A Glycine Zipper Motif Mediates the Formation of Toxic Beta-Amyloid Oligomers in Vitro and in Vivo

Background: The b-amyloid peptide (Ab) contains a Gly-XXX-Gly-XXX-Gly motif in its C-terminal region that hasbeen proposed to form a “glycine zipper” that drives the formation of toxic Ab oligomers. We have tested thishypothesis by examining the toxicity of Ab variants containing substitutions in this motif using a neuronal cell line,primary neurons, and a transgenic C. elegans model.Results: We found that a Gly37Leu substitution dramatically reduced Ab toxicity in all models tested, as measuredby cell dysfunction, cell death, synaptic alteration, or tau phosphorylation. We also demonstrated in multiplemodels that Ab Gly37Leu is actually anti-toxic, thereby supporting the hypothesis that interference with glycinezipper formation blocks assembly of toxic Ab oligomers. To test this model rigorously, we engineered second sitesubstitutions in Ab predicted by the glycine zipper model to compensate for the Gly37Leu substitution andexpressed these in C. elegans. We show that these second site substitutions restore in vivo Abtoxicity, furthersupporting the glycine zipper model.Conclusions: Our structure/function studies support the view that the glycine zipper motif present in the Cterminalportion of Ab plays an important role in the formation of toxic Ab oligomers. Compounds designed tointerfere specifically with formation of the glycine zipper could have therapeutic potential

Roots and rhizomes of wild Asparagus: Nutritional composition, bioactivity and nanoencapsulation of the most potent extract

The nutritional composition and bioactive properties of roots and rhizomes of Asparagus stipularis were evaluated. Antioxidant activity of extracts obtained by infusion was evaluated using free radicals scavenging and reducing power methods. Porcine liver primary cell was used to check the hepatotoxicity of infusions. Results revealed that Asparagus samples are likely a source of nutrients, such as dietary fibre and essential fatty acids. HPLC-DAD-ESI/MS characterization of infusions allowed the identification and quantitation of 7 phenolic compounds, all hydroxycinnamoyl derivatives, with caffeic acid as the most abundant. Roots infusion contained the highest amounts of these compounds. It also exhibited the highest antioxidant activity in all assays, with EC50 values of 0.44 ± 0.01, 0.98 ± 0.03 and 0.64 ± 0.01 mg/mL for DPPH, ABTS and FRAP assays, respectively, with no toxicity towards PLP2 primary cell cultures (GI50 > 400 μg/mL). PLGA nanoparticles loaded with root extract were prepared using solvent-evaporation double emulsion method. Nanoparticles size was about 260 nm and a polydispersity index around 0.1, with a zeta potential of about -36 mV, as well as a good encapsulation efficiency of approximately 83%. Their morphology was analysed by SEM and spherical polymeric nanoparticles with a smooth surface were observed. FTIR and DSC were also performed, which allowed corroborating the efficacy of the encapsulation and to confirm the production of a stable and robust system to load Asparagus extracts. The developed nanoparticles are expected to be used as delivery systems for bioactive compounds of A. stipularis and they could be used as an innovative dietary supplement.The UCM authors would like to thank to ALIMNOVA Research Group (UCM GR105/18) and Spanish Government through the project PID2019-109365RA-I00. Authors are also grateful to Foundation for Science and Technology (FCT, Portugal) for financial support through national funds FCT/MCTES to CIMO (UIDB/00690/2020), LAQV (UIDB/50006/2020), CCMar (UIDB/04326/2020), CBIOS (UIDB/ 04567/2020) and iBB-IST (UIDB/04565/2020). A. Fernandes contract was provided by National funding by FCT, P. I., through the institutional scientific employment program-contract. The authors are also grateful to FEDER-Interreg España-Portugal programme for financial support through the project 0377_Iberphenol_6_E. The GIP-USAL is financially supported by the Spanish Government through the project AGL2015- 64522-C2-2-R.info:eu-repo/semantics/publishedVersio

Brazilian recommendations on the safety and effectiveness of the yellow fever vaccination in patients with chronic immune-mediated inflammatory diseases

Background: In Brazil, we are facing an alarming epidemic scenario of Yellow fever (YF), which is reaching the most populous areas of the country in unvaccinated people. Vaccination is the only effective tool to prevent YF. In special situations, such as patients with chronic immune-mediated inflammatory diseases (CIMID), undergoing immunosuppressive therapy, as a higher risk of severe adverse events may occur, assessment of the risk-benefit ratio of the yellow fever vaccine (YFV) should be performed on an individual level. Main body of the abstract: Faced with the scarcity of specific orientation on YFV for this special group of patients, the Brazilian Rheumatology Society (BRS) endorsed a project aiming the development of individualized YFV recommendations for patients with CIMID, guided by questions addressed by both medical professionals and patients, followed an internationally validated methodology (GIN-McMaster Guideline Development). Firstly, a systematic review was carried out and an expert panel formed to take part of the decision process, comprising BRS clinical practitioners, as well as individuals from the Brazilian Dermatology Society (BDS), Brazilian Inflammatory Bowel Diseases Study Group (GEDIIB), and specialists on infectious diseases and vaccination (from Tropical Medicine, Infectious Diseases and Immunizations National Societies); in addition, two representatives of patient groups were included as members of the panel. When the quality of the evidence was low or there was a lack of evidence to determine the recommendations, the decisions were based on the expert opinion panel and a Delphi approach was performed. A recommendation was accepted upon achieving ≥80% agreement among the panel, including the patient representatives. As a result, eight recommendations were developed regarding the safety of YFV in patients with CIMID, considering the immunosuppression degree conferred by the treatment used. It was not possible to establish recommendations on the effectiveness of YFV in these patients as there is no consistent evidence to support these recommendations. Conclusion: This paper approaches a real need, assessed by clinicians and patient care groups, to address specific questions on the management of YFV in patients with CIMID living or traveling to YF endemic areas, involving specialists from many areas together with patients, and might have global applicability, contributing to and supporting vaccination practices. We recommended a shared decision-making approach on taking or not the YFV

Carbon-sensitive pedotransfer functions for plant available water

Currently accepted pedotransfer functions show negligible effect of management-induced changes to soil organic carbon (SOC) on plant available water holding capacity (θAWHC), while some studies show the ability to substantially increase θAWHC through management. The Soil Health Institute\u27s North America Project to Evaluate Soil Health Measurements measured water content at field capacity using intact soil cores across 124 long-term research sites that contained increases in SOC as a result of management treatments such as reduced tillage and cover cropping. Pedotransfer functions were created for volumetric water content at field capacity (θFC) and permanent wilting point (θPWP). New pedotransfer functions had predictions of θAWHC that were similarly accurate compared with Saxton and Rawls when tested on samples from the National Soil Characterization database. Further, the new pedotransfer functions showed substantial effects of soil calcareousness and SOC on θAWHC. For an increase in SOC of 10 g kg–1 (1%) in noncalcareous soils, an average increase in θAWHC of 3.0 mm 100 mm–1 soil (0.03 m3 m–3) on average across all soil texture classes was found. This SOC related increase in θAWHC is about double previous estimates. Calcareous soils had an increase in θAWHC of 1.2 mm 100 mm–1 soil associated with a 10 g kg–1 increase in SOC, across all soil texture classes. New equations can aid in quantifying benefits of soil management practices that increase SOC and can be used to model the effect of changes in management on drought resilience

Linking soil microbial community structure to potential carbon mineralization: A continental scale assessment of reduced tillage

Potential carbon mineralization (Cmin) is a commonly used indicator of soil health, with greater Cmin values interpreted as healthier soil. While Cmin values are typically greater in agricultural soils managed with minimal physical disturbance, the mechanisms driving the increases remain poorly understood. This study assessed bacterial and archaeal community structure and potential microbial drivers of Cmin in soils maintained under various degrees of physical disturbance. Potential carbon mineralization, 16S rRNA sequences, and soil characterization data were collected as part of the North American Project to Evaluate Soil Health Measurements (NAPESHM). Results showed that type of cropping system, intensity of physical disturbance, and soil pH influenced microbial sensitivity to physical disturbance. Furthermore, 28% of amplicon sequence variants (ASVs), which were important in modeling Cmin, were enriched under soils managed with minimal physical disturbance. Sequences identified as enriched under minimal disturbance and important for modeling Cmin, were linked to organisms which could produce extracellular polymeric substances and contained metabolic strategies suited for tolerating environmental stressors. Understanding how physical disturbance shapes microbial communities across climates and inherent soil properties and drives changes in Cmin provides the context necessary to evaluate management impacts on standardized measures of soil microbial activity