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Parkinson’s Disease (PD) is a common neurodegenerative disorder affecting millions of people worldwide for which there are only symptomatic therapies. Small molecules able to target key pathological processes in PD have emerged as interesting options for modifying disease progression. We have previously shown that a (poly)phenol-enriched fraction (PEF) of Corema album L. leaf extract modulates central events in PD pathogenesis, namely α-synuclein (αSyn) toxicity, aggregation and clearance. PEF was now subjected to a bio-guided fractionation with the aim of identifying the critical bioactive compound. We identified genipin, an iridoid, which relieves αSyn toxicity and aggregation. Furthermore, genipin promotes metabolic alterations and modulates lipid storage and endocytosis. Importantly, genipin was able to prevent the motor deficits caused by the overexpression of αSyn in a Drosophila melanogaster model of PD. These findings widens the possibility for the exploitation of genipin for PD therapeutics. In this work, the authors identify Genipin as a small iridoid able to prevent alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage.

Very solid evidence suggests that the core of full length PrPSc is a 4-rung β-solenoid, and that individual PrPSc subunits stack to form amyloid fibers. We recently used limited proteolysis to map the β-strands and connecting loops that make up the PrPSc solenoid. Using high resolution SDS-PAGE followed by epitope analysis, and mass spectrometry, we identified positions ~116/118, 133-134, 141, 152-153, 162, 169 and 179 (murine numbering) as Proteinase K (PK) cleavage sites in PrPSc. Such sites likely define loops and/or borders of β-strands, helping us to predict the threading of the β-solenoid. We have now extended this approach to recombinant PrPSc (recPrPSc). The term recPrPSc refers to bona fide recombinant prions prepared by PMCA, exhibiting infectivity with attack rates of ~100%. Limited proteolysis of mouse and bank vole recPrPSc species yielded N-terminally truncated PK-resistant fragments similar to those seen in brain-derived PrPSc, albeit with varying relative yields. Along with these fragments, doubly N- and C-terminally truncated fragments, in particular ~89/97-152, were detected in some recPrPSc preparations; similar fragments are characteristic of atypical strains of brain-derived PrPSc. Our results suggest a shared architecture of recPrPSc and brain PrPSc prions. The observed differences, in particular the distinct yields of specific PK-resistant fragments, are likely due to differences in threading which result in the specific biochemical characteristics of recPrPSc. Furthermore, recombinant PrPSc offers exciting opportunities for structural studies unachievable with brain-derived PrPSc.

Edible berries are considered to be among nature's treasure chests as they contain a large number of (poly)phenols with potentially health-promoting properties. However, as berries contain complex (poly)phenol mixtures, it is challenging to associate any interesting pharmacological activity with a single compound. Thus, identification of pharmacologically interesting phenols requires systematic analyses of berry extracts. Here, raspberry (Rubus idaeus, var Prestige) extracts were systematically analyzed to identify bioactive compounds against pathological processes of neurodegenerative diseases. Berry extracts were tested on different Saccharomyces cerevisiae strains expressing disease proteins associated with Alzheimer's, Parkinson's, or Huntington's disease, or amyotrophic lateral sclerosis. After identifying bioactivity against Huntington's disease, the extract was fractionated and the obtained fractions were tested in the yeast model, which revealed that salidroside, a glycosylated phenol, displayed significant bioactivity. Subsequently, a metabolic route to salidroside was reconstructed in S. cerevisiae and Corynebacterium glutamicum. The best-performing S. cerevisiae strain was capable of producing 2.1 mM (640 mg L⁻¹) salidroside from Glc in shake flasks, whereas an engineered C. glutamicum strain could efficiently convert the precursor tyrosol to salidroside, accumulating up to 32 mM (9,700 mg L⁻¹) salidroside in bioreactor cultivations (yield: 0.81 mol mol⁻¹). Targeted yeast assays verified that salidroside produced by both organisms has the same positive effects as salidroside of natural origin.

Triclosan 0.5% by scrubbing does not meet the UNE-EN12791 criteria to be used in the surgical hand preparation (SHP). Triclosan 0.5% by scrubbing followed by ethanol 70% hand rubbing is suitable without the additional characteristic of sustained effect. This limited effectiveness implies that triclosan should be avoided in SHP given the restrictions on its use in consumer antiseptic products. The trial was registered at ClinicalTrials.gov (ID: NCT04538365).

Human transmissible spongiform encephalopathies (TSEs) or prion diseases are a group of fatal neurodegenerative disorders that include Kuru, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia. GSS is a genetically determined TSE caused by a range of mutations within the prion protein (PrP) gene. Several animal models, based on the expression of PrPs carrying mutations analogous to human heritable prion diseases, support that mutations might predispose PrP to spontaneously misfold. An adapted Protein Misfolding Cyclic Amplification methodology based on the use of human recombinant PrP (recPMCA) generated different self-propagating misfolded proteins spontaneously. These were characterized biochemically and structurally, and the one partially sharing some of the GSS PrP Sc molecular features was inoculated into different animal models showing high infectivity. This constitutes an infectious recombinant prion which could be an invaluable model for understanding GSS. Moreover, this study proves the possibility to generate recombinant versions of other human prion diseases that could provide a further understanding on the molecular features of these devastating disorders.

Very solid evidence suggests that the core of full length PrP.sup.Sc is a 4-rung [beta]-solenoid, and that individual PrP.sup.Sc subunits stack to form amyloid fibers. We recently used limited proteolysis to map the [beta]-strands and connecting loops that make up the PrP.sup.Sc solenoid. Using high resolution SDS-PAGE followed by epitope analysis, and mass spectrometry, we identified positions 116/118, 133-134, 141, 152-153, 162, 169 and 179 (murine numbering) as Proteinase K (PK) cleavage sites in PrP.sup.Sc . Such sites likely define loops and/or borders of [beta]-strands, helping us to predict the threading of the [beta]-solenoid. We have now extended this approach to recombinant PrP.sup.Sc (recPrP.sup.Sc). The term recPrP.sup.Sc refers to bona fide recombinant prions prepared by PMCA, exhibiting infectivity with attack rates of 100%. Limited proteolysis of mouse and bank vole recPrP.sup.Sc species yielded N-terminally truncated PK-resistant fragments similar to those seen in brain-derived PrP.sup.Sc, albeit with varying relative yields. Along with these fragments, doubly N- and C-terminally truncated fragments, in particular 89/97-152, were detected in some recPrP.sup.Sc preparations; similar fragments are characteristic of atypical strains of brain-derived PrP.sup.Sc . Our results suggest a shared architecture of recPrP.sup.Sc and brain PrP.sup.Sc prions. The observed differences, in particular the distinct yields of specific PK-resistant fragments, are likely due to differences in threading which result in the specific biochemical characteristics of recPrP.sup.Sc . Furthermore, recombinant PrP.sup.Sc offers exciting opportunities for structural studies unachievable with brain-derived PrP.sup.Sc.

BACterial Hosts for production of Bioactive phenolics from bERRY fruits (BacHBerry) was a 3-year project funded by the Seventh Framework Programme (FP7) of the European Union that ran between November 2013 and October 2016. The overall aim of the project was to establish a sustainable and economically-feasible strategy for the production of novel high-value phenolic compounds isolated from berry fruits using bacterial platforms. The project aimed at covering all stages of the discovery and pre-commercialization process, including berry collection, screening and characterization of their bioactive components, identification and functional characterization of the corresponding biosynthetic pathways, and construction of Gram-positive bacterial cell factories producing phenolic compounds. Further activities included optimization of polyphenol extraction methods from bacterial cultures, scale-up of production by fermentation up to pilot scale, as well as societal and economic analyses of the processes. This review article summarizes some of the key findings obtained throughout the duration of the project.

Very solid evidence suggests that the core of full length PrPSc is a 4-rung β-solenoid, and that individual PrPSc subunits stack to form amyloid fibers. We recently used limited proteolysis to map the β-strands and connecting loops that make up the PrPSc solenoid. Using high resolution SDS-PAGE followed by epitope analysis, and mass spectrometry, we identified positions ~116/118, 133–134, 141, 152–153, 162, 169 and 179 (murine numbering) as Proteinase K (PK) cleavage sites in PrPSc. Such sites likely define loops and/or borders of β-strands, helping us to predict the threading of the β-solenoid. We have now extended this approach to recombinant PrPSc (recPrPSc). The term recPrPSc refers to bona fide recombinant prions prepared by PMCA, exhibiting infectivity with attack rates of ~100%. Limited proteolysis of mouse and bank vole recPrPSc species yielded N-terminally truncated PK-resistant fragments similar to those seen in brain-derived PrPSc, albeit with varying relative yields. Along with these fragments, doubly N- and C-terminally truncated fragments, in particular ~89/97-152, were detected in some recPrPSc preparations; similar fragments are characteristic of atypical strains of brain-derived PrPSc. Our results suggest a shared architecture of recPrPSc and brain PrPSc prions. The observed differences, in particular the distinct yields of specific PK-resistant fragments, are likely due to differences in threading which result in the specific biochemical characteristics of recPrPSc. Furthermore, recombinant PrPSc offers exciting opportunities for structural studies unachievable with brain-derived PrPSc.

ObjectiveTo quantify the implementation of the third Joint British Societies’ Consensus Recommendations for the Prevention of Cardiovascular Disease (JBS3) after coronary event.MethodsUsing a cross-sectional survey design, patients were consecutively identified in 36 specialist and district general hospitals between 6 months and 2 years, after acute coronary syndrome or revascularisation procedure and invited to a research interview. Outcomes included JBS3 lifestyle, risk factor and therapeutic management goals. Data were collected using standardised methods and instruments by trained study nurses. Blood was analysed in a central laboratory and a glucose tolerance test was performed.Results3926 eligible patients were invited to participate and 1177 (23.3% women) were interviewed (30% response). 12.5% were from black and minority ethnic groups. 45% were persistent smokers, 36% obese, 52.9% centrally obese, 52% inactive; 30% had a blood pressure >140/90 mm Hg, 54% non-high-density lipoprotein ≥2.5 mmol/L and 44.3% had new dysglycaemia. Prescribing was highest for antiplatelets (94%) and statins (85%). 81% were advised to attend cardiac rehabilitation (86% <60 years vs 79% ≥60 years; 82% men vs 77% women; 93% coronary artery bypass grafting vs 59% unstable angina), 85% attended if advised; 69% attended overall. Attenders were significantly younger (p=0.03) and women were less likely to attend (p=0.03).ConclusionsPatients with coronary heart disease (CHD) are not being adequately managed after event with preventive measures. They require a structured preventive cardiology programme addressing lifestyle, risk factor management and adherence to cardioprotective medications to achieve the standards set by the British Association for Cardiovascular Prevention and Rehabilitation and JBS3 guidelines.

To investigate β-lactam effects on Streptococcus pneumoniae -mixed cultures, a computerized pharmacodynamic model simulating over 24-hr concentrations obtained after several β-lactam regimens was used. Strain 1 (no penicillin binding protein [PBP] mutations) and strain 2 (mutation in pbp1a ) were penicillin/amoxicillin susceptible. Strain 3 (mutations in pbp1a , pbp2x , and pbp2b ) and strain 4 (mutations in pbp1a , pbp2x , and pbp2b [10 changes]) were penicillin/amoxicillin resistant. Initial inoculum was approximately 6 × 10 6 CFU (colony forming units)/ml (with a 1:1:1:1 proportion of each strain). Population analysis profile was performed pre- and postsimulations. Strain 1 exhibited the best fitness (growth over 24 hr) in individual cultures, and strain 2 did so in mixed cultures in antibiotic-free simulations. In antibiotic simulations with the mixed inocula, penicillin/amoxicillin-susceptible strains were eradicated with all study drugs (time that concentrations exceed the minimal inhibitory concentration [T > MIC ≥ 43%]). Penicillin-resistant strains showed different evolution depending on the antibiotic: (a) cefditoren produced >2 log 10 reduction of initial inocula at 12-24 hr (T>MIC ≥45%), with a remaining population growing in plates with ≥4 mg/L amoxicillin; (b) cefuroxime, cefixime, and cefaclor did not decrease initial inocula at 12-24 hr (T > MIC = 0%), with minor subpopulations growing in plates with 4 mg/L amoxicillin; (c) amoxicillin produced 2.6 log 10 decrease of initial inocula at 12 hr (T>MIC = 47.5%), but 1.1 log 10 increase of initial inocula at 24 hr, with a significant population growing in plates with 4 mg/L amoxicillin. Antibiotic activity against mixed inocula (susceptible and resistant strains) depends on intrinsic activity (as well as its subsequent pharmacodynamic activity: T > MIC against resistant strains), and on possible selection of intra-strain-resistant subpopulations.