Human autoinflammatory disease reveals ELF4 as a transcriptional regulator of inflammation.

Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined. We discovered loss-of-function variants in the X-linked ETS transcription factor gene ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade. Using cells from patients and newly generated mouse models, we uncovered ELF4-mutant macrophages having hyperinflammatory responses to a range of innate stimuli. In mouse macrophages, Elf4 both sustained the expression of anti-inflammatory genes, such as Il1rn, and limited the upregulation of inflammation amplifiers, including S100A8, Lcn2, Trem1 and neutrophil chemoattractants. Blockade of Trem1 reversed inflammation and intestine pathology after in vivo lipopolysaccharide challenge in mice carrying patient-derived variants in Elf4. Thus, ELF4 restrains inflammation and protects against mucosal disease, a discovery with broad translational relevance for human inflammatory disorders such as IBD.

"Deficiency in ELF4, X-Linked": a Monogenic Disease Entity Resembling Behçet's Syndrome and Inflammatory Bowel Disease.

Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet's- and inflammatory bowel disease (IBD)-like disorder termed "deficiency in ELF4, X-linked" (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses. DEX patients exhibit a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. Patients have been predominantly treated with anti-inflammatory agents, with the majority of DEX patients treated with biologics targeting TNFα.

Chemical Science Research, Elementary School Children and Their Teachers Are More Closely Related than You May Imagine: The "I Bet You Did Not Know" Project.

Topics associated with the chemical sciences form a significant part of the curriculum in science at the primary school level in the U.K. In this methodology paper, we demonstrate how a wide range of research articles associated with the chemical sciences can be disseminated to an elementary school audience and how children can carry out investigations associated with cutting-edge research in the classroom. We discuss how the Primary Science Teaching Trust's (PSTT's) "I bet you did not know" (IBYDK) articles and their accompanying Teacher Guides benefit children, primary (elementary) school teachers, and other stakeholders including the researchers themselves. We define three types of research articles; ones describing how children can reproduce the research themselves without much adaptation, others where children can mirror the research using similar methods, and some where an analogy can be used to explain the research. We provide exemplars of each type and some preliminary feedback on articles written.

Monoclonal Invariant NKT (iNKT) Cell Mice Reveal a Role for Both Tissue of Origin and the TCR in Development of iNKT Functional Subsets.

Invariant NKT (iNKT) cell functional subsets are defined by key transcription factors and output of cytokines, such as IL-4, IFN-γ, IL-17, and IL-10. To examine how TCR specificity determines iNKT function, we used somatic cell nuclear transfer to generate three lines of mice cloned from iNKT nuclei. Each line uses the invariant Vα14Jα18 TCRα paired with unique Vß7 or Vß8.2 subunits. We examined tissue homing, expression of PLZF, T-bet, and RORγt, and cytokine profiles and found that, although monoclonal iNKT cells differentiated into all functional subsets, the NKT17 lineage was reduced or expanded depending on the TCR expressed. We examined iNKT thymic development in limited-dilution bone marrow chimeras and show that higher TCR avidity correlates with higher PLZF and reduced T-bet expression. iNKT functional subsets showed distinct tissue distribution patterns. Although each individual monoclonal TCR showed an inherent subset distribution preference that was evident across all tissues examined, the iNKT cytokine profile differed more by tissue of origin than by TCR specificity.

The discovery of new deep-sea hydrothermal vent communities in the southern ocean and implications for biogeography.

Since the first discovery of deep-sea hydrothermal vents along the Galápagos Rift in 1977, numerous vent sites and endemic faunal assemblages have been found along mid-ocean ridges and back-arc basins at low to mid latitudes. These discoveries have suggested the existence of separate biogeographic provinces in the Atlantic and the North West Pacific, the existence of a province including the South West Pacific and Indian Ocean, and a separation of the North East Pacific, North East Pacific Rise, and South East Pacific Rise. The Southern Ocean is known to be a region of high deep-sea species diversity and centre of origin for the global deep-sea fauna. It has also been proposed as a gateway connecting hydrothermal vents in different oceans but is little explored because of extreme conditions. Since 2009 we have explored two segments of the East Scotia Ridge (ESR) in the Southern Ocean using a remotely operated vehicle. In each segment we located deep-sea hydrothermal vents hosting high-temperature black smokers up to 382.8°C and diffuse venting. The chemosynthetic ecosystems hosted by these vents are dominated by a new yeti crab (Kiwa n. sp.), stalked barnacles, limpets, peltospiroid gastropods, anemones, and a predatory sea star. Taxa abundant in vent ecosystems in other oceans, including polychaete worms (Siboglinidae), bathymodiolid mussels, and alvinocaridid shrimps, are absent from the ESR vents. These groups, except the Siboglinidae, possess planktotrophic larvae, rare in Antarctic marine invertebrates, suggesting that the environmental conditions of the Southern Ocean may act as a dispersal filter for vent taxa. Evidence from the distinctive fauna, the unique community structure, and multivariate analyses suggest that the Antarctic vent ecosystems represent a new vent biogeographic province. However, multivariate analyses of species present at the ESR and at other deep-sea hydrothermal vents globally indicate that vent biogeography is more complex than previously recognised.

In hot and cold water: differential life-history traits are key to success in contrasting thermal deep-sea environments.

Few species of reptant decapod crustaceans thrive in the cold-stenothermal waters of the Southern Ocean. However, abundant populations of a new species of anomuran crab, Kiwa tyleri, occur at hydrothermal vent fields on the East Scotia Ridge. As a result of local thermal conditions at the vents, these crabs are not restricted by the physiological limits that otherwise exclude reptant decapods south of the polar front. We reveal the adult life history of this species by piecing together variation in microdistribution, body size frequency, sex ratio, and ovarian and embryonic development, which indicates a pattern in the distribution of female Kiwaidae in relation to their reproductive development. High-density 'Kiwa' assemblages observed in close proximity to sources of vent fluids are constrained by the thermal limit of elevated temperatures and the availability of resources for chemosynthetic nutrition. Although adult Kiwaidae depend on epibiotic chemosynthetic bacteria for nutrition, females move offsite after extrusion of their eggs to protect brooding embryos from the chemically harsh, thermally fluctuating vent environment. Consequently, brooding females in the periphery of the vent field are in turn restricted by low-temperature physiological boundaries of the deep-water Southern Ocean environment. Females have a high reproductive investment in few, large, yolky eggs, facilitating full lecithotrophy, with the release of larvae prolonged, and asynchronous. After embryos are released, larvae are reliant on locating isolated active areas of hydrothermal flow in order to settle and survive as chemosynthetic adults. Where the cold water restricts the ability of all adult stages to migrate over long distances, these low temperatures may facilitate the larvae in the location of vent sites by extending the larval development period through hypometabolism. These differential life-history adaptations to contrasting thermal environments lead to a disjunct life history among males and females of K. tyleri, which is key to their success in the Southern Ocean vent environment. We highlight the complexity in understanding the importance of life-history biology, in combination with environmental, ecological and physiological factors contributing to the overall global distribution of vent-endemic species.

Low global sensitivity of metabolic rate to temperature in calcified marine invertebrates.

Metabolic rate is a key component of energy budgets that scales with body size and varies with large-scale environmental geographical patterns. Here we conduct an analysis of standard metabolic rates (SMR) of marine ectotherms across a 70° latitudinal gradient in both hemispheres that spanned collection temperatures of 0-30 °C. To account for latitudinal differences in the size and skeletal composition between species, SMR was mass normalized to that of a standard-sized (223 mg) ash-free dry mass individual. SMR was measured for 17 species of calcified invertebrates (bivalves, gastropods, urchins and brachiopods), using a single consistent methodology, including 11 species whose SMR was described for the first time. SMR of 15 out of 17 species had a mass-scaling exponent between 2/3 and 1, with no greater support for a 3/4 rather than a 2/3 scaling exponent. After accounting for taxonomy and variability in parameter estimates among species using variance-weighted linear mixed effects modelling, temperature sensitivity of SMR had an activation energy (Ea) of 0.16 for both Northern and Southern Hemisphere species which was lower than predicted under the metabolic theory of ecology (Ea 0.2-1.2 eV). Northern Hemisphere species, however, had a higher SMR at each habitat temperature, but a lower mass-scaling exponent relative to SMR. Evolutionary trade-offs that may be driving differences in metabolic rate (such as metabolic cold adaptation of Northern Hemisphere species) will have important impacts on species abilities to respond to changing environments.

The Exonuclease TREX1 Constitutes an Innate Immune Checkpoint Limiting cGAS/STING-Mediated Antitumor Immunity.

The DNA exonuclease three-prime repair exonuclease 1 (TREX1) is critical for preventing autoimmunity in mice and humans by degrading endogenous cytosolic DNA, which otherwise triggers activation of the innate cGAS/STING pathway leading to the production of type I IFNs. As tumor cells are prone to aberrant cytosolic DNA accumulation, we hypothesized that they are critically dependent on TREX1 activity to limit their immunogenicity. Here, we show that in tumor cells, TREX1 restricts spontaneous activation of the cGAS/STING pathway, and the subsequent induction of a type I IFN response. As a result, TREX1 deficiency compromised in vivo tumor growth in mice. This delay in tumor growth depended on a functional immune system, systemic type I IFN signaling, and tumor-intrinsic cGAS expression. Mechanistically, we show that tumor TREX1 loss drove activation of CD8+ T cells and NK cells, prevented CD8+ T-cell exhaustion, and remodeled an immunosuppressive myeloid compartment. Consequently, TREX1 deficiency combined with T-cell-directed immune checkpoint blockade. Collectively, we conclude that TREX1 is essential to limit tumor immunogenicity, and that targeting this innate immune checkpoint remodels the tumor microenvironment and enhances antitumor immunity by itself and in combination with T-cell-targeted therapies. See related article by Toufektchan et al., p. 673.

Phylogeny and systematics of deep-sea sea pens (Anthozoa: Octocorallia: Pennatulacea).

Molecular methods have been used for the first time to determine the phylogeny of families, genera and species within the Pennatulacea (sea pens). Variation in ND2 and mtMutS mitochondrial protein-coding genes proved adequate to resolve phylogenetic relationships among pennatulacean families. The gene mtMutS is more variable than ND2 and differentiates all genera, and many pennatulacean species. A molecular phylogeny based on a Bayesian analysis reveals that suborder Sessiliflorae is paraphyletic and Subselliflorae is polyphyletic. Many families of pennatulaceans do not represent monophyletic groups including Umbellulidae, Pteroeididae, and Kophobelemnidae. The high frequency of morphological homoplasy in pennatulaceans has led to many misinterpretations in the systematics of the group. The traditional classification scheme for pennatulaceans requires revision.

Marine invertebrate skeleton size varies with latitude, temperature and carbonate saturation: implications for global change and ocean acidification.

There is great concern over the future effects of ocean acidification on marine organisms, especially for skeletal calcification, yet little is known of natural variation in skeleton size and composition across the globe, and this is a prerequisite for identifying factors currently controlling skeleton mass and thickness. Here, taxonomically controlled latitudinal variations in shell morphology and composition were investigated in bivalve and gastropod molluscs, brachiopods, and echinoids. Total inorganic content, a proxy for skeletal CaCO3 , decreased with latitude, decreasing seawater temperature, and decreasing seawater carbonate saturation state (for CaCO3 as calcite (Ωcal )) in all taxa. Shell mass decreased with latitude in molluscs and shell inorganic content decreased with latitude in buccinid gastropods. Shell thickness decreased with latitude in buccinid gastropods (excepting the Australian temperate buccinid) and echinoids, but not brachiopods and laternulid clams. In the latter, the polar species had the thickest shell. There was no latitudinal trend in shell thickness within brachiopods. The variation in trends in shell thickness by taxon suggests that in some circumstances ecological factors may override latitudinal trends. Latitudinal gradients may produce effects similar to those of future CO2 -driven ocean acidification on CaCO3 saturation state. Responses to latitudinal trends in temperature and saturation state may therefore be useful in informing predictions of organism responses to ocean acidification over long-term adaptive timescales.

Initial antihypertensive agent effects on acute blood pressure after intracerebral haemorrhage.

INTRODUCTION: Current guidelines recommend blood pressure (BP) lowering in patients after acute intracerebral haemorrhage (ICH) without guidance on initial choice of antihypertensive class. This study sought to determine if initial antihypertensive class differentially effects acute BP lowering in a large multiethnic ICH cohort. METHODS: Subjects enrolled in the Ethnic/Racial Variations in ICH study between August 2010 and August 2017 with elevated admission BP and who received labetalol, nicardipine or hydralazine monotherapy as initial antihypertensive were analysed. Primary outcomes were systolic and diastolic BP changes from baseline to first BP measurement after initial antihypertensive treatment. Secondary outcomes included haematoma expansion (HE), hospital length of stay (LOS) and modified Rankin Score (mRS) up to 12 months after ICH. Exploratory outcomes assessed effects of race/ethnicity. Linear and logistic regression analyses, adjusted for relevant covariates, were performed to determine associations of antihypertensive class with outcomes. RESULTS: In total, 1156 cases were used in analyses. Antihypertensive class was associated with diastolic BP change (p=0.003), but not systolic BP change (p=0.419). Initial dosing with nicardipine lowered acute diastolic BP than labetalol (least square mean difference (labetalol-nicardipine)=5.47 (2.37, 8.57), p<0.001). Initial antihypertensive class was also found to be associated with LOS (p=0.028), but not with HE (p=0.406), mortality (p=0.118), discharge disposition (p=0.083) or mRS score at discharge, 3, 6 and 12 months follow-up (p=0.262, 0.276, 0.152 and 0.36, respectively). Race/ethnicity variably affected multivariable models. CONCLUSION: In this large acute ICH cohort, initial antihypertensive class was associated with acute diastolic, but not systolic, BP-lowering suggesting differential effects of antihypertensive agents. TRIAL REGISTRATION NUMBER: NCT01202864.

Adult antarctic krill feeding at abyssal depths.

Antarctic krill (Euphausia superba) is a large euphausiid, widely distributed within the Southern Ocean [1], and a key species in the Antarctic food web [2]. The Discovery Investigations in the early 20(th) century, coupled with subsequent work with both nets and echosounders, indicated that the bulk of the population of postlarval krill is typically confined to the top 150 m of the water column [1, 3, 4]. Here, we report for the first time the existence of significant numbers of Antarctic krill feeding actively at abyssal depths in the Southern Ocean. Biological observations from the deep-water remotely operated vehicle Isis in the austral summer of 2006/07 have revealed the presence of adult krill (Euphausia superba Dana), including gravid females, at unprecedented depths in Marguerite Bay, western Antarctic Peninsula. Adult krill were found close to the seabed at all depths but were absent from fjords close inshore. At all locations where krill were detected they were seen to be actively feeding, and at many locations there were exuviae (cast molts). These observations revise significantly our understanding of the depth distribution and ecology of Antarctic krill, a central organism in the Southern Ocean ecosystem.

The ocean is not deep enough: pressure tolerances during early ontogeny of the blue mussel Mytilus edulis.

Early ontogenetic adaptations reflect the evolutionary history of a species. To understand the evolution of the deep-sea fauna and its adaptation to high pressure, it is important to know the effects of pressure on their shallow-water relatives. In this study we analyse the temperature and pressure tolerances of early life-history stages of the shallow-water species Mytilus edulis. This species expresses a close phylogenetic relationship with hydrothermal-vent mussels of the subfamily Bathymodiolinae. Tolerances to pressure and temperature are defined in terms of fertilization success and embryo developmental rates in laboratory-based experiments. In M. edulis, successful fertilization under pressure is possible up to 500 atm (50.66 MPa), at 10, 15 and 20 degrees C. A slower embryonic development is observed with decreasing temperature and with increasing pressure; principally, pressure narrows the physiological tolerance window in different ontogenetic stages of M. edulis, and slows down metabolism. This study provides important clues on possible evolutionary pathways of hydrothermal vent and cold-seep bivalve species and their shallow-water relatives. Evolution and speciation patterns of species derive mostly from their ability to adapt to variable environmental conditions, within environmental constraints, which promote morphological and genetic variability, often differently for each life-history stage. The present results support the view that a direct colonization of deep-water hydrothermal vent environments by a cold eurythermal shallow-water ancestor is indeed a possible scenario for the Mytilinae, challenging previous hypothesis of a wood/bone to seep/vent colonization pathway.

Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology.

Phosphatidylinositol 3-kinase-gamma (PI3Kγ) is highly expressed in leukocytes and is an attractive drug target for immune modulation. Different experimental systems have led to conflicting conclusions regarding inflammatory and anti-inflammatory functions of PI3Kγ. Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110γ catalytic subunit of PI3Kγ. She has a history of childhood-onset antibody defects, cytopenias, and T lymphocytic pneumonitis and colitis, with reduced peripheral blood memory B, memory CD8+ T, and regulatory T cells and increased CXCR3+ tissue-homing CD4 T cells. PI3Kγ-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3α/ß-dependent manner upon TLR stimulation. Pik3cg-deficient mice recapitulate major features of human disease after exposure to natural microbiota through co-housing with pet-store mice. Together, our results emphasize the physiological importance of PI3Kγ in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice.

Fauna of the Kemp Caldera and its upper bathyal hydrothermal vents (South Sandwich Arc, Antarctica).

Faunal assemblages at hydrothermal vents associated with island-arc volcanism are less well known than those at vents on mid-ocean ridges and back-arc spreading centres. This study characterizes chemosynthetic biotopes at active hydrothermal vents discovered at the Kemp Caldera in the South Sandwich Arc. The caldera hosts sulfur and anhydrite vent chimneys in 1375-1487 m depth, which emit sulfide-rich fluids with temperatures up to 212°C, and the microbial community of water samples in the buoyant plume rising from the vents was dominated by sulfur-oxidizing Gammaproteobacteria. A total of 12 macro- and megafaunal taxa depending on hydrothermal activity were collected in these biotopes, of which seven species were known from the East Scotia Ridge (ESR) vents and three species from vents outside the Southern Ocean. Faunal assemblages were dominated by large vesicomyid clams, actinostolid anemones, Sericosura sea spiders and lepetodrilid and cocculinid limpets, but several taxa abundant at nearby ESR hydrothermal vents were rare such as the stalked barnacle Neolepas scotiaensis. Multivariate analysis of fauna at Kemp Caldera and vents in neighbouring areas indicated that the Kemp Caldera is most similar to vent fields in the previously established Southern Ocean vent biogeographic province, showing that the species composition at island-arc hydrothermal vents can be distinct from nearby seafloor-spreading systems. δ 13C and δ 15N isotope values of megafaunal species analysed from the Kemp Caldera were similar to those of the same or related species at other vent fields, but none of the fauna sampled at Kemp Caldera had δ 13C values, indicating nutritional dependence on Epsilonproteobacteria, unlike fauna at other island-arc hydrothermal vents.

A framework for the development of a global standardised marine taxon reference image database (SMarTaR-ID) to support image-based analyses.

Video and image data are regularly used in the field of benthic ecology to document biodiversity. However, their use is subject to a number of challenges, principally the identification of taxa within the images without associated physical specimens. The challenge of applying traditional taxonomic keys to the identification of fauna from images has led to the development of personal, group, or institution level reference image catalogues of operational taxonomic units (OTUs) or morphospecies. Lack of standardisation among these reference catalogues has led to problems with observer bias and the inability to combine datasets across studies. In addition, lack of a common reference standard is stifling efforts in the application of artificial intelligence to taxon identification. Using the North Atlantic deep sea as a case study, we propose a database structure to facilitate standardisation of morphospecies image catalogues between research groups and support future use in multiple front-end applications. We also propose a framework for coordination of international efforts to develop reference guides for the identification of marine species from images. The proposed structure maps to the Darwin Core standard to allow integration with existing databases. We suggest a management framework where high-level taxonomic groups are curated by a regional team, consisting of both end users and taxonomic experts. We identify a mechanism by which overall quality of data within a common reference guide could be raised over the next decade. Finally, we discuss the role of a common reference standard in advancing marine ecology and supporting sustainable use of this ecosystem.

Altered Binding of Tumor Antigenic Peptides to MHC Class I Affects CD8+ T Cell-Effector Responses.

T-cell priming occurs when a naïve T cell recognizes cognate peptide-MHC complexes on an activated antigen-presenting cell. The circumstances of this initial priming have ramifications on the fate of the newly primed T cell. Newly primed CD8+ T cells can embark onto different trajectories, with some becoming short-lived effector cells and others adopting a tissue resident or memory cell fate. To determine whether T-cell priming influences the quality of the effector T-cell response to tumors, we used transnuclear CD8+ T cells that recognize the melanoma antigen TRP1 using TRP1high or TRP1low TCRs that differ in both affinity and fine specificity. From a series of altered peptide ligands, we identified a point mutation (K8) in a nonanchor residue that, when analyzed crystallographically and biophysically, destabilized the peptide interaction with the MHC binding groove. In vitro, the K8 peptide induced robust proliferation of both TRP1high and TRP1low CD8+ T cells but did not induce expression of PD-1. Cytokine production from K8-stimulated TRP1 cells was minimal, whereas cytotoxicity was increased. Upon transfer into B16 tumor-bearing mice, the reference peptide (TRP1-M9)- and K8-stimulated TRP1 cells were equally effective at controlling tumor growth but accomplished this through different mechanisms. TRP1-M9-stimulated cells produced more IFNγ, whereas K8-stimulated cells accumulated to higher numbers and were more cytotoxic. We, therefore, conclude that TCR recognition of weakly binding peptides during priming can skew the effector function of tumor-specific CD8+ T cells.

Targeting Cytokine Therapy to the Pancreatic Tumor Microenvironment Using PD-L1-Specific VHHs.

Cytokine-based therapies for cancer have not achieved widespread clinical success because of inherent toxicities. Treatment for pancreatic cancer is limited by the dense stroma that surrounds tumors and by an immunosuppressive tumor microenvironment. To overcome these barriers, we developed constructs of single-domain antibodies (VHHs) against PD-L1 fused with IL-2 and IFNγ. Targeting cytokine delivery in this manner reduced pancreatic tumor burden by 50%, whereas cytokines fused to an irrelevant VHH, or blockade of PD-L1 alone, showed little effect. Targeted delivery of IL-2 increased the number of intratumoral CD8+ T cells, whereas IFNγ reduced the number of CD11b+ cells and skewed intratumoral macrophages toward the display of M1-like characteristics. Imaging of fluorescent VHH-IFNγ constructs, as well as transcriptional profiling, demonstrated targeting of IFNγ to the tumor microenvironment. Many tumors and tumor-infiltrating myeloid cells express PD-L1, rendering them potentially susceptible to this form of targeted immunotherapy. Cancer Immunol Res; 6(4); 389-401. ©2018 AACR.

Habitat associations in gastropod species at East Pacific Rise hydrothermal vents (9 degrees 50'N).

At deep-sea hydrothermal vents on the East Pacific Rise (9 degrees 50'N), distinct megafaunal assemblages are positioned along strong thermal and chemical gradients. We investigated the distribution of gastropod species to determine whether they associate with specific megafaunal zones and to determine the thermal boundaries of their habitats. Gastropods colonized a series of basalt blocks that were placed into three different zones characterized by vestimentiferan tubeworms, bivalves, and suspension-feeders, respectively. Additional gastropods were collected on selected blocks from higher temperature vestimentiferan habitat and from grab samples of alvinellid polychaetes. On the blocks, gastropod species clustered into a "Cool" group (Clypeosectus delectus, Eulepetopsis vitrea, Gorgoleptis spiralis, and Lepetodrilus ovalis) whose species tended to be most abundant in the suspension-feeder zone, and a "Warm" group (Lepetodrilus cristatus, L. elevatus, L. pustulosus, and Cyathermia naticoides) whose species all were significantly more abundant in the vestimentiferan zone than elsewhere. The temperature ranges of Cool species were generally lower than the ranges of Warm ones, although both groups were present at 3 to 6 degrees C; also present was Bathymargarites symplector, which clustered with neither group. Three additional species, Rhynchopelta concentrica, Neomphalus fretterae, and Nodopelta rigneae, co-occurred with Warm-group species on selected blocks from hotter habitats. Although a few species were found only in alvinellid collections, most species were not exclusive to a specific megafaunal zone. We propose that species in the Cool and Warm groups occupy specific microhabitats that are present in more than one zone.

Clinical Dosing Regimen of Selinexor Maintains Normal Immune Homeostasis and T-cell Effector Function in Mice: Implications for Combination with Immunotherapy.

Selinexor (KPT-330) is a first-in-class nuclear transport inhibitor currently in clinical trials as an anticancer agent. To determine how selinexor might affect antitumor immunity, we analyzed immune homeostasis in mice treated with selinexor and found disruptions in T-cell development, a progressive loss of CD8 T cells, and increases in inflammatory monocytes. Antibody production in response to immunization was mostly normal. Precursor populations in bone marrow and thymus were unaffected by selinexor, suggesting that normal immune homeostasis could recover. We found that a high dose of selinexor given once per week preserved nearly normal immune functioning, whereas a lower dose given 3 times per week did not restore immune homeostasis. Both naïve and effector CD8 T cells cultured in vitro showed impaired activation in the presence of selinexor. These experiments suggest that nuclear exportins are required for T-cell development and function. We determined the minimum concentration of selinexor required to block T-cell activation and showed that T-cell-inhibitory effects of selinexor occur at levels above 100 nmol/L, corresponding to the first 24 hours post-oral dosing. In a model of implantable melanoma, selinexor treatment at 10 mg/kg with a 4-day drug holiday led to intratumoral IFNγ+, granzyme B+ cytotoxic CD8 T cells that were comparable with vehicle-treated mice. Overall, selinexor treatment leads to transient inhibition of T-cell activation, but clinically relevant once and twice weekly dosing schedules that incorporate sufficient drug holidays allow for normal CD8 T-cell functioning and development of antitumor immunity. Mol Cancer Ther; 16(3); 428-39. ©2017 AACRSee related article by Farren et al., p. 417.