Pattern recognition receptors confer plant resistance to pathogen infection by recognizing the conserved pathogen-associated molecular patterns. The cell surface receptor chitin elicitor receptor kinase 1 of Arabidopsis (AtCERK1) directly binds chitin through its lysine motif (LysM)-containing ectodomain (AtCERK1-ECD) to activate immune responses. The crystal structure that we solved of an AtCERK1-ECD complexed with a chitin pentamer reveals that their interaction is primarily mediated by a LysM and three chitin residues. By acting as a bivalent ligand, a chitin octamer induces AtCERK1-ECD dimerization that is inhibited by shorter chitin oligomers. A mutation attenuating chitin-induced AtCERK1-ECD dimerization or formation of nonproductive AtCERK1 dimer by overexpression of AtCERK1-ECD compromises AtCERK1-mediated signaling in plant cells. Together, our data support the notion that chitin-induced AtCERK1 dimerization is critical for its activation.
Prenatal exposure to nicotine via cigarette smoke or other forms of tobacco use is a significant environmental risk factor for attention deficit hyperactivity disorder (ADHD). The neurobiological mechanisms underlying the link between prenatal nicotine exposure (PNE) and ADHD are not well understood. Animal models, especially rodent models, are beginning to bridge this gap in knowledge. Although ADHD is characterized by hyperactivity, inattention, impulsivity and working memory deficits, the majority of the animal models are based on only one or two ADHD associated phenotypes, in particular, hyperactivity or inattention. We report a PNE mouse model that displays the full range of ADHD associated behavioral phenotypes including working memory deficit, attention deficit and impulsive-like behavior. All of the ADHD-associated phenotypes respond to a single administration of a therapeutic equivalent dose of methylphenidate. In an earlier study, we showed that PNE produces hyperactivity, frontal cortical hypodopaminergic state and thinning of the cingulate cortex. Collectively, these data suggest that the PNE mouse model recapitulates key features of ADHD and may be a suitable preclinical model for ADHD research.
BackgroundPrevious studies established a possible link among hyperhomocysteinemia (HHcy), dyslipidemia, and atherosclerosis. However, there was limited epidemic data concerning the relation between HHcy and lipid profiles, especially in community-based Chinese populations. This study aim to investigate the association of plasma homocysteine (Hcy) level with lipid profiles in a Chinese community-based population without lipid-lowering treatment.MethodA total of 4660 Chinese subjects from a cohort of the Shijingshan district in Beijing were included in the analysis. Plasma total Hcy, serum lipid files including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) as well as relevant metabolic risk factors were measured. Multivariate regression models adjusting for age, gender, smoking, drinking, physical activity, vitamin B supplement, body mass index, fasting blood glucose level, serum creatinine, systolic and diastolic blood pressure were used to evaluate associations of Hcy and lipid profiles.ResultSubjects were 56.75 ± 8.91 years old, and 38.15% were male. Median (IQR) Hcy was 11.98 (10.00–14.93) μmol/L, and 24.4% had HHcy (defined as Hcy ≥ 15 μmol/L). Mean (SD) baseline TC was 5.34 ± 0.98 mmol/L, LDL-C was 3.27 ± 0.81 mmol/L, and HDL-C was 1.43 ± 0.38 mmol/L. Median (IQR) of TG was 1.28 (0.91–1.85) mmol/L. In multivariable linear-regression analyses, lnHcy (ln transformation for Hcy) level was positively associated with lnTG (adjusted β = 0.075, SE = 0.021, P = 0.001). Using Hcy < 15 μmol/L as a reference, HHcy was independently associated with both lnTG (adjusted β = 0.056, SE = 0.020, P = 0.004) and lnHDL (adjusted β = −0.018, SE = 0.009, P = 0.038). In multivariable logistic-regression analyses, HHcy was associated with increasing risk of low HDL-C (HDL-C < 1.04 mmol/L; adjusted odds ratio [OR] =1.406, 95% confidence interval [CI]: 1.143 – 1.728, P = 0.001) and hypertriglyceridemia (TG ≥ 1.7 mmol/L; adjusted OR = 1.293, 95% CI: 1.096–1.524, P = 0.002) after adjusting the confounders. However, there were no significant associations between Hcy and TC or LDL-C.ConclusionThe present study showed that HHcy was independently associated with hypertriglyceridemia and low levels of HDL-C, which provides evidence that Hcy levels might affect HDL-C and TG metabolism.
Abstract-This study aimed to investigate the association of noninvasive central aortic blood pressure with kidney function decline in a Chinese community-based population with normal kidney function at baseline. A total of 3153 Chinese participants from an atherosclerosis cohort were included in our analysis. The primary outcome was renal function decline defined as a drop in estimated glomerular filtration rate (eGFR) category accompanied by a ≥25% drop in eGFR from baseline; or a sustained decline in eGFR of >5 mL/min per 1.73 m 2 /y. The secondary outcomes were rapid eGFR decline (a decline in eGFR of >3 mL/min per 1.73 m 2 /y) and new incidence of chronic kidney disease. Participants were 56.6±8.5 years old, 36.0% were males, and 48.8% had hypertension. Mean (SD) baseline eGFR was 101.2±10.6 mL/min per 1.73 m 2 . After a mean 2.35-year follow-up, the incidence of renal function decline, rapid eGFR decline and chronic kidney disease were 7.3%, 19.7%, and 0.7%, respectively. In multivariate logistic-regression analyses, central and peripheral systolic blood pressure (SBP) were both independently associated with all outcomes after adjustment for various confounders. When peripheral SBP was forced into the model with central SBP simultaneously, its significant association with the 3 outcomes all disappeared; however, central SBP was still significantly related with all outcomes even after further adjusting peripheral SBP. In conclusion, central SBP is a stronger predictor compared with peripheral SBP for early kidney function decline in a Chinese communitybased population with normal kidney function at baseline.
Multiscale simulations have been performed to address the longstanding issue of “dioxygen activation” by the binuclear copper monooxygenases (PHM and DβM), which have been traditionally classified as “noncoupled” binuclear copper enzymes. Our QM/MM calculations rule out that CuM(II)-O2 • is an active species for H-abstraction from the substrate. In contrast, CuM(II)-O2 • would abstract an H atom from the cosubstrate ascorbate to form a CuM(II)-OOH intermediate in PHM and DβM. Consistent with the recently reported structural features of DβM, the umbrella sampling shows that the “open” conformation of the CuM(II)-OOH intermediate could readily transform into the “closed” conformation in PHM, in which we located a mixed-valent μ-hydroperoxodicopper(I,II) intermediate, (μ-OOH)Cu(I)Cu(II). The subsequent O–O cleavage and OH moiety migration to CuH generate the unexpected species (μ-O•)(μ-OH)Cu(II)Cu(II), which is revealed to be the reactive intermediate responsible for substrate hydroxylation. We also demonstrate that the flexible Met ligand is favorable for O–O cleavage reactions, while the replacement of Met with the strongly bound His ligand would inhibit the O–O cleavage reactivity. As such, the study not only demonstrates a “coupled” mechanism for O2 activation by binuclear copper monooxygenases but also deciphers the full catalytic cycle of PHM and DβM in accord with the available experimental data. These findings of O2 activation and substrate hydroxylation by binuclear copper monooxygenases could expand our understanding of the reactivities of the synthetic monocopper complexes.
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