An AI Approach to Identifying Novel Therapeutics for Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that has a significant impact on quality of life and work capacity. Treatment of RA aims to control inflammation and alleviate pain; however, achieving remission with minimal toxicity is frequently not possible with the current suite of drugs. This review aims to summarise current treatment practices and highlight the urgent need for alternative pharmacogenomic approaches for novel drug discovery. These approaches can elucidate new relationships between drugs, genes, and diseases to identify additional effective and safe therapeutic options. This review discusses how computational approaches such as connectivity mapping offer the ability to repurpose FDA-approved drugs beyond their original treatment indication. This review also explores the concept of drug sensitisation to predict co-prescribed drugs with synergistic effects that produce enhanced anti-disease efficacy by involving multiple disease pathways. Challenges of this computational approach are discussed, including the availability of suitable high-quality datasets for comprehensive analysis and other data curation issues. The potential benefits include accelerated identification of novel drug combinations and the ability to trial and implement established treatments in a new index disease. This review underlines the huge opportunity to incorporate disease-related data and drug-related data to develop methods and algorithms that have strong potential to determine novel and effective treatment regimens

Distinct sulfur saturation histories within the Palaeogene Magilligan Sill, Northern Ireland: Implications for Ni-Cu-PGE mineralisation in the North Atlantic Igneous Province

This is the author accepted manuscript. The final version is available from NRC Research Press via the DOI in this record.The ~60 m thick Magilligan Sill is part of the British Palaeogene Igneous Province in the North Atlantic. The sill comprises layers of dolerite and olivine gabbro, and it intrudes a thick sequence of Mesozoic mudstones and marls, which are locally baked at the sill margins. Since 2014, the sill has been an exploration target for orthomagmatic Ni-Cu-PGE sulfide mineralisation analogous to the Noril’sk-Talnakh intrusion in Russia. We present new petrological, geochemical and S-isotope data to assess the prospectivity of the sill and the underlying magmatic plumbing system. Most sulfides in the dolerite portions of the sill are < 50 μm in size and comprise only pyrite with PGE abundances below detection limit. In the olivine gabbros, > 150 μm size pentlandite, chalcopyrite and pyrrhotite grains contain < 4 ppm total PGE, 1 460 ppm Co and 88 ppm Ag. Pyrite from the dolerites have δ34S ranging from -10.0 to +3.4 ‰ and olivine gabbro sulfides range from -2.5 to -1.1 ‰, suggesting widespread crustal contamination. The S/Se ratios of sulfides in the dolerites and olivine gabbros range from 3 500 to 19 500 and from 1 970 to 3 710, respectively, indicating that the latter may have come from upstream in the magma plumbing system. The Magilligan Sill records multiple injections of mafic magma into an inflating sill package, each with distinct mechanisms towards S-saturation. Whilst the sulfide minerals in the sill do not constitute significant mineralisation themselves, detailed in-situ studies highlight a divergence in Ssaturation histories, and suggest that a larger volume of olivine gabbro sulfides at depth may be prospective

Occurrence and bioconcentration of micropollutants in Silver Perch (Bidyanus bidyanus) in a reclaimed water reservoir

© 2018 This study examined the occurrence of 49 micropollutants in reclaimed water and Silver Perch (Bidyanus bidyanus) living in a reclaimed water reservoir. The numbers of micropollutants detected in reclaimed water, Silver Perch liver, and Silver Perch flesh were 20, 23, and 19, respectively. Concentrations of all micropollutants in reclaimed water, except benzotriazole, were well below the Australian Guideline for Recycled Water (AGRW) values for potable purposes. The concentration of benzotriazole in reclaimed water was 675 ± 130 ng/L while the AGRW value for this compound was 7 ng/L. Not all micropollutants detected in the water phase were identified in the Silver Perch flesh and liver tissues. Likewise, not all micropollutants detected in the Silver Perch flesh and liver were identified in the reclaimed water. In general, micropollutant concentrations in the liver were higher than in the flesh. Perfluorooctane sulfonate (PFOS) was detected at a trace level in reclaimed water well below the AGRW guideline value for potable purposes, but showed a high and medium bioconcentration factor in Silver Perch liver and flesh, respectively. In addition, the risk quotient for PFOS was medium and high when considering its concentration in Silver Perch liver and flesh, respectively. Results reported here highlight the need to evaluate multiple parameters for a comprehensive risk assessment. The results also single out PFOS as a notable contaminant of concern for further investigation

Hexagon patterns in optical bistability

The mean-field model of optical bistability in a ring cavity is extended to include diffraction in two transverse dimensions. Nonlinear analysis in the neighborhood of the instability of the homogeneous solution indicates the formation of stable hexagonal patterns, and this is confirmed by numerical simulation, with reasonable quantitative agreement. Simulations with higher excitation show defect structures and complex dynamical patterns

FKBPL is associated with metabolic parameters and is a novel determinant of cardiovascular disease.

Type 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD). As disturbed angiogenesis and endothelial dysfunction are strongly implicated in T2D and CVD, we aimed to investigate the association between a novel anti-angiogenic protein, FK506-binding protein like (FKBPL), and these diseases. Plasma FKBPL was quantified by ELISA cross-sectionally in 353 adults, consisting of 234 T2D and 119 non-diabetic subjects with/without CVD, matched for age, BMI and gender. FKBPL levels were higher in T2D (adjusted mean: 2.03 ng/ml ± 0.90 SD) vs. non-diabetic subjects (adjusted mean: 1.79 ng/ml ± 0.89 SD, p = 0.02), but only after adjustment for CVD status. In T2D, FKBPL was negatively correlated with fasting blood glucose, HbA1c and diastolic blood pressure (DBP), and positively correlated with age, known diabetes duration, waist/hip ratio, urinary albumin/creatinine ratio (ACR) and fasting C-peptide. FKBPL plasma concentrations were increased in the presence of CVD, but only in the non-diabetic group (CVD: 2.02 ng/ml ± 0.75 SD vs. no CVD: 1.68 ng/ml ± 0.79 SD, p = 0.02). In non-diabetic subjects, FKBPL was positively correlated with an established biomarker for CVD, B-type Natriuretic Peptide (BNP), and echocardiographic parameters of diastolic dysfunction. FKBPL was a determinant of CVD in the non-diabetic group in addition to age, gender, total-cholesterol and systolic blood pressure (SBP). FKBPL may be a useful anti-angiogenic biomarker in CVD in the absence of diabetes and could represent a novel CVD mechanism

Melting mud in Earth's mantle

Melting of subducted sediment remains controversial, as direct observation of sediment melt generation at mantle depths is not possible. Geochemical fingerprints provide indirect evidence for subduction delivery of sediment to the mantle; however, sediment abundance in mantle-derived melt is generally low (0%–2%), and difficult to detect. Here we provide evidence for melting of subducted sediment in granite sampled from an exhumed mantle section. Peraluminous granite dikes that intrude peridotite in the Oman–United Arab Emirates ophiolite have U-Pb ages of 99.8 ± 3.3 Ma that predate obduction. The dikes have unusually high oxygen isotope (δ18O) values for whole rock (14–23‰) and quartz (20–22‰), and yield the highest δ18O zircon values known (14–28‰; values relative to Vienna standard mean ocean water [VSMOW]). The extremely high oxygen isotope ratios uniquely identify the melt source as high-δ18O marine sediment (pelitic and/or siliciceous mud), as no other source could produce granite with such anomalously high δ18O. Formation of high-δ18O sediment-derived (S-type) granite within peridotite requires subduction of sediment to the mantle, where it melted and intruded overlying mantle wedge. The granite suite described here contains the highest oxygen isotope ratios reported for igneous rocks, yet intruded mantle peridotite below the Mohorovičić seismic discontinuity, the most primitive oxygen isotope reservoir in the silicate Earth. Identifying the presence and quantifying the extent of sediment melting within the mantle has important implications for understanding subduction recycling of supracrustal material and effects on mantle heterogeneity over time.National Geographi