Welwyn Archaeological Society

Abstract Current food production challenges of soil degradation, rising demand, and climate change require a more holistic approach to crop nutrition. Scalable, multi‐nutrient fertilizers that can enhance yield and reduce nutrient losses are a promising solution. Polyhalite is a natural mineral containing potassium (K), magnesium (Mg), calcium (Ca), and sulfur (S) that has multiple agronomic benefits. The main objective of this study was to combine evidence from hundreds of trials across different soils, crop species, and environments to quantify the yield response to polyhalite. Factors affecting the yield response to polyhalite, including soil K and S availability and crop species, were investigated. To compare polyhalite's performance with conventional fertilizers, we contrasted the results of restricted maximum likelihood meta‐analysis, with and without the exclusion of outliers, with simpler comparisons of means and medians. The data included 921 replicated trials conducted on 47 crops across 33 countries over 10 years. Fertilizer programs based on polyhalite outperformed conventional fertilizers, with a 6.6% yield increase over nitrogen + phosphorus (NP) and 3.2% over nitrogen + phosphorus + potassium (NPK) controls for all the trials. For the trials that were responsive to K or S, this increase was 12.2% over NP and 4.8% over NPK controls. Polyhalite increased yields over NP control by 3.8%–16.3% across different crops, with the highest responses of 16.3% in sugarcane ( Saccharum officinarum L.), 12.5% in vegetables, and 9.5% in potatoes ( Solanum tuberosum L.). These results demonstrated polyhalite's consistent yield enhancement benefits as compared with conventional fertilizers across a range of soils, crops, and geographies.

Parkinson's disease is one of the fastest-growing neurodegenerative disorders, with no effective treatments to modify its progression. Microglial-driven neuroinflammation, mediated by NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome activation, plays a key role in disease onset and progression. The NLRP3 inflammasome is upregulated in microglia from Parkinson's disease patients and activated by oxidative stress and α-synuclein aggregates, triggering the release of pro-inflammatory mediators that contribute to neuroinflammation and neuronal death. MCC950, the first described specific NLRP3 inhibitor, has shown promise in Parkinson's disease models but is limited by suboptimal pharmacokinetics and safety, hindering its clinical development. Here, we developed a novel NLRP3 inflammasome inhibitor, MCC7840 (also known as Inzomelid or Emlenoflast), and utilized clinically relevant PET-MRI imaging biomarkers to assess its therapeutic efficacy in preclinical models of Parkinson's disease. MCC7840 inhibited NLRP3 in human and mouse microglia with nanomolar potency, while demonstrating improved systemic exposure, half-life, brain permeability and bioavailability compared with MCC950. In a murine NLRP3 gain-of-function model of Muckle-Wells syndrome, MCC7840 effectively inhibited mortality and demonstrated superior potency compared with MCC950. Chronic oral administration of MCC7840 protected against neuroinflammation, motor deficits and dopamine loss in both 6-hydroxydopamine and preformed α-synuclein fibril mouse models of Parkinson's disease. Radiotracer imaging of multiple PET markers in the same mouse revealed that MCC7840 attenuated neuroinflammation (translocator protein ligand; 18F-DPA-714), preserved dopamine uptake (fluorodopa; 18F-FDOPA), mitigated dopamine transporter (DAT) loss (DAT ligand; 18F-FBCTT) and reduced blood-brain barrier leakage (gadolinium contrast MRI). Notably, MCC7840 was effective in a slowly progressing 12-month α-synuclein model, even when administered after symptom onset, 4 months post-α-synuclein injection. These findings highlight the utility of PET/MRI as a non-invasive tool to evaluate drug efficacy and support MCC7840, and other brain-penetrant NLRP3 inhibitors, as promising disease-modifying therapies for Parkinson's disease, warranting future clinical investigation.

Aus 2,4-Difluortoluol wurden nach ublichen Methoden 2,4-Difluorbenzaldehyd und 2,4-Difluorzimtsaure hergestellt.