatic steatosis (chemical shift MRI), hepatic fibrosis (transient elastography) and dietary composition (food frequency questionnaire) were assessed. Fifty-two NAFLD patients and forty-six HC were included in this study. Small intestinal (P <0.001), colonic (P = 0.004) and whole gut (P <0.001) permeability were increased in NAFLD patients compared to HC. Furthermore, colonic permeability (P = 0.029) was significantly higher in NAFLD patients with clinically significant fibrosis compared to those without. Colonic permeability remained positively associated with the presence of clinically significant fibrosis (P = 0.017) after adjustment for age, sex and BMI. Colonic permeability is increased in at least a subset of NAFLD patients compared to HC and is independently associated with clinically significant NAFLD fibrosis. [ABSTRACT FROM AUTHOR]