Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker

A prerequisite to dephosphorylation at Ser–Pro or Thr–Pro motifs is the isomerization of the imidic peptide bond preceding the proline. The peptidyl-prolyl cis/trans isomerase named Pin1 catalyzes this mechanism. Through isomerization, Pin1 regulates the function of a growing number of targets including the microtubule-associated tau protein and is supposed to be deregulated Alzheimer's disease (AD). Using proteomics, we showed that Pin1 is posttranslationally modified on more than 5 residues, comprising phosphorylation, N-acetylation, and oxidation. Although Pin1 expression remained constant, Pin1 posttranslational two-dimensional pattern was modified by tau overexpression in a tau-inducible neuroblastoma cell line, in our THY-Tau22 mouse model of tauopathy as well as in AD. Interestingly, in all of these systems, Pin1 modifications were very similar. In AD brain tissue when compared with control, Pin1 is hyperphosphorylated at serine 16 and found in the most insoluble hyperphosphorylated tau fraction of AD brain tissue. Furthermore, in all tau pathology conditions, acetylation of Pin1 may also contribute to the differences observed. In conclusion, Pin1 displays several posttranslational modifications, which are specific in tauopathies and may be useful as biomarker.     

Biomonitoring and bioaccessibility of environmental airborne manganese in relation to motor function in a healthy adult population

Background/aimSantander, the capital of Cantabria, Spain (172,000 inhabitants) is 7 km from an industrial emission source (IES) of Mn located in a 10,000 inhabitants town (Maliaño) (annual air Mn arithmetic mean = 231.8 ng/m³; reference WHO guideline = 150 ng/m³). Our objective was to compare the motor function of adult healthy volunteers living in both places.MethodsCross-sectional study analyzing 130 consecutive participants. Exposure to Mn was assessed in terms of source distance from the IES, by Personal Environmental Monitors (PEMs) carried for 24 h by participants consisting of a portable impactor connected to a personal pump, and by biomarkers (blood, hair and fingernails). The impactor allowed the separation of fine (PM2.5) and coarse (PM10-2.5) particles and for each particle size in-vitro bioaccessibility tests with biologically active fluids were performed to separate the soluble (bioaccessible) from the insoluble (non-bioaccessible) fraction. Mean Differences (MDs) adjusted for age, sex, and study level, were obtained for motor function tests results.ResultsRegarding Grooved Pegboard, overall mean time to complete the test was 59.31 and 65.27 seconds (Standard Deviation = 10.11 and 11.69) for dominant and nondominant hands respectively. Statistically significant higher times (indicating worse function) were observed when living near the IES in both hands but MDs of only 1.22 and 2.05 seconds were obtained after adjusting for the predefined confounders (p = 0.373 and 0.221 respectively). Regarding Mn levels in their PEMs (in both bioaccessible and non-bioaccessible coarse&fine fractions) higher times were computed in participants with higher levels for the bioaccessible-fine fraction, with a MD that diminished but still yielded statistical significance after controlling for confounding: adjusted MD = 3.01 more seconds; 95%CI (0.44–5.38), p = 0.022. Poorer results were also observed for fingernails levels. Regarding Finger Tapping Test, no statistically significant differences were found with the exception of Mn fingernails levels.ConclusionsOur results suggest poorer motor function as assessed by Grooved Pegboard test in relation to “proximity to IES”, “bioaccessible-fine fraction as determined by PEMs and “Mn fingernails levels”. However, our findings were affected by confounding, and only the adjusted MD for the Mn bioaccessible-fine fraction remained of sufficient magnitude to maintain statistical significance.     

Serum neurofilament is associated with motor function,cognitive decline and subclinical cardiac damage in advanced Parkinson's disease (MARK-PD)

IntroductionSerum neurofilament light chain (NfL) levels are associated with disease severity in early Parkinson's disease (PD). We assessed the association of serum NfL with motor and cognitive function and decline in advanced PD patients.MethodsNfL concentrations were analyzed with single molecule array (Simoa) assay in serum of 289 PD patients with advanced disease from the single-center prospective observational biobank study Biomarkers in Parkinson's disease (MARK-PD). Motor and cognitive symptoms were assessed with MDS-UPDRS III, Hoehn&Yahr stages and Montreal Cognitive Assessment (MoCA) at baseline and during 520 [364, 674] days of follow-up.ResultsSerum NfL concentrations were associated with Hoehn&Yahr stages. During follow-up, baseline NfL levels were associated with time to cognitive decline in adjusted Cox regression models (hazard ratio: 3.23; 95% CI [1.16, 9.00], P < 0.025). Serum NfL was associated with NT-proBNP in adjusted models linking neuronal and cardiac damage in advanced PD patients.ConclusionIn advanced PD patients, serum NfL concentrations are associated with motor function, cognitive decline and subclinical cardiac damage.     

Biomarkers for the Prediction and Diagnosis of Fibrostenosing Crohn’s Disease: A Systematic Review

1. Download : Download high-res image (161KB)
2. Download : Download full-size image

     

Th‐17 Alloimmune Responses in Renal Allograft Biopsies From Recipients of Kidney Transplants Using Extended Criteria Donors During Acute T Cell–Mediated Rejection

Although renal transplantation using expanded criteria donors has become a common practice, immune responses related to immunosenescence in those kidney allografts have not been studied yet in humans. We performed a retrospective molecular analysis of the T cell immune response in 43 kidney biopsies from patients with acute T cell–mediated rejection including 25 from recipients engrafted with a kidney from expanded criteria donor and 18 from recipients grafted with optimal kidney allograft. The clinical, transplant and acute T cell–mediated rejection characteristics of both groups were similar at baseline. The expression of RORγt, Il‐17 and T‐bet mRNA was significantly higher in the elderly than in the optimal group (p = 0.02, p = 0.036, and p = 0.01, respectively). Foxp3 mRNA levels were significantly higher in elderly patients experiencing successful acute T cell–mediated rejection reversal (p = 0.03). The presence of IL‐17 mRNA was strongly associated with nonsuccessful reversal in elderly patients (p = 0.008). Patients with mRNA IL17 expression detection and low mRNA Foxp3 expression experienced significantly more treatment failure (87.5%) than patients with no mRNA IL17 expression and/or high mRNA Foxp3 expression (26.7%; p = 0.017). Our study suggests that the Th17 pathway is involved in pathogenesis and prognosis of acute T cell–mediated rejection in recipients of expanded criteria allograft.     

miRNA在冠心病中的作用机制

MicroRNA(miRNA)是一类新发现的非编码小RNA分子.近来研究表明,miRNA在冠心病的发病机制中都起到了重要的调控作用,有望成为新型的特异性心肌损伤标记物及药物治疗的新靶点.本文系统性总结了近年来miRNA在冠心病领域的相关研究成果,并对其在临床中的应用价值进行了探讨.     

降钙素原指导慢性阻塞性肺疾病急性加重抗生素治疗的研究进展

急性加重是慢性阻塞性肺疾病(COPD)进展过程中的自然现象,而且在全球范围内的发病率和病死率居高不下。生物标志物(如降钙素原)的检测已经成为诊断及指导COPD抗生素治疗的一种重要工具。然而,关于降钙素原指导COPD治疗的潜在作用仍在临床研究阶段。该文将通过目前国内外现有的证据证明降钙素原可以用于指导COPD的抗生素治疗。