Manganese (II) accumulation in human brain microvascular endothelial cells is mediated by the metal-ion transporters ZRT IRT-like protein 8 (ZIP8) and ZRT IRT-like protein 14 (ZIP14). The plasma ...membrane occupancy of ZIP14, in particular, is increased in cells treated with Mn2+, lipopolysaccharide, or IL-6, but the mechanism of this regulation has not been elucidated. The calcium-transporting type 2C member 1 ATPase, SPCA1, is a Golgi-localized Ca2+-uptake transporter thought to support Golgi uptake of Mn2+ also. Here, we show using surface protein biotinylation, indirect immunofluorescence, and GFP-tagged proteins that cytoplasmic Ca2+ regulates ZIP8- and ZIP14-mediated manganese accumulation in human brain microvascular endothelial cells by increasing the plasma membrane localization of these transporters. We demonstrate that RNAi knockdown of SPCA1 expression results in an increase in cytoplasmic Ca2+ levels. In turn, we found increased cytoplasmic Ca2+ enhances membrane-localized ZIP8 and ZIP14 and a subsequent increase in 54Mn2+ uptake. Furthermore, overexpression of WT SPCA1 or a gain-of-function mutant resulted in a decrease in cytoplasmic Ca2+ and 54Mn2+ accumulation. While addition of Ca2+ positively regulated ZIP-mediated 54Mn2+ uptake, we show chelation of Ca2+ diminished manganese transport. In conclusion, the modulation of ZIP8 and ZIP14 membrane cycling by cytoplasmic calcium is a novel finding and provides new insight into the regulation of the uptake of Mn2+ and other divalent metal ions–mediated ZIP metal transporters.
Although feathers are commonly used to monitor mercury (Hg) in avian populations, their reliability as a sampling matrix has not been thoroughly assessed for many avian species, including most ...songbirds (Order Passeriformes). To better understand relationships between total Hg (THg) concentrations in feathers and other tissues for birds in the thrush and sparrow families, we (1) examined variation in THg concentrations among tissues, including feathers from six different tracts, nails, liver, and muscle; (2) tested relationships between THg concentrations in the various feather tracts and those in internal tissues from the same birds, to assess the predictive power of feather THg, and; (3) compared these relationships to those between THg concentrations in nails and internal tissues, to assess the viability of nails as a non-lethal sampling alternative. THg concentrations in all feather tracts and nails were consistently higher than those in the liver and muscle, and THg was higher in the thrushes than the sparrows. When comparing feather tracts, we observed high variation within some individuals, suggesting that estimates of Hg exposure could vary depending on which feather was sampled. Despite this variation, feather type had little effect on the predictive power of feather THg concentrations, which ranged from extremely weak in the sparrows (0.09 ≤
R
2
≤ 0.16) to moderate (0.29 ≤
R
2
≤ 0.42) in the thrushes. Alternatively, we found that nail samples better predicted internal tissue THg concentrations in both the thrushes (0.44 ≤
R
2
≤ 0.48) and sparrows (0.70 ≤
R
2
≤ 0.78). Nails have been used to monitor Hg in mammals and reptiles, but their reliability as a sampling matrix for monitoring Hg in avian populations has yet to be assessed for most taxa. While nails exhibit stronger relationships to internal tissue THg concentrations, they may not be an effective sampling option for all avian species because the collection of sizable nail samples could harm living birds, particularly small songbirds. However, this method may be reasonable for retrospective museum studies. Overall, our results suggest that, despite their current use in the literature, feathers are not a suitable sampling matrix for Hg monitoring in some songbird species.
Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there ...remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein kinases to deconvolute the sequence of phosphorylation events mediated by three host protein kinase families (SRPK, GSK-3, and CK1) that coordinately phosphorylate a cluster of serine and threonine residues in the viral N protein, which is required for viral replication. We also showed that loss or inhibition of SRPK1/2, which we propose initiates the N protein phosphorylation cascade, compromised the viral replication cycle. Because these phosphorylation sites are highly conserved across coronaviruses, inhibitors of these protein kinases not only may have therapeutic potential against COVID-19 but also may be broadly useful against coronavirus-mediated diseases.
Conflicts between groups of animals have individual‐level fitness consequences that can influence the evolution of social behaviour. In the cooperatively breeding greater ani (Crotophaga major), ...groups occasionally destroy the eggs of their neighbours, causing the attacked group to abandon their nest. Prior research suggested that such conflicts occur when two groups build nests in close proximity, and that established groups tend to evict newcomers. However, inter‐group conflict had never been directly observed. Here, we report the first photographic evidence of egg destruction by greater anis. Twelve artificial nests containing clay eggs were placed in the field with the intent of attracting nest predators. Camera footage revealed that although only two nests were discovered by heterospecific predators (white‐faced capuchins, Cebus capucinus), five nests were visited by resident anis, who in three cases damaged the clay eggs by grasping them with their bills and ejecting them from the nest cup. Nests were discovered between 2 and 96 hr after being placed in the field (mean = 34 hr) and were visited up to 18 times by up to 4 individuals simultaneously. The distance between artificial nests and the nearest known ani territory ranged from 0.13 to 0.28 km (mean = 0.2 km). Resident groups did not subsequently breed at the nest sites that they attacked, consistent with the hypothesis that the main benefit of inter‐group conflict is to reduce competition for local resources rather than to usurp nest sites. This accidental experiment reveals that greater anis closely monitor nesting activity near their territories, which may contribute to the strong “home field advantage” that resident groups hold over intruders.
Cooperatively breeding greater anis (Crotophaga major) have previously been suspected to destroy the nesting attempts of neighboring groups. In this study, we used camera traps to provide the first documentation of this behaviour, showing that ani nesting groups quickly locate and attack artificial nests placed near their territories. Close monitoring of nearby nesting activity may help explain the strong “home field advantage” that resident groups hold over intruders.
Aberrant Myc expression is a major factor in the pathogenesis of aggressive lymphoma, and these lymphomas, while clinically heterogeneous, often are resistant to currently available treatments and ...have poor survival. Myc expression can also be seen in aggressive lymphomas that are observed in the context of CLL, and we sought to develop a mouse model that could be used to study therapeutic strategies for aggressive lymphoma in the context of CLL.
We crossed the Eμ-TCL1 mouse model with the Eμ-Myc mouse model to investigate the clinical phenotype associated with B-cell-restricted expression of these oncogenes. The resulting malignancy was then extensively characterized, from both a clinical and biologic perspective.
Eμ-TCL1xMyc mice uniformly developed highly aggressive lymphoid disease with histologically, immunophenotypically, and molecularly distinct concurrent CLL and B-cell lymphoma, leading to a significantly reduced lifespan. Injection of cells from diseased Eμ-TCL1xMyc into WT mice established a disease similar to that in the double-transgenic mice. Both Eμ-TCL1xMyc mice and mice with disease after adoptive transfer failed to respond to ibrutinib. Effective and durable disease control was, however, observed by selective inhibition of nuclear export protein exportin-1 (XPO1) using a compound currently in clinical development for relapsed/refractory malignancies, including CLL and lymphoma.
The Eμ-TCL1xMyc mouse is a new preclinical tool for testing experimental drugs for aggressive B-cell lymphoma, including in the context of CLL.
Four green iguanas (
) and one blue iguana (
) from five facilities were diagnosed with sodium urate cholelithiasis. One case was diagnosed antemortem via ultrasonography, and the iguana underwent a ...choledochotomy for treatment. The other four cases were identified at necropsy. Pathologic hepatic and biliary changes were present in four of the five cases at necropsy. Histologically, four iguanas had hepatic fibrosis, three had bile duct hyperplasia, and one had cholangiohepatitis and pancreaticocholedochitis. Two iguanas had pathologic renal changes. This is the first report of sodium urate cholelithiasis in reptiles. This case series highlights the potential significant clinical disease caused by sodium urate cholelithiasis and the importance of biliary system evaluation. Further investigation is recommended to explore the pathogenesis of reptilian sodium urate cholelith formation.
Novel technologies, such as camera traps, have expanded the opportunities for species detection, especially for rare species. Corresponding changes in data processing must occur to handle the large ...volume of data gathered from technology like camera traps. Automated image data processing, usually by running images through different types of computer algorithms, is an overarching goal to reduce the number of images that researchers must manually review. However, differences in camera trap setups and species characteristics can make automatic processing a challenge. Here, we evaluated the detection accuracy and efficiency of a time‐lapse triggered camera trapping technique combined with a pixel change detection algorithm as part of a monitoring program for a translocated population of the rare and federally threatened Louisiana Pinesnake (Pituophis ruthveni). We paired 5 cameras with automated pit tag readers to collect observations of P. ruthveni. We evaluated an image dataset of 1,500,187 images, collected over 7 months, both manually (i.e., researchers looking at each individual picture to determine snake presence) and automatically using a change detection algorithm. There were 18 P. ruthveni observations recorded by the tag readers, 7 of which occurred while a paired camera was not operational. Ten of the tag reader P. ruthveni observations were captured by the paired camera trap, with an additional P. ruthveni observation from a paired camera trap not recorded by the tag reader. There were 132 snake observations of 13 additional species and 18 observations of unknown snakes from the camera traps. The algorithm reduced the number of images reviewers evaluated by an average of 78.5% per camera (range = 37.3–98.7%) but had a 54.5% success rate at detecting observations of P. ruthveni (47.1% for individual images), and a slightly lower 48.9% success rate detecting other large snakes. Large snakes were 4 times more likely to be flagged by the algorithm than small snakes. Our time‐lapse triggered camera trapping technique performed well with respect to P. ruthveni detection accuracy, compared to the tag readers. However, further research is needed to improve quality assurances of camera trap image filtering and object recognition algorithms across different sites or environments.
We evaluated the detection accuracy and efficiency of a time‐lapse triggered camera trapping technique along with a pixel change detection algorithm in an on‐going monitoring program for a translocated population of the rare and federally threatened Louisiana Pinesnake (Pituophis ruthveni). Our time‐lapse triggered camera trapping technique performed well with respect to P. ruthveni detection accuracy, compared to the tag readers; however, further research is needed to improve quality assurances of camera trap image filtering and object recognition algorithms across different sites or environments.
From December 2012 to March 2014, three randomized trials, each implementing a unique intervention in primary care settings (repeated mailing, an electronic health record best practice alert BPA, and ...patient solicitation), evaluated hepatitis C virus (HCV) antibody testing, diagnosis, and costs for each of the interventions compared with standard‐of‐care testing. Multilevel multivariable models were used to estimate the adjusted risk ratio (aRR) for receiving an HCV antibody test, and costs were estimated using activity‐based costing. The goal of this study was to estimate the effects of interventions conducted as part of the Birth‐Cohort Evaluation to Advance Screening and Testing for Hepatitis C study on HCV testing and costs among persons of the 1945‐1965 birth cohort (BC). Intervention resulted in substantially higher HCV testing rates compared with standard‐of‐care testing (26.9% versus 1.4% for repeated mailing, 30.9% versus 3.6% for BPA, and 63.5% versus 2.0% for patient solicitation) and significantly higher aRR for testing after controlling for sex, birth year, race, insurance type, and median household income (19.2 95% confidence interval (CI), 9.7–38.2 for repeated mailing, 13.2 95% CI, 3.6–48.6 for BPA, and 32.9 95% CI, 19.3–56.1 for patient solicitation). The BPA intervention had the lowest incremental cost per completed test ($24 with fixed startup costs, $3 without) and also the lowest incremental cost per new case identified after omitting fixed startup costs ($1691). Conclusion: HCV testing interventions resulted in an increase in BC testing compared with standard‐of‐care testing but also increased costs. The effect size and incremental costs of BPA intervention (excluding startup costs) support more widespread adoption compared with the other interventions. (Hepatology 2017;65:44‐53).
There is a relationship between cerebral vasculature and multiple sclerosis (MS) lesions: abnormal accumulations of iron have been found in the walls of dilated veins in MS plaques. The sources of ...this iron can be varied, but capillary and venous hemorrhages leading to blood extravasation have been recorded, and could result in the release of hemoglobin extracellularly. Extracellular hemoglobin oxidizes quickly and is known to become a reactive molecule that triggers low-density lipoprotein oxidation and plays a pivotal role in atherogenesis. In MS, it could lead to local oxidative stress, inflammation, and tissue damage. Here, we investigated whether extracellular hemoglobin and its breakdown products can cause direct oxidative damage to myelin components in a peroxidative environment such as occurs in inflamed tissue. Oxidation of lipids was assessed by the formation of fluorescent peroxidized lipid–protein covalent adducts, by the increase in conjugated diene and malondialdehyde. Oxidation of proteins was analyzed by the change in protein mass. The results suggest that the globin radical could be a trigger of myelin basic protein oxidative cross-linking, and that heme transferred to the lipids is involved in lipid peroxidation. This study provides new insight into the mechanism by which hemoglobin exerts its pathological oxidative activity towards myelin components. This work supports further research into the vascular pathology in MS, to gain insight into the origin and role of iron deposits in disease pathogenesis, or in stimulation of different comorbidities such as cardiovascular disease.
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•Extracellular hemoglobin (ExHb) is toxic to immortalized cultured oligodendrocytes.•We show that ExHb directly damages myelin components under peroxidative conditions.•Heme transferred to myelin lipids is involved in lipid peroxidation.•Ferryl state and globin radical trigger myelin basic protein oxidative cross-linking.•ExHb may exacerbate oxidative stress and tissue damage in multiple sclerosis.
Background and Objectives
Although minority race has been associated with worse cancer outcomes, the interaction of race with pathologic variables and outcomes of patients with gastroenteropancreatic ...neuroendocrine tumors (GEP‐NETs) is not known.
Methods
Patients from the US Neuroendocrine Study Group (2000‐2016) undergoing curative‐intent resection of GEP‐NETs were included. Given few patients of other races, only Black and White patients were analyzed.
Results
A total of 1143 patients were included. Median age was 58 years, 49% were male, 14% Black, and 86% White. Black patients were more likely to be uninsured (7% vs 2%, P = .011), and to have symptomatic bleeding (13% vs 7%, P = .009), emergency surgery (7% vs 3%, P = .006), and positive lymph nodes (LN) (47% vs 36%, P = .021). However, Black patients had improved 5‐year recurrence‐free survival (RFS) (90% vs 80%, P = .008). Quality of care was comparable between races, seen by similar LN yield, R0 resections, postoperative complications, and need for reoperation/readmission (all P > .05). While both races were more likely to have pancreas‐NETs, Black patients had more small bowel‐NETs (22% vs 13%, P < .001). LN positivity was prognostic for pancreas‐NETs (5‐year RFS 67% vs 83%, P = .001) but not for small‐bowel NETs.
Conclusions
Black patients with GEP‐NETs had more adverse characteristics and higher LN positivity. Despite this, Black patients have improved RFS. This may be attributed to the epidemiologic differences in the primary site of GEP‐NETs and variable prognostic value of LN‐positive disease.
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