Potential Fate Research Articles

Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity.

Chimeric antigen receptor (CAR) T cell therapy is revolutionizing cancer immunotherapy for patients with B cell malignancies and is now being developed for solid tumors and chronic viral infections. Although clinical trials have demonstrated the curative potential of CAR T cell therapy, a substantial and well-established limitation is the heightened contraction and transient persistence of CAR T cells during prolonged antigen exposure. The underlying mechanism(s) for this dysfunctional state, often termed CAR T cell exhaustion, remains poorly defined. Here, we report that exhaustion of human CAR T cells occurs through an epigenetic repression of the T cell’s multipotent developmental potential. Deletion of the de novo DNA methyltransferase 3 alpha (DNMT3A) in T cells expressing first- or second-generation CARs universally preserved the cells’ ability to proliferate and mount an antitumor response during prolonged tumor exposure. The increased functionality of the exhaustion-resistant DNMT3A knockout CAR T cells was coupled to an up-regulation of interleukin-10, and genome-wide DNA methylation profiling defined an atlas of genes targeted for epigenetic silencing. This atlas provides a molecular definition of CAR T cell exhaustion, which includes many transcriptional regulators that limit the “stemness” of immune cells, including CD28, CCR7, TCF7, and LEF1. Last, we demonstrate that this epigenetically regulated multipotency program is firmly coupled to the clinical outcome of prior CAR T cell therapies. These data document the critical role epigenetic mechanisms play in limiting the fate potential of human T cells and provide a road map for leveraging this information for improving CAR T cell efficacy.

Abstract 11266: Murine Adult Epicardium Requires Hypoxia for Progenitor and Multipotency Ability

Introduction: The epicardium is a source of the coronary vasculature and stroma during heart development. Although quiescent in the physiological adult heart, increasing evidences indicate the potential epicardium activation and differentiation into its progeny after cardiac injury; however, this remains debated. Hypothesis: We hypothesize that in vivo hypoxia exposure can mimic the embryonic cardiac profile and prime the adult epicardial progenitor cell to a more immature profile. Methods: Perinatal and adult BL6 and Pw1 nLacz hearts were used to track the expression of PW1 - progenitor cell marker - together with cell surface proteins. In vivo hypoxia (10% O 2 ) exposure was used to stimulate the adult heart. Histology, protein expression profiles and single cell analysis were assessed. Freshly FACS isolated Gp38 + PW1 + epicardial cells were cultured to determine their progenitor cell potential (clonogenicity, self-renewal and cell fate potential). Results: Here, we report that PW1 expression decreases during postnatal life, but is maintained in the cardiac hypoxic niche epicardium and subepicardium. Adult mice exhibit increased PW1 expression in epicardial/subepicardial cells and endothelial cells in response to hypoxia. The epicardium and subepicardium are activated to undergo cell proliferation and re-express a subset of embryonic genes in response to hypoxia. We established a new in vitro model to study purified PW1 + /Gp38 + epicardial cells, and we found properties of clonogenicity, self-renewal and multipotency (fibroblast, smooth muscle and endothelial cells) at single cell level in the developing epicardial cells. Cell fate potential towards an endothelial profile is dependent upon low levels of oxygen, and the in vitro ability to grow in culture is restore after in vivo priming of the adult heart. Conclusions: In conclusion our data support that the resident PW1 + /Gp38 + epicardial cells are a reminiscent progenitor population in adult mammalian heart that can be reactivated by exposure to hypoxia, highlighting the potential therapeutic role of hypoxia in regenerative medicine.

CD19-CAR T Cells Develop Exhaustion Epigenetic Programs during a Clinical Response

Background:CD19-CAR T-cell therapy has emerged as a curative approach for patients with relapsed/refractory B-cell malignancies, including lymphoma and acute lymphoblastic leukemia (ALL). However, many patients develop recurrent disease after initial responses. Therapeutic failure is most likely due to T cell extrinsic and intrinsic mechanisms. While CD19-negative relapse has emerged as a major extrinsic mechanism, T cell intrinsic mechanisms remain elusive. T-cell exhaustion is driven by epigenetic programs, however epigenetic changes in CAR T cells pre and post infusion have not been determined longitudinally. Thus, the goal of this study was to determine the epigenetic landscape of CD19-CAR T cells pre and post infusion as an initial step to elucidate intrinsic mechanisms that limit CAR T-cell effector functions in humans.Methods/Results:A longitudinal analysis of CD8+ CD19-CAR T cell epigenetic changes was performed by whole-genome DNA methylation profiling of CAR T cells during manufacturing and from peripheral blood mononuclear cells (PBMCs) of infused patients. DNA methylation profiling was performed on samples from 15 patients enrolled on our institutional, autologous CD19-CAR T cell therapy study (NCT03573700). CAR T cell expansion and persistence was determined by measuring vector copy numbers in the PBMCs of treated patients. B cell aplasia was tracked by monitoring B cell reconstitution as an additional measure of CD19-CAR T cell function. We had previously established novel exhaustion DNA methylation datasets that delineate between progenitor and fully exhausted T cells. These datasets served as a guide for stratifying our post-infusion CAR T cells along the exhaustion developmental trajectory. Lastly, publicly available single-cell transcriptional profiles of CD19-CAR T cells from patients were mined to validate expression of the transitory exhaustion signature.Our data show that CD19-CAR T cells lose repressive DNA methylation at effector loci (e.g. PRF1, TBET) while gaining methylation at genes (e.g. LEF1, TCF7) associated with memory potential. We confirmed that these epigenetic changes are coupled to endogenous human T cell effector and memory differentiation by cross-referencing our epigenetic data with publicly available transcriptional profiles for antigen-specific effector and long-lived memory CD8 T cells from individuals vaccinated for yellow fever. Furthermore, we show that CAR T cells were unable to mount an in vivo recall response after recovery of antigen-positive B cells or disease relapse. This observation, coupled to the fact that these patients' CAR T cells developed exhaustion-associated DNA methylation programs, further supports the broader conclusion that CAR T cells acquire stable epigenetic exhaustion programs that limit their protective capacity.Conclusion:Our data demonstrate for the first time that CAR T cell expansion during a clinical response is coupled to progressive restriction of gene regulatory programs that control T cell fate potential. Furthermore, we show that CD19-CAR T cells undergo exhaustion epigenetic programs that are coupled to an inability to mount a recall response in the presence of antigen-positive normal and malignant B cells. This work lays the foundation for future efforts aimed at improving the efficacy of cellular therapy by reversing epigenetic programs that are coupled to CAR T-cell exhaustion. DisclosuresTriplett: Miltenyi: Other: Travel, meeting registration. Gottschalk: Other: Other: patents and patent applications in the field of cancer cell and gene therapy ; Catamaran Bio: Consultancy; Novartis: Consultancy; Tidal: Consultancy; Immatics: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Consultancy. Youngblood: ElevateBio: Consultancy; ElevateBio: Honoraria; AstraZeneca: Honoraria; Cell Signaling: Honoraria; Merck: Research Funding; other: Other: patents and patent applications in the field of cancer cell and gene therapy .

Quantifying production rates and size fractions of parrotfish-derived sediment: A key functional role on Maldivian coral reefs.

Coral reef fish perform numerous important functional roles on coral reefs. Of these, carbonate sediment production, as a by‐product of parrotfish feeding, is especially important for contributing to reef framework construction and reef‐associated landform development. However, only limited data exist on: (i) how production rates vary among reef habitats as a function of parrotfish assemblages, (ii) the relative importance of sediment produced from eroded, reworked, and endogenous sources, or (iii) the size fractions of sediment generated by different parrotfish species and size classes. These parameters influence not only overall reef‐derived sediment supply, but also influence the transport potential and depositional fate of this sedimentary material. Here, we show that parrotfish sediment production varies significantly between reef‐platform habitats on an atoll‐margin Maldivian reef. Highest rates of production (over 0.8 kg m−2 year−1) were calculated in three of the eight platform habitats; a rubble‐dominated zone, an Acropora spp. dominated zone, and a patch reef zone. Habitat spatial extent and differences in associated parrotfish assemblages strongly influenced the total quantities of sediment generated within each habitat. Nearly half of total parrotfish sediment production occurred in the rubble habitat, which comprised only 8% of the total platform area. Over 90% of this sedimentary material originated from eroded reef framework as opposed to being reworked existing or endogenously produced sediment, and comprised predominantly coral sands (predominantly 125–1000 µm in diameter). This is comparable to the dominant sand types and size fractions found on Maldivian reef islands. By contrast, nearly half of the sediment egested by parrotfish in the Acropora spp. dominated and patch reef habitats resulted from reworked existing sediments. These differences between habitats are a result of the different parrotfish assemblages supported. Endogenous carbonate production was found to be insignificant compared to the quantity of eroded and reworked material. Our findings have important implications for identifying key habitats and species which act as major sources of sediment for reef‐island systems.

Queen Egg Laying and Egg Hatching Abilities are Hindered in Subterranean Termite Colonies When Exposed to a Chitin Synthesis Inhibitor Bait Formulation.

Subterranean termite control methods using chitin synthesis inhibitors (CSIs) aim at eliminating colonies that feed upon a bait formulation. Several benzoylurea active ingredient formulations are currently commercially available as alternative termite management strategies to liquid termiticides. Individual workers need to molt on a regular basis and CSIs interfere with such molting process, allowing sufficient time for the acquisition of a colony-wide lethal dose prior to widespread mortality. As workers progressively die, the colony eventually collapses, leaving only soldiers and primary reproductives that starve to death. One common observation is that young workers often die early owing to their relatively short molting cycle. However, the absence of brood in dying colonies raises questions about the potential fate of eggs laid by the queen. This study aims to determine if CSI baits also terminate the ability of a colony to produce a new cohort of workers by disabling the ongoing brood development. Incipient termite colonies were used to test the impact of noviflumuron on the queen's ability to lay eggs and on the eggs' ability to hatch. Our results showed that queens in colonies exposed to CSI not only initially laid less eggs than the control queens, but eggs also did not develop and were progressively cannibalized, eventually leading to colony establishment failure. This result implies that queens of mature colonies exposed to CSI would lose the ability to lay viable eggs as the colony collapses, leading to an absence of worker replacement, aiding in colony elimination.

The Many Potential Fates of Non-Canonical Protein Substrates Subject to NEDDylation.

Neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) is a ubiquitin-like protein (UBL) whose canonical function involves binding to, and thus, activating Cullin–Ring finger Ligases (CRLs), one of the largest family of ubiquitin ligases in the eukaryotic cell. However, in recent years, several non-canonical protein substrates of NEDD8 have been identified. Here we attempt to review the recent literature regarding non-canonical NEDDylation of substrates with a particular focus on how the covalent modification of NEDD8 alters the protein substrate. Like much in the study of ubiquitin and UBLs, there are no clear and all-encompassing explanations to satisfy the textbooks. In some instances, NEDD8 modification appears to alter the substrates localization, particularly during times of stress. NEDDylation may also have conflicting impacts upon a protein’s stability: some reports indicate NEDDylation may protect against degradation whereas others show NEDDylation can promote degradation. We also examine how many of the in vitro studies measuring non-canonical NEDDylation were conducted and compare those conditions to those which may occur in vivo, such as cancer progression. It is likely that the conditions used to study non-canonical NEDDylation are similar to some types of cancers, such as glioblastoma, colon and rectal cancers, and lung adenocarcinomas. Although the full outcomes of non-canonical NEDDylation remain unknown, our review of the literature suggests that researchers keep an open mind to the situations where this modification occurs and determine the functional impacts of NEDD8-modification to the specific substrates which they study.

Realignments of the Colorado River by ∼2 m.y. of rotational bedrock landsliding: The Surprise Valley landslide complex, Grand Canyon, Arizona

Abstract The Surprise Valley landslide complex is the name used here for a group of prominent river-damming landslides in Grand Canyon (Arizona, USA) that has shifted the path of the Colorado River several times in the past 2 m.y. We document a sequence of eight landslides. Three are Toreva-block landslides containing back-rotated but only mildly disrupted bedrock stratigraphy. The largest of these landslides, Surprise Valley landslide, is hypothesized to have dammed the Colorado River, cut off a meander loop through Surprise Valley, and rerouted the river 2.5 km south to near its present course at the Granite Narrows. Another bedrock landslide, Poncho's runup, involved a mass detachment from the north side of the river that drove a kilometer-scale bedrock slab across the river and up the south canyon wall to a height of 823 m above the river. A lake behind this landslide is inferred from the presence of mainstem gravels atop the slide that represent the approximate spillway elevation. We postulate that this landslide lake facilitated the upriver 133 Mile slide detachment and Toreva block formation. The other five landslides are subsequent slides that consist of debris from the primary slides; these also partially blocked and diverted the Colorado River as well as the Deer Creek and Tapeats Creek tributaries into new bedrock gorges over the past 1 m.y. The sequence of landslides is reconstructed from inset relationships revealed by geologic mapping and restored cross-sections. Relative ages are estimated by measuring landslide base height above the modern river level in locations where landslides filled paleochannels of the Colorado River and its tributaries. We calculate an average bedrock incision rate of 138 m/m.y. as determined by a 0.674 ± 0.022 Ma detrital sanidine maximum depositional age of the paleoriver channel fill of the Piano slide, which has its base 70 m above the river level and ∼93 m above bedrock level beneath the modern river channel. This date is within error of, and significantly refines, the prior cosmogenic burial date of 0.88 ± 0.44 Ma on paleochannel cobbles. Assuming steady incision at 138 m/m.y., the age of Surprise Valley landslide is estimated to be ca. 2.1 Ma; Poncho's runup is estimated to be ca. 610 ka; and diversion of Deer Creek to form modern Deer Creek Falls is estimated to be ca. 400 ka. The age of the most recent slide, Backeddy slide, is estimated to be ca. 170 ka based on its near-river-level position. Our proposed triggering mechanism for Surprise Valley landslides involves groundwater saturation of a failure plane in the weak Bright Angel Formation resulting from large volumes of Grand Canyon north-rim groundwater recharge prior to establishment of the modern Deer, Thunder, and Tapeats springs. Poncho's and Piano landslides may have been triggered by shale saturation caused by 600–650 ka lava dams that formed 45 river miles (73 river km; river miles are measured along the Colorado River downstream from Lees Ferry, with 1 river mile = 1.62 river kms) downstream near Lava Falls. We cannot rule out effects from seismic triggering along the nearby Sinyala fault. Each of the inferred landslide dams was quickly overtopped (tens of years), filled with sediment (hundreds of years), and removed (thousands of years) by the Colorado River, as is also the potential fate of modern dams.

The 3D organisation of mitochondria in primate photoreceptors

Vertebrate photoreceptors contain large numbers of closely-packed mitochondria which sustain the high metabolic demands of these cells. These mitochondria populations are dynamic and undergo fusion and fission events. This activity serves to maintain the population in a healthy state. In the event of mitochondrial damage, sub-domains, or indeed whole mitochondria, can be degraded and population homeostasis achieved. If this process is overwhelmed cell death may result. Death of photoreceptors contributes to loss of vision in aging individuals and is associated with many eye diseases. In this study we used serial block face scanning electron microscopy of adult Macaca fascicularis retinae to examine the 3D structure of mitochondria in rod and cone photoreceptors. We show that healthy-looking photoreceptors contain mitochondria exhibiting a range of shapes which are associated with different regions of the cell. In some photoreceptors we observe mitochondrial swelling and other changes often associated with cellular stress. In rods and cones that appear stressed we identify elongated domains of mitochondria with densely-packed normal cristae associated with photoreceptor ciliary rootlet bundles. We observe mitochondrial fission and mitochondrion fragments localised to these domains. Swollen mitochondria with few intact cristae are located towards the periphery of the photoreceptor inner-segment in rods, whilst they are found throughout the cell in cones. Swollen mitochondria exhibit sites on the mitochondrial inner membrane which have undergone complex invagination resulting in membranous, electron-dense aggregates. Membrane contact occurs between the mitochondrion and the photoreceptor plasma membrane in the vicinity of these aggregates, and a series of subsequent membrane fusions results in expulsion of the mitochondrial aggregate from the photoreceptor. These events are primarily associated with rods. The potential fate of this purged material and consequences of its clearance by retinal pigment epithelia are discussed.

Discrete cis-acting element regulates developmentally timed gene-lamina relocation and neural progenitor competence invivo.

SUMMARYThe nuclear lamina is typically associated with transcriptional silencing, and peripheral relocation of genes highly correlates with repression. However, the DNA sequences and proteins regulating gene-lamina interactions are largely unknown. Exploiting the developmentally timed hunchback gene movement to the lamina in Drosophila neuroblasts, we identified a 250 bp intronic element (IE) both necessary and sufficient for relocation. The IE can target a reporter transgene to the lamina and silence it. Endogenously, however, hunchback is already repressed prior to relocation. Instead, IE-mediated relocation confers a heritably silenced gene state refractory to activation in descendent neurons, which terminates neuroblast competence to specify early-born identity. Surprisingly, we found that the Polycomb group chromatin factors bind the IE and are required for lamina relocation, revealing a nuclear architectural role distinct from their well-known function in transcriptional repression. Together, our results uncover in vivo mechanisms underlying neuroblast competence and lamina association in heritable gene silencing.

Phototransformation of Graphene Oxide on the Removal of Sulfamethazine in a Water Environment.

Graphene oxide (GO) is widely used in various fields and has raised concerns regarding its potential environmental fate and effect. However, there are few studies on its influence on coexisting pollutants. In this study, the phototransformation of GO and coexisting sulfamethazine (SMZ) under UV irradiation was investigated, with a focus on the role of reactive oxygen species. The results demonstrated that GO promoted the degradation of SMZ under UV irradiation. The higher the concentration of GO, the higher the degradation rate of SMZ, and the faster the first-order reaction rate. Two main radicals, ∙OH and 1O2, both contributed greatly in terms of regulating the removal of SMZ. Cl−, SO42−, and pH mainly promoted SMZ degradation by increasing the generation of ∙OH, while humic acid inhibited SMZ degradation due to the reduction of ∙OH. Moreover, after UV illumination, the GO suspension changed from light yellow to dark brown with increasing absorbance at a wavelength of 225 nm. Raman spectra revealed that the ID/IG ratio slightly decreased, indicating that some of the functional groups on the surface of GO were removed under low-intensity UV illumination. This study revealed that GO plays important roles in the photochemical transformation of environmental pollutants, which is helpful for understanding the environmental behaviors and risks of nanoparticles in aquatic environments.

Heterogeneity of germinal center B cells: New insights from single-cell studies.

Upon antigen exposure, activated B cells in antigen-draining lymphoid organs form microanatomical structures, called germinal centers (GCs), where affinity maturation occurs. Within the GC microenvironment, GC B cells undergo proliferation and B cell receptor (BCR) genes somatic hypermutation in the dark zone (DZ), and affinity-based selection in the light zone (LZ). In the current paradigm of GC dynamics, high-affinity LZ B cells may be selected by cognate T- follicular helper cells to either differentiate into plasma cells or memory B cells, or re-enter the DZ and initiate a new round of proliferation and BCR diversification, before migrating back to the LZ. Given the diversity of cell states and potential cell fates that GC B cells may adopt, the two-state DZ-LZ paradigm has been challenged by studies that explored GC B-cell heterogeneity with a variety of single-cell technologies. Here, we review studies and single-cell technologies which have allowed to refine the working model of GC B-cell cellular and molecular heterogeneity during affinity maturation. This review also covers the use of single-cell quantitative data for mathematical modeling of GC reactions, and the application of single-cell genomics to the study of GC-derived malignancies.

ScGPS: Determining Cell States and Global Fate Potential of Subpopulations.

Finding cell states and their transcriptional relatedness is a main outcome from analysing single-cell data. In developmental biology, determining whether cells are related in a differentiation lineage remains a major challenge. A seamless analysis pipeline from cell clustering to estimating the probability of transitions between cell clusters is lacking. Here, we present Single Cell Global fate Potential of Subpopulations (scGPS) to characterise transcriptional relationship between cell states. scGPS decomposes mixed cell populations in one or more samples into clusters (SCORE algorithm) and estimates pairwise transitioning potential (scGPS algorithm) of any pair of clusters. SCORE allows for the assessment and selection of stable clustering results, a major challenge in clustering analysis. scGPS implements a novel approach, with machine learning classification, to flexibly construct trajectory connections between clusters. scGPS also has a feature selection functionality by network and modelling approaches to find biological processes and driver genes that connect cell populations. We applied scGPS in diverse developmental contexts and show superior results compared to a range of clustering and trajectory analysis methods. scGPS is able to identify the dynamics of cellular plasticity in a user-friendly workflow, that is fast and memory efficient. scGPS is implemented in R with optimised functions using C++ and is publicly available in Bioconductor.

Abstract 3022: Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma indentity

Abstract Rhabdomyosarcoma (RMS) is an embryonal tumor resembling developing skeletal muscle and the most common pediatric soft-tissue sarcoma. RMS is molecularly defined by the presence or absence of a fusion oncoprotein corresponding with the histological subtypes alveolar and embryonal RMS, respectively. Embryonal, or fusion-negative, RMS (FN-RMS) is heterogeneous in its molecular alteration profile; the major exception is the near universal PTEN promoter hypermethylation found in FN-RMS corresponding with decreased PTEN expression. PTEN's functional role in FN-RMS remains unclear as does PTEN's role in defining tumor fate decisions. Organismal cancer models can help elucidate these decisions by defining the potential tumor fate landscape that can occur in transformed multipotent progenitor cells. Our laboratory leverages a highly penetrant, early onset model of FN-RMS driven by the transdifferentiation of endothelial progenitors into skeletal muscle-like RMS cells by Hedgehog pathway activation. Therefore, our model is uniquely primed to empirically determine the core regulatory factors critical in FN-RMS initiation. Here, we conditionally deleted Pten in these cells (ASPcKO). ASPcKO tumors presented earlier than wild-type tumors and more closely resemble human FN-RMS with a less differentiated skeletal muscle state. These were unique characteristics of ASPcKO tumors as mice with homozygous loss of other tumor suppressors - Cdkn2a, Trp53, and Rb1 - did not recapitulate these phenotypes. We further probed the downstream transcriptional outputs of ASPcKO tumors revealing a profound increase in expression of the neural developmental transcription factors Dbx1 and Pax7. These outputs are functionally important as human FN-RMS patient-derived xenografts are dependent on both DBX1 and PAX7. Subsequently, we also show that DBX1 is a downstream transcriptional target of PAX7 highlighting how Pten loss engages a unique transcriptional program for tumor maintenance. PAX7 is also a core FN-RMS regulatory circuit component. To further interrogate the role of PAX7 on tumor initiation, we concomitantly deleted Pten and Pax7 in our FN-RMS model and found not only that Pax7 loss rescues the survival kinetics observed when Pten is lost, but also alters the developmental trajectory of the tumors that do develop. Instead of Smoothened trans-differentiating our aP2-Cre expressing primordial endothelial cell into a skeletal-muscle like FN-RMS, Pten and Pax7 loss dictates these endothelial cells to give rise to tumors with smooth muscle-like differentiation, including human-like leiomyosarcoma. Together, this synthetic essential interaction between Pten and Pax7 in FN-RMS stresses the importance of the bifunctional role of PAX7 in tumor initiation and maintenance and how specific tumor suppressor loss can engage developmental transcriptional programs to alter tumor fate. Citation Format: Casey G. Langdon, Katherine E. Gadek, Matthew R. Garcia, Kristin B. Reed, Madeline Bush, Jason A. Hanna, Catherine J. Drummond, Matthew C. Maguire, Patrick J. Leavey, David Finkelstein, Hongjian Jin, Jerold E. Rehg, Mark E. Hatley. Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma indentity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3022.

Study on the Adsorption Properties of Iron Tailings for GO

Iron tailings can be used as adsorbents to effectively remove graphene oxide (GO) in aqueous solutions. Experimental data show that pH, iron tailing quality, GO concentration and temperature have significant effects on the removal of GO, the adsorption of the tail involves a single layer adsorbed Langmuir model with exothermic reaction, and it compliance with the proposed dynamics model meets the requirements, the adsorption process is a spontaneous physical adsorption process. Combining scanning electron microscopy (SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), X-ray diffractometry (XRD), Fourier transform infrared spectroscopy (FT-IR) and X-ray photoelectron spectroscopy (XPS) to analyze the iron tail according to the mechanisms of ore adsorption of GO, it was concluded that iron tailings might be a very promising material to effectively remove GO in aqueous solutions. The results of this research provide key information for the transportation and potential fate of GO in the natural environment.

Physicochemical Parameters of Insensitive Munition Constituent Methylnitroguanidine (MeNQ) of Importance to Environmental Fate and Transport

Abstract1‐methyl‐3‐nitroguandine (MeNQ) is being pursued as an insensitive munition to replace legacy munitions such as TNT and RDX. This study was intended to determine the basic physicochemical properties of MeNQ as well as potential environmental fate pathways. The solubility of MeNQ was determined to be 12.92±0.52 g/L and aqueous photolysis was found to efficiently degrade the munition, where its quantum yield and half‐life were found to be 0.009 and 0.59 days, respectively. Hydrolysis was an insignificant degradation pathway resulting in 8.1 % degradation at pH 4, 2.6 % at pH 7, and 6.2 % at pH 9 after five days at an elevated temperature. Volatilization at environmentally relevant conditions was found to be insignificant as the molecule thermally degrades, leading to an inability to calculate Henry's Constant for volatilization from water. Spectroscopic (UV‐vis, FTIR, NMR) and analytical (HPLC) studies were undertaken and are shown alongside the parent molecule, NQ, for comparison to characterize the emerging munition.

Ingestion of PIT Tags by Hatchery‐Reared Juvenile Steelhead and Subsequent Detection at Main‐Stem Dams in the Columbia River Basin

AbstractDuring the past 30 years, millions of hatchery‐reared Pacific salmon Oncorhynchus spp. have been implanted with PIT tags to estimate their survival and track their migration through the extensive system of hydroelectric dams in the Columbia River basin. The mark–recapture models that are used for these analyses assume that the tags are not lost, making it important to understand retention rates for PIT tags and the fate of shed tags. To understand the potential fate of shed PIT tags in a production hatchery, we distributed 12‐mm PIT tags in two traditional cement raceways and the two circular tanks of a partial reuse aquaculture system (PRAS) containing juvenile summer steelhead O. mykiss. We then monitored the detection of these PIT tags at the time that the fish were released as smolts and at main‐stem dams during their migration. The probability that a loose PIT tag was inside a steelhead smolt at release ranged from 0.200 to 0.519 across the raceways and tanks, confirming that the fish consumed tags during hatchery rearing. Detections at six dams—including one located 1,208 km from the release site—and up to 36 d after smolt release confirmed that some ingested tags remained in the steelhead during their migration. The estimates of apparent survival for smolts with ingested and implanted PIT tags suggested that some ingested tags were being excreted during migration through the Columbia River basin. The results highlight the need to reevaluate assumptions about the fate of shed PIT tags in steelhead production hatcheries and ensure that biologists and managers have reliable estimates of tag retention.

Potential environmental fate and risk based on the hydroxyl radical-initiated transformation of atmospheric 1,2-dibromo-4-(1,2dibromoethyl)cyclohexane stereoisomers

1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane (TBECH), as an emerging brominated flame retardant (EBFR) pollutant, has been often observed in the air, and to comprehend its fate in the environment is still challenging due to the diversity of its stereoisomers. In this work, the environmental transformation behavior and potential toxicological implications of TBECH stereoisomers under the oxidation of OH· in the gas phase were investigated by computational chemistry. Our results indicate the complexity of the TBECH transformation reactions and the diversity of its transformation products in the atmosphere. Although the reactions of TBECH enantiomers with OH· exhibit highly consistency, it is obvious that the reactions of the four diastereoisomers of TBECH with OH· and their subsequent reactions have both specificity and similarity. The dehydrogenation intermediates produced by H-abstraction of OH· in the initial reactions may undergo oxidative debromination, hydroxylation and decomposition reactions, leading to the transformation into low bromine and monohydroxy substituted compounds, as well as debrominated or unbrominated unsaturated fatty ketones. The toxicity assessments show that all transformation products are less toxic to aquatic organisms than TBECH, but some of them are still classified at toxic or harmful levels. More importantly, some transformation products still exhibit carcinogenic and teratogenic activity. To our knowledge, this study provides, for the first time, a deep insight into the transformation mechanism, kinetics, and environmental impacts of atmospheric TBECH by theoretical calculations.

Comparison of adsorption behaviors of selected endocrine-disrupting compounds in soil.

Bisphenol-A (BPA), 17α-ethinylestradiol (EE2), and 4-nonylphenol (4NP) are endocrine-disrupting chemicals (EDCs) that are useful models for studying the potential fate and transport of EDCs in soil and water environments. Two alluvial soils with contrasting physicochemical properties were used as adsorbents for this study. The Zook soil material had more organic matter and clay than the sandy loam Hanlon soil material. Batch equilibrium experiments were performed to generate adsorption isotherms, to determine the adsorption parameters, and to assess desorption hysteresis. Adsorption of BPA to both soils followed an L-type isotherm, and 4NP adsorbed to both Hanlon and Zook soils exhibited S-shape isotherms. EE2 adsorbed to the Zook soil also followed an S-shaped isotherm, but EE2 adsorbed to the Hanlon soil showed an H-type isotherm. Overall, the Sips model fit the data well, with standard errors of prediction generally ≤6%. The adsorption affinity (KLF ) values were highest for 4NP, and BPA had the lowest hysteresis indices. The data suggest that BPA was most likely adsorbed by soil organic matter via hydrogen bonding involving its two phenolic groups. In contrast, isotherm shape, model affinity indices, lack of desorption, and molecular-scale characteristics led us to infer that 4NP was adsorbed largely by the retention of molecular clusters, perhaps in clay nanopores. Finally, the adsorption of EE2 exhibited different isotherm shapes for the two soils as well as intermediate affinity and desorption indices, suggesting that EE2 molecules could be retained both by soil organic matter and by clay.

Theoretical evaluation of metal release potential of emerging third generation solar photovoltaics

With rapid growth in solar industry, the potential fate and management of solar modules has raised concerns due to the presence of few toxic metals. Present work addressed this issue by (i) estimating potential release values (solubility product, Ksp at pH 7) of various compounds used in different layers of emerging solar cells in neutral water and landfill leachate conditions, and (ii) further comparing their metal release values (termed as loss factors, LFs, hereafter) with that of first and second generation photovoltaics. Top five compounds with highest metal release probability (probability>0.5) were found to be: PbI 2 (highest LF)> CuI> Cd(OH) 2 > CuSCN> CdO (smallest LF). Also, the identified compounds with lowest risk were: PbSe <Sb 2 S 3 <CdSe <Al 2 O 3 <SnS (lowest probability: 10 −10 to 10 −16 ). With respect to solar cells, perovskite solar cells were ranked first in terms of hazard as it mostly contains compounds like PbI 2 , CuSCN, CuI, NiO, and Al 2 O 3 . Quantum dot solar cells were ranked second due to presence of category II compounds (i.e., ZnO). Further, the organic and dye-sensitized solar cells are of least concern as they do not contain compounds with high LF values. With respect to different layers of an emerging PV, electron- and hole-transport layers were found to be with highest risk for material release. With respect to third generation solar cells, metal LFs for first generation solar cells were less for lead, cadmium and copper. Following the conservative approach, the calculated conversion factors for metal loss values from neutral water (pH7) to landfill leachate (i.e., CFs = LF MSW leachate /LF pH7 ) for Pb (0.075), Cu (0.263), Ni (0.426), Zn (0.591) were used for estimating metal loss values from emerging solar cells in landfill leachate conditions. Among all generation solar PVs, mostly lead-containing compounds were found to be exceeding the LF cut-off values. Thus, perovskites solar cells with lead–based compounds might pose risk to groundwater or surface runoff due to lead. • The range of metal loss factors (LF) for eight solar photovoltaics is 0 to 103. • Conversion factors for estimating metal release from emerging solar cells in MSW leachate ranged from 0.07 to 1.52. • The top five concernable compounds are: PbI 2 >CuI > Cd(OH) 2 > CuSCN > CdO. • In MSW leachate, PbI 2 exceeds the metal loss factor cut-off. • Perovskites and quantum dot solar cells may cause concern.

Adherens junction engagement regulates functional patterning of the cardiac pacemaker cell lineage.

Cardiac pacemaker cells (CPCs) rhythmically initiate the electrical impulses that drive heart contraction. CPCs display the highest rate of spontaneous depolarization in the heart despite being subjected to inhibitory electrochemical conditions that should theoretically suppress their activity. While several models have been proposed to explain this apparent paradox, the actual molecular mechanisms that allow CPCs to overcome electrogenic barriers to their function remain poorly understood. Here, we have traced CPC development at single-cell resolution and uncovered a series of cytoarchitectural patterning events that are critical for proper pacemaking. Specifically, our data reveal that CPCs dynamically modulate adherens junction (AJ) engagement to control characteristics including surface area, volume, and gap junctional coupling. This allows CPCs to adopt a structural configuration that supports their overall excitability. Thus, our data have identified a direct role for local cellular mechanics in patterning critical morphological features that are necessary for CPC electrical activity.