Ecotoxicology of mercury concentrations in arctic lamprey (Lethenteron camtschaticum).

Arctic lamprey (Lethenteron camtschaticum) is an important dietary resource for rural and indigenous communities in parts of Alaska, with some commercial use. As with many fish species harvested for human consumption, there are concerns regarding mercury concentrations ([Hg]) in Arctic lamprey that may impact human health. To date, information regarding the life cycle and diet of Arctic lamprey is scarce, with no published studies examining [Hg] in Arctic lamprey tissues. Our goals were to investigate the feeding ecology of Arctic lamprey from the Bering Sea, determine how diet and potential dietary shifts might influence [Hg] in muscle, and determine if current [Hg] may pose a human health risk. The mean total [Hg] in Arctic lamprey muscle (n = 98) was 19 ng/g wet-weight. Log transformed total [Hg] were not associated with any measured biological variables including length, mass, δ13C values, or δ15N values. A stable isotope mixing model estimated that capelin (Mallotus villosus) accounted for 40.0 ± 4.0% of the Arctic lamprey diet, while Pacific sand lance (Ammodytes hexapterus) and Pacific herring (Clupea pallasii) accounted for 37.8 ± 3.1% and 22.2 ± 3.5% respectively. Finally, diet percentage compositions shifted based on size class (i.e., medium versus large). These results indicated that feeding location, bioaccumulation, and biomagnification are not important drivers of [Hg] in Arctic lamprey and current [Hg] do not pose a human health risk. Taken together, this research further expands our knowledge of Arctic lamprey trophic ecology in the eastern Bering Sea.

Comparison of Two Total Mercury Screening and Assessment Methods in Fishes: Biopsy Punch and Dried Muscle Samples.

Rapid and effective quantification of total mercury concentrations ([THg]) in fish muscle is an important part of ongoing monitoring to provide reliable and near real-time public health guidance. Methods for quantifying THg in fish muscle frequently require the use of large sample mass and numerous preparation steps. Wet (aka fresh weight) biopsy punch samples of fish muscle have been used to quantify THg directly, without drying and homogenization. Both methods have advantages and disadvantages. We compare the use of fresh weight biopsy punches for quantifying THg to using larger, dried homogenized samples. The [THg] determination for the two sampling methods was EPA method 7473. Three separate biopsy punch samples and a large muscle sample were taken from each fish and analyzed on a Direct Mercury Analyzer. There were no statistical differences between mean log transformed wet weight [THg] from biopsy punches and homogenized muscle across all samples or within individual species. Similarly, across the range of [THg] (7.5-612.7 ng/g ww), linear regression of [THg] from biopsy punch and homogenized muscle samples was not different from a 1:1 linear relationship. Linear regression statistics of [THg] with fish fork length produced similar results for both biopsy punch and homogenized muscle samples. However, the coefficient of variation among biopsy punch replicates for individual fish was frequently above the acceptable threshold of 15%. We recommend biopsy punches be used as an effective tool for broad-scale rapid monitoring of fish resources for Hg, while homogenized muscle samples be used for fine-scale ecological and health questions.

Intercepted Retro-Nazarov Reaction: Syntheses of Amidino-Rocaglate Derivatives and Their Biological Evaluation as eIF4A Inhibitors.

Rocaglates are a family of natural products isolated from the genus Aglaia which possess a highly substituted cyclopenta[b]benzofuran skeleton and inhibit cap-dependent protein synthesis. Rocaglates are attractive compounds due to their potential for inhibiting tumor cell maintenance in vivo by specifically targeting eukaryotic initiation factor 4A (eIF4A) and interfering with recruitment of ribosomes to mRNA. In this paper, we describe an intercepted retro-Nazarov reaction utilizing intramolecular tosyl migration to generate a reactive oxyallyl cation on the rocaglate skeleton. Trapping of the oxyallyl cation with a diverse range of nucleophiles has been used to generate over 50 novel amidino-rocaglate (ADR) and amino-rocaglate derivatives. Subsequently, these derivatives were evaluated for their ability to inhibit cap-dependent protein synthesis where they were found to outperform previous lead compounds including the rocaglate hydroxamate CR-1-31-B.

Ecological drivers of mercury concentrations in fish species in subsistence harvests from Kotzebue Sound, Alaska.

The State of Alaska assesses human exposure to mercury (Hg) via fish consumption producing consumption guidelines for fish tailored for children and women of childbearing age. Under these guidelines, unrestricted consumption is suggested for many fish species, while limited consumption is recommended for others. Subsequent questions have arisen regarding ecological drivers influencing [Hg] in fishes consumed by Alaskans. This community-assisted public health study evaluates [Hg] in fishes from Kotzebue Sound to examine factors that may drive observed [Hg]. We examined eight species of subsistence harvested fish (least cisco, chum salmon, Pacific herring, humpback whitefish, sheefish, starry flounder, Pacific tomcod, and fourhorn sculpin) from Kotzebue Sound. We report total Hg concentrations ([THg]) and monomethyl Hg+ concentrations ([MeHg+]) in the context of various factors (such as species, fork length, carbon and nitrogen stable isotope (δ15N or δ13C)) values that may influence [Hg] and [MeHg+]. Across all 297 fish, [THg] ranged from 3.4 - 235.2 ng/g ww. [THg] was positively correlated with fork length in six of eight fish species, as well as with trophic level (indicated by δ15N values) in five species. [MeHg+] was positively correlated with fork length in four species, and with δ15N values over all specimens examined, and specifically for three individual species. In six of the seven species analyzed, %MeHg was >80% of [THg]. This value decreased with fork length in three species, with no relationship for δ15N values in any species. Among top ranked models based on Akaike Information Criterion correction (AICc), fork length was more frequently included as an explanatory factor for [Hg] than δ15N or δ13C values. The food web magnification factor for [THg] was 11.3, and 12.6 for [MeHg+]. Biomagnification is likely driving [THg] and [MeHg+] over the entire food web, while within species, bioaccumulation is likely a stronger driver of [THg] and [MeHg+] than feeding ecology or trophic position. The [THg] for all species fell within the established unrestricted consumption guideline of 200 ng/g weight wet as established by the State of Alaska's fish consumption guidelines for Hg.

A Cryptic Case of an Anaerobic Hepatic Abscess Following a Cesarean Section.

Postpartum infectious complications can present with a wide range of nonspecific symptoms. Herein, we describe a complicated late postpartum presentation of recurrent fever following a cesarean delivery complicated by chorioamnionitis. Following discharge, the patient experienced cyclical fever and was treated with antipyretics as an outpatient. The patient continued to experience symptoms and reported to the hospital for further evaluation. Initially thought to be septic pelvic thrombophlebitis, the patient was trialed on clindamycin and gentamycin without resolution of symptoms. After extensive evaluation, the fevers were found to be the result of an infected periuterine hematoma and a concomitant subcapsular inferior hepatic abscess. Bacterial cultures isolated two rare anaerobic organisms: Peptoniphilus ssp. and Finegoldia magna. Source control was achieved by drainage of the two abscesses followed by antibiotic treatment with ertapenem and metronidazole, and the patient recovered successfully. This is the first reported case, to the authors' knowledge, of this complicated postpartum picture due to these anaerobic organisms.

Ecotoxicology of mercury in burbot (Lota lota) from interior Alaska and insights towards human health.

Fish consumption has many health benefits, but exposure to contaminants, such as mercury (Hg), in fish tissue can be detrimental to human health. The Tanana River drainage, Alaska, USA supports the largest recreational harvest of burbot (Lota lota) in the state, yet information to evaluate the potential risks of consumption by humans is lacking. To narrow this knowledge gap, we sought to (i) quantify the concentrations of total Hg ([THg]) in burbot muscle and liver tissue and the ratio between the two tissues, (ii) assess the effect of age, length, and sex on [THg] in muscle and liver tissue, (iii) evaluate if [THg] in muscle tissue varied based on trophic information, and (iv) compare observed [THg] to consumption guidelines and statewide baseline data. The mean [THg] was 268.2 ng/g ww for muscle tissue and 62.3 ng/g ww for liver tissue. Both muscle [THg] and liver [THg] values were positively associated with fish length. Trophic information (δ15N and δ13C) was not significantly related to measured [THg] in burbot muscle, which is inconsistent with typical patterns of biomagnification observed in other fishes. All burbot sampled were within the established categories for consumption recommendations determined by the State of Alaska for women of childbearing age and children. Our results provide the necessary first step towards informed risk assessment of burbot consumption in the Tanana drainage and offer parallels to fisheries and consumers throughout the subarctic and Arctic region.

PARP-inhibition reprograms macrophages toward an anti-tumor phenotype.

Poly(ADP)ribosylation inhibitors (PARPis) are toxic to cancer cells with homologous recombination (HR) deficiency but not to HR-proficient cells in the tumor microenvironment (TME), including tumor-associated macrophages (TAMs). As TAMs can promote or inhibit tumor growth, we set out to examine the effects of PARP inhibition on TAMs in BRCA1-related breast cancer (BC). The PARPi olaparib causes reprogramming of TAMs toward higher cytotoxicity and phagocytosis. A PARPi-related surge in NAD+ increases glycolysis, blunts oxidative phosphorylation, and induces reverse mitochondrial electron transport (RET) with an increase in reactive oxygen species (ROS) and transcriptional reprogramming. This reprogramming occurs in the absence or presence of PARP1 or PARP2 and is partially recapitulated by addition of NAD derivative methyl-nicotinamide (MNA). In vivo and ex vivo, the effect of olaparib on TAMs contributes to the anti-tumor efficacy of the PARPi. In vivo blockade of the "don't-eat-me signal" with CD47 antibodies in combination with olaparib improves outcomes in a BRCA1-related BC model.

A novel 4p16.3 microduplication distal to WHSC1 and WHSC2 characterized by oligonucleotide array with new phenotypic features.

Larger imbalances on chromosome 4p in the form of deletions associated with Wolf-Hirschhorn syndrome (WHS) and duplications of chromosome 4p have a defined clinical phenotype. The critical region for both these clinical disorders has been narrowed based on the genotype-phenotype correlations. However, cryptic rearrangements in this region have been reported infrequently. We report on a male patient with a microduplication of chromosome 4p, who presents with findings of macrocephaly, irregular iris pigmentation-heterochromia, and preserved linear growth in addition to overlapping features of trisomy 4p such as seizures, delayed psychomotor development, and dysmorphic features including prominent glabella, low-set ears, and short neck. Using a high-density oligonucleotide microarray, we have identified a novel submicroscopic duplication involving dosage sensitive genes TACC3, FGFR3, and LETM1. The microduplication did not involve WHSC1 and WHSC2 which are considered in the critical region for WHS and trisomy 4p. This patient's presentation and genomic findings help further delineate clinical significance of re-arrangements in the 4p16 region without the involvement of WHS critical region.

Mercury concentrations in Baja California Sur fish: Dietary exposure assessment.

Total mercury concentrations ([THg]) in muscle were determined in commercial finfish and elasmobranchs from Baja California Sur (BCS), Mexico to evaluate dietary Hg exposure for BCS communities, including the relationship of trophic ecology, length and mass with [THg] that might drive future consumption advice (e.g., recommend limited consumption of large fish for some species). The [THg] ranged from 0.06 to 528.02 µg kg-1 ww in finfish and 17.68-848.26 µg kg-1 ww in elasmobranchs. Relative to the consumption threshold set for predatory fish in Mexico, all species had a concentration below 1000 µg kg-1 ww. As expected, 16 (4.02%) and 75 (18.84%) individual fish were above advisory thresholds of 500 and 200 µg kg-1 ww, respectively. The hazard quotients (HQs) in most species were significantly <1.0, only banded guitarfish showed a significant median HQ > 1.0. Thus, the relative level of risk of high Hg exposure is low for most species.

Transcription factor NF-κB in a basal metazoan, the sponge, has conserved and unique sequences, activities, and regulation.

Herein, we characterize transcription factor NF-κB from the demosponge Amphimedon queenslandica (Aq). Aq-NF-κB is most similar to NF-κB p100/p105 among vertebrate proteins, with an N-terminal DNA-binding domain, a C-terminal Ankyrin (ANK) repeat domain, and a DNA binding-site profile akin to human NF-κB proteins. Like mammalian NF-κB p100, C-terminal truncation allows nuclear translocation of Aq-NF-κB and increases its transcriptional activation activity. Expression of IκB kinases (IKKs) induces proteasome-dependent C-terminal processing of Aq-NF-κB in human cells, and processing requires C-terminal serines in Aq-NF-κB. Unlike NF-κB p100, C-terminal sequences of Aq-NF-κB do not inhibit its DNA-binding activity. Tissue of a black encrusting demosponge contains NF-κB site DNA-binding activity, as well as nuclear and processed NF-κB. Treatment of sponge tissue with LPS increases both DNA-binding activity and processing of NF-κB. A. queenslandica transcriptomes contain homologs to upstream NF-κB pathway components. This is first functional characterization of NF-κB in sponge, the most basal multicellular animal.

Mercury concentrations in marine species from the Aleutian Islands: Spatial and biological determinants.

Several species found in the Bering Sea show significant spatial variation in total mercury concentrations ([THg]) longitudinally along the Aleutian Island chain. We assessed [THg] in other members of the Bering Sea food web to better understand the factors shaping regional differences. [THg] and stable carbon and nitrogen isotope ratios (δ15N and δ13C values) were measured in muscle tissue from 1052 fishes and cephalopods from parts of the Bering Sea and North Pacific Ocean adjacent to the Aleutian Islands. The spatial distribution of the samples enabled regional comparisons for 8 species of fish and one species of cephalopod. Four species showed higher mean length-standardized [THg] in the western Aleutian Islands management area. [THg] in yellow Irish lord were very different relative to those observed in other species and when included in multi-species analyses drove the overall regional trends in mean [THg]. Multi-species analyses excluding measurements for yellow Irish lord showed mean length-standardized [THg] was greater in the western Aleutian Islands than in the central Aleutian Islands management area. Linear regression of [THg] and δ15N values showed a significant and positive relationship across all species, varying between regions and across species. Isotopic space of all species was significantly different between the western Aleutian Islands and central Aleutian Islands, driven largely by δ13C values. Stable isotope values observed follow the same regional trend of lower trophic taxa reported in the literature, with significantly lower δ13C values in the western Aleutian Islands. We conclude that there are regional differences in carbon and nitrogen stable isotope ecology, as well as species-specific feeding ecology that influence [THg] dynamics in part of the marine food web along the Aleutian Island chain. These regional differences are likely contributors to the observed regional variations of [THg] in some high-level predators found in these regions.

Assessing the influence of migration barriers and feeding ecology on total mercury concentrations in Dolly Varden (Salvelinus malma) from a glaciated and non-glaciated stream.

Assimilation of mercury (Hg) into food webs is directly influenced by ecological factors such as local habitat characteristics, species feeding behavior, and movement patterns. Total Hg concentrations ([THg]) in biota from Subarctic latitudes are driven both by broad spatial processes such as long-range atmospheric transport and more local influences such as biovectors and geology. Thus, even relatively pristine protected lands such as national parks are experiencing Hg accumulation. We analyzed [THg] and stable isotopes of carbon (δ13C) and nitrogen (δ15N) in 104 Dolly Varden (Salvelinus malma) collected from two rivers in southeastern Alaska, upstream and downstream of apparent anadromous migration barriers in watersheds with and without glacial coverage. To assess the potential magnitude of marine-derived THg returning to freshwater, we analyzed [THg] in ten adult pink salmon from each study system. There were no differences in Dolly Varden mean [THg] between sites after the data were standardized for fork length, but unadjusted [THg] varied relative to fish size and δ15N values. While previous studies generally show that [THg] increases with higher δ15N values, we found that Dolly Varden below migration barriers and foraging on salmon eggs had the highest δ15N values among all sampled individuals, but the lowest [THg]. Dolly Varden residing below anadromous barriers had δ13C values consistent with marine influence. Since salmon eggs typically have low [Hg], our results suggest that abundant salmon populations and the dietary subsidy they provide may reduce the annual exposure to [Hg] in egg-eating stream fishes such as Dolly Varden. In addition to identifying a suitable species for freshwater Hg monitoring in southeastern Alaska, our study more broadly implies that river characteristics, location within a river, fish size, and feeding ecology are important factors influencing Hg accumulation.