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Abstract Objective Neurofilament heavy‐chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk. Methods Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta‐analyses of published case–control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole‐genome sequencing data. Results Fixed‐effects meta‐analysis found that rare (MAF

Abstract Spatial overlap between wildlife and related domestic animals can lead to disease transmission, with substantial evidence for viral and bacterial spillover. Domestic and wild animals can also share potentially harmful helminth parasites, many of which have environmental transmission stages that do not require direct contact between hosts. We used camera traps, fecal sampling, and mathematical modeling to evaluate the potential for hookworm parasites to spillover from domestic dogs to wild cats in the Osa Peninsula, Costa Rica. Traditional microscopy was found to be more sensitive than DNA‐based diagnostics for parasites, though the methods were complementary. We found high hookworm (Ancylostoma spp.) prevalence in domestic dogs (74.2%, 95% CI: 67.0%–80.7%, N = 155), and considerable spatial overlap with ocelots (Leopardus pardalis) and pumas (Puma concolor), particularly on trails and dirt roads. Pumas had hookworm prevalence of 36.4% (18.6%–57.2%, N = 22), and ocelots had 27.3% (7.6%–56.5%, N = 11); however, molecular identification of these parasites was inconclusive. We developed a macroparasite transmission model to infer the likelihood of spillover, compared with separate parasite cycles, or different parasite species in each host. According to the model, spillover of hookworm from dogs would lead to a prevalence of less than 10% in wild hosts. Low presumed compatibility between wild hosts and parasites adapted to domestic species limits the prevalence that could be reached in wild species, even under potentially higher overlap. The prevalence observed was more consistent with a model that assumes hookworms in wild cats in the Osa are a cat‐specific parasite. The combination of parasitology, molecular diagnostics, and mathematical modeling used here could complement wildlife disease monitoring programs worldwide to shed light on understudied helminth–host dynamics at the domestic–wild animal interface.

Abstract Objective We aimed to describe plasma protein biomarkers of multiple sclerosis risk and to explore protein biomarkers of disease severity using radiological outcome measures. Methods Multiple sclerosis cases and controls were identified in UK Biobank, a longitudinal cohort study of ~500,000 British adults. Plasma proteins were assayed in ~50,000 UK Biobank participants using the Olink proximity extension assay. We performed case–control association testing to examine the association between 2911 proteins and multiple sclerosis, using linear models adjusted for confounding covariates. Associations with radiological lesion burden and brain volume were determined in a subset of the cohort with available magnetic resonance imaging, using normalized T2‐hyperintensity volume or whole brain volume as the outcome measure. Results In total, 407 prevalent multiple sclerosis cases and 39,979 healthy controls were included. We discovered 72 proteins associated with multiple sclerosis at a Bonferroni‐adjusted p value of 0.05, including established markers such as neurofilament light chain and glial fibrillary acidic protein. We observed a decrease in plasma Granzyme A, a marker of T cell and NK cell degranulation, which was specific to multiple sclerosis. Higher levels of plasma proteins involved in coagulation were associated with lower T2 lesion burden and preserved brain volume. Interpretation We report the largest plasma proteomic screen of multiple sclerosis, replicating important known associations and suggesting novel markers, such as the reduction in granzyme A. While these findings require external validation, they demonstrate the power of biobank‐scale datasets for discovering new biomarkers for multiple sclerosis.

Abstract Carboxylic ester hydrolases with the capacity to degrade polyesters are currently highly sought after for their potential use in the biological degradation of PET and other chemically synthesized polymers. Here, we describe MarCE, a carboxylesterase family protein identified via genome mining of a Maribacter sp. isolate from the marine sponge Stelligera stuposa. Based on phylogenetic analysis, MarCE and its closest relatives belong to marine‐associated genera from the Cytophaga–Flavobacterium–Bacteroides taxonomic group and appear evolutionarily distinct to any homologous carboxylesterases that have been studied to date in terms of structure or function. Molecular docking revealed putative binding of BHET, a short‐chain PET derivative, onto the predicted MarCE three‐dimensional structure. The synthetic ester‐degrading activity of MarCE was subsequently confirmed by MarCE‐mediated hydrolysis of 2 mM BHET substrate, indicated by the release of its breakdown products MHET and TPA, which were measured, respectively, as 1.28 and 0.12 mM following 2‐h incubation at 30°C. The findings of this study provide further insight into marine carboxylic ester hydrolases, which have the potential to display unique functional plasticity resulting from their adaptation to complex and fluctuating marine environmentsw.

Abstract Parentage analyses via molecular markers have revealed multiple paternity within the broods of polytocous species, reshaping our understanding of animal behavior, ecology, and evolution. In a meta‐analysis of multiple paternity in bird and mammal species, we conducted a literature search and found 138 bird and 64 mammal populations with microsatellite DNA paternity results. Bird populations averaged 19.5% multiple paternity and mammals more than twice that level (46.1%). We used a Bayesian approach to construct a null model for how multiple paternity should behave at random among species, under the assumption that all mated males have equal likelihood of siring success, given mean brood size and mean number of sires. We compared the differences between the null model and the actual probabilities of multiple paternity. While a few bird populations fell close to the null model, most did not, averaging 34.0‐percentage points below null model predictions; mammals had an average probability of multiple paternity 13.6‐percentage points below the null model. Differences between bird and mammal species were also subjected to comparative phylogenetic analyses that generally confirmed our analyses that did not adjust for estimated historical relationships. Birds exhibited extremely low probabilities of multiple paternity, not only compared to mammals but also relative to other major animal taxa. The generally low probability of multiple paternity in birds might be produced by a variety of factors, including behaviors that reflect sexual selection (extreme mate guarding or unifocal female choice) and sperm competition (e.g., precedence effects favoring fertilization by early or late matings).

Abstract Introduction The binding of drugs to plasma proteins is an important consideration in drug development. We have reported that the dose of adenosine, lidocaine, and magnesium (ALM) fluid therapy for resuscitation from hemorrhagic shock is nearly 3‐times higher for pigs than rats. Since lidocaine strongly binds to serum alpha‐1‐acid glycoprotein (AGP), the aim of the study was to investigate the effect of hemorrhagic shock on levels of AGP in rats and pigs. Materials and Methods Healthy adult male Sprague–Dawley rats and female crossbred pigs (n = 33 each) underwent tail vein and peripheral ear vein blood sampling, respectively, to collect plasma for AGP measurements. Rats (n = 17) and pigs (n = 16) underwent surgical instrumentation and uncontrolled hemorrhage via liver resection, and were treated with 3% NaCl ± ALM IV bolus followed 60 min later by 4 h 0.9% NaCl ± ALM IV drip. Rats were monitored for 72 h with blood samples taken post‐surgery, and at 5.25, 24, and 72 h. Pigs were monitored for 6 h with blood samples taken post‐surgery, and at 60 min and 6 h. Plasma AGP was measured with rat‐ and pig‐specific enzyme‐linked immunosorbent assay kits. Results Baseline AGP levels in rats were 3.91 μg/mL and significantly 83‐fold lower than in pigs (325 μg/mL). Surgical instrumentation was associated with ~10‐fold increases in AGP in rats and a 21% fall in pigs. AGP levels remained elevated in rats after hemorrhage and resuscitation (28–29 μg/mL). In contrast, no significant differences in plasma AGP were found in ALM‐ or Saline‐treated pigs over the monitoring period. Conclusions We conclude that the trauma of surgery alone was associated with significant increases in AGP in rats, compared to a contrasting decrease in pigs. Higher levels of plasma AGP in pigs prior to hemorrhagic shock is consistent with the higher ALM doses required to resuscitate pigs compared with rats.

Abstract Background ALM solution, a combination of adenosine, lidocaine and Mg2+, is an emerging small volume therapy that has been shown to prevent and correct coagulopathy and surgery-related inflammation in preclinical models, though its application in orthopaedic surgery is yet to be demonstrated. The effect of ALM solution on chondrocytes is unknown. The aim of this preliminary study was to investigate the effect of ALM solution on viability and inflammatory responses of chondrogenically-differentiated human bone marrow-derived mesenchymal stem cells (chondro-MSC), in vitro. Methods Chondro-MSC were exposed to media only, saline (0.9% NaCl or 1.3% NaCl) only, or saline containing ALM (1 mM adenosine, 3 mM lidocaine, 2.5 mM Mg2+) or tranexamic acid (TXA, 100 mg/ml) for 1 or 4 h. Responses to ALM solutions containing higher lidocaine concentrations were also compared. Chondrocyte viability was determined using WST-8 colorimetric assays and inflammatory cytokine (TNF-α, IL-1β, IL-8) and matrix metalloproteinases (MMP-3, MMP-12, MMP-13) concentrations using multiplex bead arrays. Results The viability of chondro-MSC was significantly greater after 1 h treatment with ALM compared to saline (96.2 ± 7.9 versus 75.6 ± 7.3%). Extension of exposure times to 4 h had no significant adverse effect on cell viability after treatment with ALM (1 h, 85.4 ± 5.6 v 4 h, 74.0 ± 15.2%). Cytotoxicity was evident following exposure to solutions containing lidocaine concentrations greater than 30 mM. There were no significant differences in viability (80 ± 5.4 v 57.3 ± 16.2%) or secretion of IL-8 (60 ± 20 v 160 ± 50 pg/ml), MMP-3 (0.95 ± 0.6 v 3.4 ± 1.6 ng/ml), and MMP-13 (4.2 ± 2.4 v 9.2 ± 4.3 ng/ml) in chondro-MSC exposed to saline, ALM or TXA. Conclusions Short-term, in vitro exposure to clinically-relevant concentrations of ALM solution had no adverse inflammatory or chondrotoxic effects on human chondro-MSC, with responses comparable to saline and TXA. These findings provide support for continued evaluation of ALM solution as a possible therapeutic to improve outcomes following orthopaedic procedures.

Abstract Pseudotachylites are generally considered to be produced by flash melting of the most fusible minerals, with compositions often dominated by biotite mica. We present phase fraction calculations for 237 pseudotachylite analyses from 28 localities spanning a range of host rock compositions from granites to peridotites. Pseudotachylite matrix compositions cannot be reproduced by a simple linear mixture of the minerals in their host rocks and commonly show a potassium deficit in pseudotachylites which contain significant contributions from biotite or muscovite. This is strongly indicative of peritectic melting of mica under fluid‐absent conditions. Occasionally, a negative contribution from an aluminosilicate phase is required but with a positive contribution from potassium feldspar. This is most consistent with peritectic melting of micas under fluid present conditions. The present data therefore suggest that, while fluid absent flash melting might be the most common mode of formation of pseudotachylite, in some instances pseudotachylites can be produced in the presence of a free fluid. Potassium mass balance of pseudotachylites might therefore be a diagnostic indicator of fluid‐absent conditions in their source regions during seismogenic rupture. We give some examples of observational evidence of peritectic liquidus phases in pseudotachylites and suggest that the significance of these phases might have been overlooked in previous studies.