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In a randomized trial, patients with brain amyloid deposition but no dementia who received a β-site amyloid precursor protein–cleaving enzyme 1 inhibitor had no benefit with respect to clinical outcomes and worsening on some measures of cognition and daily function.

Background/Objectives: This study characterized the endogenous peptide profile of human milk from a Chinese multicenter cohort (n = 200 mothers) using the Orbitrap Fusion Lumos LC-MS/MS. Methods: Samples were collected across different lactation stages (2 and 6 months postpartum) and seven geographic regions (Beijing, Chengdu, Guangzhou, Jinhua, Lanzhou, Weihai, and Zhengzhou). Results: In total, 6960 peptides derived from 621 proteins were identified. Peptides from the polymeric immunoglobulin receptor (PIGR) were more abundant in the 2nd month than the 6th month, providing a high antimicrobial activity and immune functions for the infants. Moreover, region-specific variations were observed, with milk from Lanzhou exhibiting significantly higher levels of β-casein (CASB) and butyrophilin subfamily 1 member A1 (BTN1A1) peptides compared to other cities. Conclusions: Furthermore, maternal dietary intake of oils and total fat correlated positively with the intensity of specific antimicrobial peptides, including CASB_199–216, CASB_200–226, and CASB_201–226. Infant growth parameters were inversely correlated with several antimicrobial peptides, although CASB_200–225 demonstrated positive associations. These findings offer novel insights into the dynamics of endogenous peptides in human milk and may guide breastfeeding recommendations and infant formula design.

By incorporating a high proton affinity moiety to the charge localized free radical-initiated peptide sequencing (CL-FRIPS) reagent, FRIPS-MS technique has extended the applicability to hydrophobic peptides and peptides without basic amino acid residues (lysine, arginine, and histidine). Herein, the CL-FRIPS reagent has three moieties: (1) pyridine acting as the basic site to locate the proton, (2) 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO, a stable free radical) acting as the free radical precursor to generate the nascent free radical in the gas phase, and (3) N-hydroxysuccinimide (NHS) activated carboxylic acid acting as the coupling site to derivatize the N-terminus of peptides. The CL-FRIPS reagent allows for the characterization of peptides by generating sequencing ions, enzymatic cleavage-like radical-induced side chain losses, and the loss of TEMPO simultaneously via one-step collisional activation. Further collisional activation of enzymatic cleavage-like radical-induced side chain loss ions provides more information for the structure determination of peptides. The application of CL-FRIPS reagent to characterize peptides is proved by employing bovine insulin as the model peptide. Both scaffold structure of bovine insulin and sequencing information of each chain are achieved.Graphical Abstractᅟ

Previous studies have reported that natriuretic peptides in the blood and pleural fluid (PF) are effective diagnostic markers for heart failure (HF). These natriuretic peptides include N-terminal pro-brain natriuretic peptide (NT-proBNP), brain natriuretic peptide (BNP), and midregion pro-atrial natriuretic peptide (MR-proANP). This systematic review and meta-analysis evaluates the diagnostic accuracy of blood and PF natriuretic peptides for HF in patients with pleural effusion. PubMed and EMBASE databases were searched to identify articles published in English that investigated the diagnostic accuracy of BNP, NT-proBNP, and MR-proANP for HF. The last search was performed on 9 October 2014. The quality of the eligible studies was assessed using the revised Quality Assessment of Diagnostic Accuracy Studies tool. The diagnostic performance characteristics (sensitivity, specificity, and other measures of accuracy) were pooled and examined using a bivariate model. In total, 14 studies were included in the meta-analysis, including 12 studies reporting the diagnostic accuracy of PF NT-proBNP and 4 studies evaluating blood NT-proBNP. The summary estimates of PF NT-proBNP for HF had a diagnostic sensitivity of 0.94 (95% confidence interval [CI]: 0.90-0.96), specificity of 0.91 (95% CI: 0.86-0.95), positive likelihood ratio of 10.9 (95% CI: 6.4-18.6), negative likelihood ratio of 0.07 (95% CI: 0.04-0.12), and diagnostic odds ratio of 157 (95% CI: 57-430). The overall sensitivity of blood NT-proBNP for diagnosis of HF was 0.92 (95% CI: 0.86-0.95), with a specificity of 0.88 (95% CI: 0.77-0.94), positive likelihood ratio of 7.8 (95% CI: 3.7-16.3), negative likelihood ratio of 0.10 (95% CI: 0.06-0.16), and diagnostic odds ratio of 81 (95% CI: 27-241). The diagnostic accuracy of PF MR-proANP and blood and PF BNP was not analyzed due to the small number of related studies. BNP, NT-proBNP, and MR-proANP, either in blood or PF, are effective tools for diagnosis of HF. Additional studies are needed to rigorously evaluate the diagnostic accuracy of PF and blood MR-proANP and BNP for the diagnosis of HF.

We examined preadipocyte differentiation in obese and nonobese individuals and the effect of cytokines and wingless-type MMTV (mouse mammary tumor virus) integration site family, member 3A (Wnt3a) protein on preadipocyte differentiation and phenotype. Abdominal subcutaneous adipose tissue biopsies were obtained from a total of 51 donors with varying BMI. After isolation of the adipose and stromalvascular cells, inflammatory cells (CD14- and CD45-positive cells) were removed by immune magnetic separation. CD133-positive cells, containing early progenitor cells, were also isolated and quantified. The CD14- and CD45-negative preadipocytes were cultured with tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, resistin, or Wnt3a with or without a differentiation cocktail. The number of preadipocytes able to differentiate to adipose cells was negatively correlated with both BMI and adipocyte cell size of the donors, whereas the number of CD133-positive cells was positively correlated with BMI, suggesting an impaired differentiation of preadipocytes in obesity. Cultured preadipocytes, like freshly isolated mature adipocytes, from obese individuals had an increased expression of mitogen-activated protein 4 kinase 4 (MAP4K4), which is known to inhibit peroxisome proliferator-activated receptor-gamma induction. TNF-alpha, but not IL-6 or resistin, increased Wnt10b, completely inhibited the normal differentiation of the preadipocytes, and instead induced a proinflammatory and macrophage-like phenotype of the cells. The apparent number of preadipocytes in the abdominal subcutaneous tissue that can undergo differentiation is reduced in obesity with enlarged fat cells, possibly because of increased MAP4K4 levels. TNF-alpha promoted a macrophage-like phenotype of the preadipocytes, including several macrophage markers. These results document the plasticity of human preadipocytes and the inverse relationship between lipid storage and proinflammatory capacity.

The interaction of protein and peptide amyloid oligomers with membranes is thought to be one of the mechanisms contributing to cellular toxicity. However, techniques to study these interactions in the complex membrane environment of live cells are lacking. Spectral phasor analysis is a recently developed biophysical technique that can enable visualisation and analysis of membrane-associated fluorescent dyes. When the spectral profile of these dyes changes as a result of changes to the membrane microenvironment, spectral phasor analysis can localise those changes to discrete membrane regions. In this study, we investigated whether spectral phasor analysis could detect changes in the membrane microenvironment of live cells in the presence of fibrillar aggregates of the disease-related Aβ42 peptide or the functional amyloid neurokinin B. Our results show that the fibrils cause distinct changes to the microenvironment of nile red associated with both the plasma and the nuclear membrane. We attribute these shifts in nile red spectral properties to changes in membrane fluidity. Results from this work suggest that cells have mechanisms to avoid or control membrane interactions arising from functional amyloids which have implications for how these peptides are stored in dense core vesicles. Furthermore, the work highlights the utility of spectral phasor analysis to monitor microenvironment changes to fluorescent probes in live cells.

Neurogenic inflammation is involved in the development and progression of respiratory inflammatory diseases. However, its role in community-acquired pneumonia (CAP) remains unclear. We therefore aimed to investigate plasma levels of neurogenic inflammation-related neuropeptides, calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY), and procalcitonin (PCT) in pediatric patients with CAP and to assess their diagnostic value in viral and bacterial/mixed pneumonia. A total of 124 pediatric patients with CAP (1 month-18 years old) and 56 healthy children of similar ages were prospectively enrolled. The patients were classified as viral (n = 99) and bacterial/mixed (n = 25) pneumonia. Plasma levels of the peptides were quantified by ELISA. ROC analysis was performed to evaluate possible diagnostic value of the peptides. While plasma levels of CGRP, VIP and PCT were significantly higher in patients with CAP than in the control group, respectively, NPY levels were significantly lower. Moreover, plasma levels of all neuropeptides and PCT were significantly higher in bacterial pneumonia patients compared to viral pneumonia patients. ROC analysis revealed that CGRP, SP and NPY had a diagnostic value in distinguishing viral and bacterial/mixed pneumonia. Conclusions : Our findings suggest that these neuropeptides may be implicated in pediatric CAP. CGRP, SP and NPY together may be a promising candidate in distinguishing viral and bacterial/mixed pneumonia, however, for this, further studies are needed. What is Known: • Neurogenic inflammation contributes to the development and progression of respiratory inflammatory diseases such as chronic obstructive pulmonary disease and bronchial asthma. What is New: • Plasma levels of neurogenic inflammation related neuropeptides calcitonin gene-related peptide, substance P, vasoactive intestinal peptide and neuropeptide Y are changed in pediatric community-acquired pneumonia. Calcitonin gene-related peptide, substance P and neuropeptide Y are promising candidates in distinguishing viral and bacterial/mixed pneumonia.

ObjectivesThis study aimed to characterise diurnal dynamics of salivary peptidome and variations induced by sampling procedures.Materials and methodsA supervised short-term longitudinal study was conducted amongst ten healthy participants. Saliva samples were collected by different procedures (stimulated/unstimulated conditions, forepart/midstream segments) on three consecutive days. The peptidome compositions of saliva samples were analysed using matrix-assisted laser desorption/ionisation-time of flight-mass spectrometry (MALDI-TOF MS).ResultsThe salivary peptidome exhibited a stable trend generally, even though some diurnal dynamics happened in aspects of both overall structure and certain single peptides. The results indicated saliva samples collected under unstimulated and stimulated conditions have significantly different structures of peptidome, whilst the peptidome profile of stimulated saliva was more abundant than that of unstimulated saliva. It was also indicated that the midstream segment effect might exist in the segmented process of saliva sampling.ConclusionsIn summary, salivary peptidome was able to maintain stability though some dynamic changes might happen within a short-term period. Stimulated and unstimulated saliva samples had significantly different peptidome profiles, whilst the stimulated whole saliva was a larger pool of low molecular weight peptides.Clinical relevanceThe stability of the salivary peptidome highlights the reliability of salivary peptidome as a source of diagnostic biomarker. We recommend keeping one collection condition (stimulated/unstimulated) consistently within one study on salivary peptidome. Stimulated whole saliva would be preferred if more abundant peptidome profile is needed.

Histone acetylation is generally associated with gene activation and chromatin decondensation. Recent mass spectrometry analysis has revealed that histone H4 lysine 20, a major methylation site, can also be acetylated. To understand the function of H4 lysine 20 acetylation (H4K20ac), we have developed a specific monoclonal antibody and performed ChIP-seq analysis using HeLa-S3 cells. H4K20ac was enriched around the transcription start sites (TSSs) of minimally expressed genes and in the gene body of expressed genes, in contrast to most histone acetylation being enriched around the TSSs of expressed genes. The distribution of H4K20ac showed little correlation with known histone modifications, including histone H3 methylations. A motif search in H4K20ac-enriched sequences, together with transcription factor binding profiles based on ENCODE ChIP-seq data, revealed that most transcription activators are excluded from H4K20ac-enriched genes and a transcription repressor NRSF/REST co-localized with H4K20ac. These results suggest that H4K20ac is a unique acetylation mark associated with gene repression.

Alzheimer's disease (AD) pathology is common in patients with amnestic mild cognitive impairment (aMCI) without dementia, but the prevalence of AD pathology in patients with subjective cognitive impairment (SCI) and non-amnestic mild cognitive impairment (naMCI) is unknown. AD is characterised by decreased CSF concentrations of Aβ 42 and increased concentrations of tau. We investigated the prevalence of a CSF AD profile in patients with SCI, naMCI, or aMCI and the association of this profile with cognitive outcome in each group. Patients with SCI, naMCI, aMCI, and neurologically healthy controls were recruited from 20 memory clinics across Europe, between January, 2003, and June, 2005, into this prospective cohort study. A CSF AD profile was defined as an abnormal ratio of Aβ 42:tau. Patients were assessed annually up to 3 years. Outcome measures were changes in memory, overall cognition, mini-mental state examination (MMSE) score, daily function, and progression to AD-type dementia. The CSF AD profile was more common in patients with SCI (31 of 60 [52%]), naMCI (25 of 37 [68%]), and aMCI (56 of 71 [79%]) than in healthy controls (28 of 89 [31%]). The profile was associated with cognitive decline in patients with naMCI (memory, MMSE, and daily function) and in patients with aMCI (MMSE and daily function). In patients with aMCI, a CSF AD profile was predictive of AD-type dementia (OR 26·8, 95% CI 1·6–456·4). AD is a common cause of SCI, naMCI, and aMCI and is associated with cognitive decline in patients with naMCI or aMCI. Patients with SCI might be in the early stages of AD, and cognitive decline might become apparent only after longer follow-up. European Commission; Ana Aslan International Foundation.