Assessing the contribution of the chemical exposome to neurodegenerative disease.

Over the past few decades, numerous environmental chemicals from solvents to pesticides have been suggested to be involved in the development and progression of neurodegenerative diseases. Most of the evidence has accumulated from occupational or cohort studies in humans or laboratory research in animal models, with a range of chemicals being implicated. What has been missing is a systematic approach analogous to genome-wide association studies, which have identified dozens of genes involved in Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases. Fortunately, it is now possible to study hundreds to thousands of chemical features under the exposome framework. This Perspective explores how advances in mass spectrometry make it possible to generate exposomic data to complement genomic data and thereby better understand neurodegenerative diseases.

Human sperm cells can form paracetamol metabolite AM404 that directly interferes with sperm calcium signalling and function through a CatSper-dependent mechanism.

STUDY QUESTION: Do paracetamol (N-acetyl-para-aminophenol (APAP) or acetaminophen) and/or its metabolites affect human sperm Ca2+-signalling and function? SUMMARY ANSWER: While APAP itself does not interact with Ca2+-signalling in human sperm, its metabolite N-arachidonoyl phenolamine (AM404), produced via fatty acid amide hydrolase (FAAH), interferes with human sperm Ca2+-signalling and function through a suggested CatSper channel-dependent action. WHAT IS KNOWN ALREADY: Studies have shown that adult men with high urinary levels of over-the-counter mild analgesic APAP have impaired sperm motility and increased time-to-pregnancy. STUDY DESIGN, SIZE, DURATION: This study consists of (i) an in vivo human pharmaceutical APAP exposure experiment to understand to what degree APAP reaches the sperm cells in the seminal fluid; (ii) in vitro calcium imaging and functional experiments in freshly donated human sperm cells to investigate CatSper channel-dependent activation by APAP and its metabolites; and (iii) experiments to understand the in situ capabilities of human sperm cells to form APAP metabolite AM404. PARTICIPANTS/MATERIALS, SETTING, METHODS: Three healthy young males participated in the in vivo human exposure experiment after prior consent. Human semen samples were provided by healthy young volunteer donors after prior consent on the day of the in vitro experiments. MAIN RESULTS AND THE ROLE OF CHANCE: Pharmaceutical APAP exposure reaches the seminal plasma in high micromolar concentrations and accumulates in the seminal plasma between 3 and 5 days of exposure (P-value 0.023). APAP and its primary metabolite 4-aminophenol (4AP) do not interact with human sperm Ca2+-signalling. Instead, the APAP metabolite AM404 produced via FAAH interferes with human sperm Ca2+-signalling through a CatSper-dependent action. Also, AM404 significantly increases sperm cell penetration into viscous mucous (P-value of 0.003). FAAH is functionally expressed in human sperm cells in the neck/midpiece region, as evidenced by immunohistochemical staining and the ability of human sperm cells to hydrolyse the fluorogenic FAAH substrate arachidonyl 7-amino, 4-methyl coumarin amide in an FAAH-dependent manner. Importantly, human sperm cells have the capacity to form AM404 in situ after exposure to 4AP (P-value 0.0402 compared to vehicle-treated sperm cells). LIMITATIONS, REASONS FOR CAUTION: The experiments were conducted largely in vitro. Future studies are needed to test whether APAP can disrupt human sperm function in vivo through the action of AM404. WIDER IMPLICATIONS OF THE FINDINGS: We hypothesize that these observations could, at least in part, be responsible for the negative association between male urinary APAP concentrations, sperm motility and time-to-pregnancy. STUDY FUNDING/COMPETING INTEREST(S): D.M.K. is funded by the Lundbeck Foundation, grant number R324-2019-1881, and the Svend Andersen Foundation. A.R. is funded by a BRIDGE-Translational Excellence Programme grant funded by the Novo Nordisk Foundation, grant agreement number: NNF18SA0034956. All authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Characterization of novel human intragenic antimicrobial peptides, incorporation and release studies from ureasil-polyether hybrid matrix.

Intragenic antimicrobial peptides (IAPs) are internal sequences of proteins with physicochemical similarities to Antimicrobial Peptides (AMPs) that, once identified and synthesized as individual entities, present antimicrobial activity. Many mature proteins encoded by the genomes of virtually any organism may be regarded as inner reservoirs of IAPs, conferring them ample biotechnological potential. However, IAPs may also share shortcomings with AMPs, such as low half-life in biological media and non-specific adsorption in eukaryotic cells. The present manuscript reports a translational approach that encompasses the uncovering of two novel IAPs from human proteins as well as the first results concerning the incorporation and sustained release of one of these peptides from ureasil-polyether hybrid polymeric films. For such, the software Kamal was used to scan putative IAPs in the human proteome, and two peptides, named Hs05 and Hs06, were identified, synthesized, and tested as antimicrobials. Biophysical assays were conducted using model phospholipid vesicles and 1H NMR solution structures in phospholipid micelles were obtained for the IAP Hs05. This peptide was incorporated in a polymeric matrix composed of the ureasil/PPO-PEO-PPO triblock copolymer, and the resulting films were evaluated by atomic force microscopy and imaging mass spectrometry. The release rate of Hs05 from the polymeric matrix was assessed and the antimicrobial activity of Hs05-loaded hybrid polymeric films was evaluated against the bacterium Escherichia coli. This study represents the first steps towards the development of polymeric films enriched with IAPs obtained from the human proteome as sustained release devices for topical application.

Modeling the fate of organic nitrogen during anaerobic digestion: Development of a bioaccessibility based ADM1.

Simulating the fate of nitrogen during anaerobic digestion is required to predict the characteristics of digestates and to improve their exploitation for agricultural uses. The aim of this study was to develop a modified ADM1 model that includes bioaccessibility-based fractionation to accurately simulate the fate of nitrogen during anaerobic digestion. To this end, two complementary approaches were used: (i) changes in the bioaccessibility of protein and non-protein compounds were assessed on eight substrates during anaerobic digestion in batch experiments using the "EPS" fractionation method; (ii) experimental results were used to develop a bio-kinetic model based on anaerobic digestion model n°1. This new model incorporates bioaccessibility-based fractionation in its input state variables. The model was successfully calibrated and model evaluation showed that predicted methane production, ammonium production and changes in protein and non-protein bioaccessibility during anaerobic digestion were accurate.

Soil forensics: How far can soil clay analysis distinguish between soil vestiges?

Soil traces are useful as forensic evidences because they frequently adhere to individuals and objects associated with crimes and can place or discard a suspect at/from a crime scene. Soil is a mixture of organic and inorganic components and among them soil clay contains signatures that make it reliable as forensic evidence. In this study, we hypothesized that soils can be forensically distinguished through the analysis of their clay fraction alone, and that samples of the same soil type can be consistently distinguished according to the distance they were collected from each other. To test these hypotheses 16 Oxisol samples were collected at distances of between 2m and 1.000m, and 16 Inceptisol samples were collected at distances of between 2m and 300m from each other. Clay fractions were extracted from soil samples and analyzed for hyperspectral color reflectance (HSI), X-ray diffraction crystallographic (XRD), and for contents of iron oxides, kaolinite and gibbsite. The dataset was submitted to multivariate analysis and results were from 65% to 100% effective to distinguish between samples from the two soil types. Both soil types could be consistently distinguished for forensic purposes according to the distance that samples were collected from each other: 1000m for Oxisol and 10m for Inceptisol. Clay color and XRD analysis were the most effective techniques to distinguish clay samples, and Inceptisol samples were more easily distinguished than Oxisol samples. Soil forensics seems a promising field for soil scientists as soil clay can be useful as forensic evidence by using routine analytical techniques from soil science.

Reducing size-dispersion in one-pot aqueous synthesis of maghemite nanoparticles.

Nanosized maghemite-like particles with reduced size-distribution were obtained using a one-pot synthesis route in aqueous medium. Forced hydrolysis of iron ions in ammoniac solution led to the formation of magnetite nanoparticles that were oxidized to maghemite in a hydrothermal digestion step that reduced the polydispersity of nanograins. The prepared nanoparticles were characterized by chemical analysis, X-ray diffractometry, magnetization, Raman spectroscopy and transmission electron microscopy measurements. Data showed that 14 nm-sized particles with polydispersity of about 0.14 were produced and, differently from other procedures, neither additional steps nor toxic reagents were needed to reduce size-dispersion or to oxidize magnetite to maghemite. These facts per se turn such nanodevice into a good potential choice for biomedical applications.