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KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients1–7. Whether inactive-state selective inhibition can be used to therapeutically target non-G12C KRAS mutants remains under investigation. Here we report the discovery and characterization of a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS while sparing NRAS and HRAS. Although limited to only a few amino acids, the evolutionary divergence in the GTPase domain of RAS isoforms was sufficient to impart orthosteric and allosteric constraints for KRAS selectivity. The inhibitor blocked nucleotide exchange to prevent the activation of wild-type KRAS and a broad range of KRAS mutants, including G12A/C/D/F/V/S, G13C/D, V14I, L19F, Q22K, D33E, Q61H, K117N and A146V/T. Inhibition of downstream signalling and proliferation was restricted to cancer cells harbouring mutant KRAS, and drug treatment suppressed KRAS mutant tumour growth in mice, without having a detrimental effect on animal weight. Our study suggests that most KRAS oncoproteins cycle between an active state and an inactive state in cancer cells and are dependent on nucleotide exchange for activation. Pan-KRAS inhibitors, such as the one described here, have broad therapeutic implications and merit clinical investigation in patients with KRAS-driven cancers.

Contains fulltext : 283431.pdf (Publisher’s version ) (Closed access) Aberrations in nuclear size and shape are commonly used to identify cancerous tissue. However, it remains unclear whether the disturbed nuclear structure directly contributes to the cancer pathology or is merely a consequence of other events occurring during tumorigenesis. Here, we show that highly invasive and proliferative breast cancer cells frequently exhibit Akt-driven lower expression of the nuclear envelope proteins lamin A/C, leading to increased nuclear deformability that permits enhanced cell migration through confined environments that mimic interstitial spaces encountered during metastasis. Importantly, increasing lamin A/C expression in highly invasive breast cancer cells reflected gene expression changes characteristic of human breast tumors with higher LMNA expression, and specifically affected pathways related to cell-ECM interactions, cell metabolism, and PI3K/Akt signaling. Further supporting an important role of lamins in breast cancer metastasis, analysis of lamin levels in human breast tumors revealed a significant association between lower lamin A levels, Akt signaling, and decreased disease-free survival. These findings suggest that downregulation of lamin A/C in breast cancer cells may influence both cellular physical properties and biochemical signaling to promote metastatic progression.

Inactive state-selective KRAS(G12C) inhibitors1–8 demonstrate a 30–40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer9. The genetic basis for resistance to these first-in-class mutant GTPase inhibitors remains under investigation. Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib. Multiple treatment-emergent alterations were observed across 27 patients, including alterations in KRAS, NRAS, BRAF, EGFR, FGFR2, MYC and other genes. In preclinical patient-derived xenograft and cell line models, resistance to KRAS(G12C) inhibition was associated with low allele frequency hotspot mutations in KRAS(G12V or G13D), NRAS(Q61K or G13R), MRAS(Q71R) and/or BRAF(G596R), mirroring observations in patients. Single-cell sequencing in an isogenic lineage identified secondary RAS and/or BRAF mutations in the same cells as KRAS(G12C), where they bypassed inhibition without affecting target inactivation. Genetic or pharmacological targeting of ERK signalling intermediates enhanced the antiproliferative effect of G12C inhibitor treatment in models with acquired RAS or BRAF mutations. Our study thus suggests a heterogenous pattern of resistance with multiple subclonal events emerging during G12C inhibitor treatment. A subset of patients in our cohort acquired oncogenic KRAS, NRAS or BRAF mutations, and resistance in this setting may be delayed by co-targeting of ERK signalling intermediates. These findings merit broader evaluation in prospective clinical trials. Multiple treatment-emergent alterations appear in patients with advanced-stage cancer who were treated with a KRAS inhibitor.

Fluid resuscitation is crucial in the initial management of sepsis; however, little is known about the serial changes and overall distribution of fluids administered into the body. To identify the feasibility of longitudinal bioelectrical impedance analysis during fluid treatment, a preclinical porcine model of Escherichia coli-induced sepsis was used. After sepsis induction, pigs were treated with fluid and vasopressors and monitored for up to 12 h after bacterial infusion or until death. Bipolar electrodes for bioelectrical impedance analysis were attached to the left extremities and measurements were performed every 10 min. Among the 12 subjects, 7 pigs expired during the experiment, and the median survival was 9.5 h. As sepsis progressed with an increase in cumulative fluid balance, R0 [∝ 1/extracellular water (ECW)] decreased, while Ri [∝ 1/intracellular water (ICW)] and ratio of extracellular water to total body water (ECW/TBW) increased. The phase angle constantly decreased throughout the monitoring period, and all non-survivors died when the phase angle decreased by more than 10%. Among the variables, ΔR0 and Δphase angle showed moderate negative correlations, and ΔECW/TBW showed a moderate positive correlation with the hourly fluid balance. Compared to survivors, a greater increase in ΔECW/TBW and a decrease in phase angle were observed in non-survivors over time, with an increase in cumulative fluid balance. Differences in ΔECW/TBW and phase angle emerged at 240 min when the difference in cumulative fluid balance between the two groups (survivors vs non-survivors) exceeded 1000 mL. In conclusion, continuous measurements of bioelectrical impedance analysis in a porcine sepsis model are feasible and may reflect changes in the body water profile during fluid resuscitation.

Since the discovery of mutationally activated RAS in human cancers, small molecule inhibitors have been long sought but disappointingly elusive. RAS is in an inactive, “off” state when bound to guanosine diphosphate (GDP) and in an active, “on” state when bound to guanosine triphosphate (GTP). According to dogma, mutationally activated RAS is insensitive to GTPase activating proteins (GAPs) that accelerate conversion of active GTP-bound RAS to inactive, GDP-bound RAS. Yet, a small molecule blocks the growth of cancer cells expressing a KRAS Gly(12)→Cys (KRAS(G12C)) mutant, despite binding only GDP-bound KRAS(G12C) (1). The US Food and Drug Administration recently approved sotorasib, a KRAS(G12C) off inhibitor, and more are in the pipeline. How can there be sufficient GDP-bound KRAS(G12C) to enable inhibitor efficacy? On page 197 of this issue, Li et al. (2) find that a GAP for heterotrimeric Gα subunits can also promote GTP hydrolysis to stimulate formation of GDP-bound KRAS(G12C).

Early and appropriate antibiotic treatment is a keystone in treating patients with sepsis. Despite its importance, blood culture which requires a few days remains as a pillar of diagnostic method for microorganisms and their antibiotic susceptibility.

Animals living in extreme environments, such as hydrothermal vents, would be expected to have evolved protective shells or exoskeletons to maintain homeostasis. The outer part of the exoskeleton of vent crabs (Austinograea sp.) in the Indian Ocean hydrothermal vent was one of the hardest (approximately 7 GPa) biological materials ever reported. To explore the exoskeletal characteristics of vent crabs which enable them to adapt to severe environments, a comparative analysis was conducted with the Asian paddle crab (Charybdis japonica) living in coastal areas. Nanoindentation, thermogravimetric analysis, scanning electron microscopy, energy dispersive x-ray analysis, and Raman spectroscopy were used to analyze the mechanical properties, thermal stability, structure, surface components, and the composition of compounds, respectively. Though both species have four-layered exoskeletons, the outermost layer of the vent crab, a nano-granular structure, was much thicker than that of the coastal crab. The proportions of aluminum and sulfur that constitute the epicuticle of the exoskeleton were higher in the vent crab than in the coastal crab. There was a lack of water or volatile substances, lots of CaCO3, and no carotenoid-based compounds in the exoskeleton of the vent crab. These might have improved the mechanical properties and thermal stability of the hydrothermal species.

KRAS mutations are among the most common genetic alterations in lung, colorectal, and pancreatic cancers. Direct inhibition of KRAS oncoproteins has been a long-standing pursuit in precision oncology, one established shortly after the discovery of RAS mutations in human cancer cells nearly 40 years ago. Recent advances in medicinal chemistry have established inhibitors targeting KRAS(G12C), a mutation found in ∼13% of lung adenocarcinomas and, at a lower frequency, in other cancers. Preclinical studies describing their discovery and mechanism of action, coupled with emerging clinical data from patients treated with these drugs, have sparked a renewed enthusiasm in the study of KRAS and its therapeutic potential. Here, we discuss how these advances are reshaping the fundamental aspects of KRAS oncoprotein biology and the strides being made toward improving patient outcomes in the clinic.

Habitat heterogeneity is one of the major factors shaping community structure and diversity of many fauna. The present study aimed to reveal the influence of habitat heterogeneity on the nematode community structures and diversity in a seasonally hypoxic bay (Omura Bay of Nagasaki in Western Kyushu, Japan). The severity of hypoxia varies typically along north–south axis of the bay, which is intensified southwardly. Nematode abundance and diversity were highest in the northern site than the other sites, and nematode communities were clustered into three groups by sampling site. There were significant differences in composition (Two-way ANOSIM, Rho = 0.726, p

A new species of chionelasmatid sessile vent barnacle, Eochionelasmus coreana sp. nov., is described and illustrated on the basis of specimens collected from the Solitaire hydrothermal vent field in the Central Indian Ridge of the Indian Ocean. This new species is morphologically very similar to E. ohtai, the type species of the genus Eochionelasmus. However, it differs from E. ohtai in its distribution, the status of the notch on the maxillule, and the positions of rl1 and cl1 on whorls of the imbricating plates. In addition, a molecular phylogenetic tree indicated that the chionelasmatid Eochionelasmus was closely related to the waikalasmatid Waikalasma with high supporting values rather than the other chionelasmatid Chionelasmus. The new species is not only the first record of a sessile vent barnacle from outside of the Pacific Ocean, but is also the first sessile barnacle from the Indian Ocean.

The recently discovered Onnuri hydrothermal vent field (OVF) is a typical off-axis ultramafic-hosted vent system, located on the summit of the dome-like ocean core complex (OCC) at a distance of ∼12 km from the ridge axis along the middle region of the Central Indian Ridge (CIR). The plume chemistry with high methane anomaly was consistent with the precursor of hydrothermal activity; however, the fundamental characteristic of the OVF system, such as the hydrothermal circulation process and source of heat, remains poorly understood. Here, we focus on the geochemical features of surface sediments and minerals collected at and around the OVF region in order to better understand this venting system. The results reveal that the OVF sediments are typified by remarkably high concentrations of Fe, Si, Ba, Cu, and Zn, derived from hydrothermal fluid and S and Mg from seawater; depleted C-S isotope compositions; and abundant hydrothermally precipitated minerals (i.e., Fe–Mn hydroxides, sulfide and sulfate minerals, and opal silica). Notably, the occurrence of pure talc and barite bears witness to strong hydrothermal activity in the OVF, and their sulfur and strontium isotope geochemistry agree with extensive mixing of the unmodified seawater with high-temperature fluid derived from the gabbroic rock within the ultramafic-dominated ridge segment. The findings reveal that the OVF is a representative example of an off-axis, high-temperature hydrothermal circulation system, possibly driven by the exothermic serpentinization of exposed peridotites. Given the widespread distribution of OCC with detachment faults, furthermore, the OVF may be the most common type of hydrothermal activity in the CIR, although the paucity of data precludes generalizing this result. This study provides important information contributing to our understanding of the ultramafic-hosted hydrothermal vent system with a non-magmatic heat source along mid-ocean ridges.

OBJECTIVE: We examined the change in foreleg raising power after Sion's local paralysis (SLP) with succinylcholine in the shoulder muscle. METHODS: A randomized, double blind, placebo-controlled, porcine study was designed and performed at a research institution. Ten male Korean native pigs were randomized into an intervention group (n = 5) and a control group (n = 5). The injection points were in the middle of the left trapezius muscle and the middle of the left deltoid muscle. The control group received 2 ml normal saline (NS), 1 ml injected in each point. The intervention group received 0.4 mg/kg succinylcholine diluted to 2 ml in NS, and 1 ml was injected in each point. To represent the foreleg raising power, the height of the left forelegs from baseline (experiment table) was measured. We measured the foreleg height and oxygen saturation at −4, −2, 0, +2, +4, +6, +8, +10, +20, +30, and +60 min. RESULTS: After SLP, foreleg height immediately declined in the intervention group. It recovered slightly for a few minutes and declined from 4 to 8 min. In the control group, foreleg height was relatively similar throughout the study period. A repeated-measure analysis of variance revealed a significant group × time interaction (F(10,80) = 2.37, P = 0.017), a significant main effect for group (F(1,8) = 6.25, P = 0.037), and a significant main effect for time (F(10,80) = 4.41, P

The dispersal of organisms in an isolated environment of a hydrothermal vent remains unclear. Here, we provide direct evidence that meroplanktonic larvae may migrate thousands of meters above the ocean floor. The morphological quantitative measurements of mesozooplankton were conducted in the Onnuri Vent Field (OVF), the Solitaire Fields (SF), and the reference site (ref-site). Only one species of bivalve larva that appeared at the OVF and the ref-site (0–200 m) was similar to Bathymodiolus spp. Sixteen species of gastropod larvae were distinguished, among which, species 1–4, 6, and 13 had holoplanktonic features (Atlanta, Oxygrus, and Limacina), whereas species 5, 7–12, and 14–16 had meroplanktonic features. Species 5, 11, and 12 appeared only at the OVF, 9 and 10 appeared only in the SF, 14–16 appeared only at the ref-site, and species 7 and 8 appeared in all surveyed stations. The species 5, 8, 12, 14, and 15 have morphological features similar to Vetulonia spp., and species 7 was similar to Lepetodrilidae; species 9–11 and 16 were similar to Phymorphynchus protoconchs. The morphologically distinguished mollusk larvae in the upper layers of the water column (0–200 m) indicate that larvae associated with deep-sea hydrothermal vents may disperse approximately 2000 m above the vents.

Cellular proliferation depends on the accurate and timely replication of the genome. Several genetic diseases are caused by mutations in key DNA replication genes; however, it remains unclear whether these genes influence the normal program of DNA replication timing. Similarly, the factors that regulate DNA replication dynamics are poorly understood. To systematically identify trans-acting modulators of replication timing, we profiled replication in 184 cell lines from three cell types, encompassing 60 different gene knockouts or genetic diseases. Through a rigorous approach that considers the background variability of replication timing, we concluded that most samples displayed normal replication timing. However, mutations in two genes showed consistently abnormal replication timing. The first gene was RIF1, a known modulator of replication timing. The second was MCM10, a highly conserved member of the pre-replication complex. Cells from a single patient carrying MCM10 mutations demonstrated replication timing variability comprising 46% of the genome and at different locations than RIF1 knockouts. Replication timing alterations in the mutated MCM10 cells were predominantly comprised of replication delays and initiation site gains and losses. Taken together, this study demonstrates the remarkable robustness of the human replication timing program and reveals MCM10 as a novel candidate modulator of DNA replication timing.

Balanomorph Eochionelasmus species are hydrothermal vent endemic barnacles. In the genus Eochionelasmus, three species are known to date and they distribute at three different vent fields in Pacifi...

Diamond field emitter array field emission cathodes (DFEA FECs) are attractive for the next generation of injectors due to their ability to produce transversely shaped beams without the need for complex masking or laser schemes. However, reliability of this cathode technology remains a challenging issue as principal mechanisms guiding and allowing for output beam shaping remained poorly understood. This paper reports the results of testing two DFEA FECs with the same pattern and emitter tip geometry. Although both cathodes were able to sustain gradients of 44 MV/m and produce maximum output integral charge of 0.5 nC per radio frequency pulse, their emission patterns were different. One cathode did not produce a shaped beam, while the other one did. This difference was explained by the extent of the local variations of the diamond material across the arrays as discovered by spatially resolved Raman spectroscopy. The main practical takeaways were (i) tip sharpness was not a prerequisite for producing a shaped beam and instead (ii) material characteristics resulting in different cathode ballast resistance affected emission spatial uniformity across the array and hence the beam shaping.

Cellular proliferation depends on the accurate and timely replication of the genome. Several genetic diseases are caused by mutations in key DNA replication genes; however, it remains unclear whether these genes influence the normal program of DNA replication timing. Similarly, the factors that regulate DNA replication dynamics are poorly understood. To systematically identify trans-acting modulators of replication timing, we profiled replication in 184 cell lines from three cell types, encompassing 60 different gene knockouts or genetic diseases. Through a rigorous approach that considers the background variability of replication timing, we concluded that most samples displayed normal replication timing. However, mutations in two genes showed consistently abnormal replication timing. The first gene was RIF1, a known modulator of replication timing. The second was MCM10, a highly conserved member of the pre-replication complex. MCM10 mutant cells demonstrated replication timing variability comprising 46% of the genome and at different locations than RIF1 knockouts. Replication timing alterations in MCM10-mutant cells was predominantly comprised of replication initiation defects. Taken together, this study demonstrates the remarkable robustness of the human replication timing program and reveals MCM10 as a novel modulator of DNA replication timing.

KRAS GTPases are activated in one-third of cancers, and KRAS(G12C) is one of the most common activating alterations in lung adenocarcinoma1,2. KRAS(G12C) inhibitors3,4 are in phase-I clinical trials and early data show partial responses in nearly half of patients with lung cancer. How cancer cells bypass inhibition to prevent maximal response to therapy is not understood. Because KRAS(G12C) cycles between an active and inactive conformation4–6, and the inhibitors bind only to the latter, we tested whether isogenic cell populations respond in a non-uniform manner by studying the effect of treatment at a single-cell resolution. Here we report that, shortly after treatment, some cancer cells are sequestered in a quiescent state with low KRAS activity, whereas others bypass this effect to resume proliferation. This rapid divergent response occurs because some quiescent cells produce new KRAS(G12C) in response to suppressed mitogen-activated protein kinase output. New KRAS(G12C) is maintained in its active, drug-insensitive state by epidermal growth factor receptor and aurora kinase signalling. Cells without these adaptive changes—or cells in which these changes are pharmacologically inhibited—remain sensitive to drug treatment, because new KRAS(G12C) is either not available or exists in its inactive, drug-sensitive state. The direct targeting of KRAS oncoproteins has been a longstanding objective in precision oncology. Our study uncovers a flexible non-uniform fitness mechanism that enables groups of cells within a population to rapidly bypass the effect of treatment. This adaptive process must be overcome if we are to achieve complete and durable responses in the clinic. Populations of KRAS(G12C)-mutant cancer cells can rapidly bypass the effects of treatment with KRAS(G12C) inhibitors because a subset of cells escapes drug-induced quiescence by producing new KRAS(G12C) that is maintained in its active, drug-insensitive state.

Diamond field-emitter arrays (DFEAs) are arrays of diamond pyramids with exquisitely sharp tips and micrometer-scale bases that produce high current densities. These arrays can be fabricated in arbitrary shapes, ranging from single tips to many millions of tips, so that they produce an inherently shaped electron beam. Each tip emits a modest current, but the large dense array can produce many Amps. We are investigating these cathodes for use in dielectric wakefield accelerators; however, they may also be applicable to vacuum microwave tubes. Recently, shaped beam production and transport have been demonstrated in the 1.3-GHz RF gun at the Argonne Cathode Test Stand at the Argonne National Laboratory. The charge was measured on a Faraday cup and the beam imaged on a YAG screen with peak electric field gradients on the cathode ranging from 12 to 35 MV/m. Three cathode geometries were tested: one 1-mm equilateral triangle with 7- $\mu \text{m}$ base pyramids and 10- $\mu \text{m}$ pitch, one 1-mm equilateral triangle with 10- $\mu \text{m}$ base and 25- $\mu \text{m}$ pitch, and one sparse $5\times 5$ square array with 20- $\mu \text{m}$ base and 400- $\mu \text{m}$ pitch. The two triangular arrays emitted 35 nC in an RF macropulse at 35 MV/m and 13-nC charge at 27 MV/m, respectively, while the sparse array emitted 0.060-nC charge at 15 MV/m. This article presents the results of the triangular array experiments, including damage due to breakdown in the RF gun and initial models of tip-to-tip shielding.

SUMMARY Wnt signaling pathways direct key physiological decisions in development. Here, we establish a role for a pleckstrin homology domain-containing protein, PLEKHA4, as a modulator of signaling strength in Wnt receiving cells. PLEKHA4 oligomerizes into clusters at PI(4,5)P2-rich regions of the plasma membrane and recruits the Cullin-3 (CUL3) E3 ubiquitin ligase substrate adaptor Kelch-like protein 12 (KLHL12) to these assemblies. This recruitment decreases CUL3-KLHL12-mediated polyubiquitination of Dishevelled, a central intermediate in canonical and non-canonical Wnt signaling. Knock down of PLEKHA4 in mammalian cells demonstrates that PLEKHA4 positively regulates canonical and non-canonical Wnt signaling via these effects on the Dishevelled polyubiquitination machinery. In vivo knockout of the Drosophila melanogaster PLEKHA4 homolog, kramer, selectively affects the non-canonical, planar cell polarity (PCP) signaling pathway. We propose that PLEKHA4 tunes the sensitivities of cells toward the stimulation of Wnt or PCP signaling by sequestering a key E3 ligase adaptor controlling Dishevelled polyubiquitination within PI(4,5) P2-rich plasma membrane clusters., Graphical Abstract, In Brief Regulation of Wnt signaling is critical to metazoan development. Shami Shah et al. identify a phosphoinositide-binding protein, PLEKHA4/kramer, that enhances Wnt signaling in mammalian cells and the non-canonical pathway, planar cell polarity, in Drosophila. Mechanistically, PLEKHA4 sequesters the Cullin-3 E3 ligase adaptor KLHL12 in plasma membrane clusters, preventing Dishevelled polyubiquitination.

Balanomorph Eochionelasmus species are hydrothermal vent endemic barnacles. In the genus Eochionelasmus, three species are known to date and they distribute at three different vent fields in Pacific and Indian Oceans, E. ohtai in the Southwest Pacific Ocean, E. paquensis in the East Pacific Ocean, and E. coreana in the Indian Ocean. Therefore, Eochionelasmus species are considered to be a meaningful model taxon to elucidate the evolutionary history of vent organism in relation to geotectonic events. Here, we characterized the partial mitogenome of a newly described vent barnacle Eochionelasmus coreana Chan et al., 2020 from the Solitaire vent field in the Indian Ocean. The length of mitogenome was 16,804 bp with 64.0% AT content. Its gene content and organization was identical to those of E. ohtai. There was one significant part in the mitogenome of E. coreana, which was a long intergenic region over 2 kb found between tRNAPro and tRNAThr. The phylogenetic tree suggested the monophyly of E. ohtai and E. coreana with high supporting values. In the future, additional mitogenome analysis of the last Eochionelasmus species, E. paquensis, could expand our understanding about the speciation and global distribution of Eochionelasmus species.

This article contains supplementary data from the research paper entitled "A newly discovered Gigantidas bivalve mussel from the Onnuri Vent Field on the northern Central Indian Ridge" [1], describes a new mussel species within the subfamily Bathymodiolinae named Gigantidas vrijenhoeki. Data are comprised of two parts: 1) shell image and molecular analyses of G. vrijenhoeki and 2) metagenomic community analyses of gill-associated symbiotic bacteria on G. vrijenhoeki. G. vrijenhoeki data were obtained from type specimens described in Jang et al. 2020 [1]. The molecular analysis was conducted by calculating genetic distance at intra- and inter-specific level within genus Gigantidas based on the sequence data of two mitochondrial genes (COI and ND4). The metagenomic dataset of gill-associated symbionts were generated by Illumina Miseq sequencing of the V3-V4 region of 16S rRNA from 12 specimens of G. vrijenhoeki collected from the same vent site, Onnuri Vent Field.

Most cancer cells experience oncogene-induced replication stress and, as a result, exhibit high intrinsic activation of the ATR kinase. Although cancer cells often become more dependent on ATR for survival, the precise mechanism by which ATR signaling ensures cancer cell fitness and viability remains incompletely understood. Here, we find that intrinsic ATR signaling is crucial for the ability of cancer cells to promote DNA end resection, the first step in homology-directed DNA repair. Inhibition of ATR over multiple cell division cycles depletes the pool of pro-resection factors and prevents the engagement of RAD51 as well as RAD52 at nuclear foci, leading to toxic DNA-PKcs signaling and hypersensitivity to PARP inhibitors. The effect is markedly distinct from acute ATR inhibition, which blocks RAD51-mediated repair but not resection and engagement of RAD52. Our findings reveal a key pro-resection function for ATR and define how ATR inhibitors can be used for effective manipulation of DNA end resection capacity and DNA repair outcomes in cancer cells.

Hydrothermal vent is the one of the main natural Hg sources to the deep ocean. Thus, we investigated which Hg speciation in the sediment core can be the past records for geothermal activities in mid-ocean ridges of the Central Indian Ocean. The result showed that the hydrothermal Hg in the core sediments was mainly associated with Fe-Mn oxides with the elevated concentrations of other hydrothermal-derived trace metals [Co + Zn + Cu]. In addition, the [Sm]/[Nd] and [Rb]/[Sr] ratios and ɛNdCHUR and 87Sr/86Sr isotopic values supported that the extremely high Hg concentrations were possibly originated from the hydrothermal vent. However, the Hg emitted from submarine volcano was mainly associated with sulfides-organic matters because the volcanos did not release Fe and Mn. Thus, our results showed that the sedimentary Hg is an independent toll for reconstruction of paleodynamics of hydrothermal and/or volcanic activities in deep sea basin of the Central Indian Ocean.

This article contains supplementary data from the research paper entitled “A newly discovered Gigantidas bivalve mussel from the Onnuri Vent Field on the northern Central Indian Ridge” [1], describes a new mussel species within the subfamily Bathymodiolinae named Gigantidas vrijenhoeki. Data are comprised of two parts: 1) shell image and molecular analyses of G. vrijenhoeki and 2) metagenomic community analyses of gill-associated symbiotic bacteria on G. vrijenhoeki. G. vrijenhoeki data were obtained from type specimens described in Jang et al. 2020 [1]. The molecular analysis was conducted by calculating genetic distance at intra- and inter-specific level within genus Gigantidas based on the sequence data of two mitochondrial genes (COI and ND4). The metagenomic dataset of gill-associated symbionts were generated by Illumina Miseq sequencing of the V3-V4 region of 16S rRNA from 12 specimens of G. vrijenhoeki collected from the same vent site, Onnuri Vent Field.

Eight species of copepods belonging to the family Dirivultidae (Siphonostomatoida) are described from deep-water hydrothermal vent fields on the Central Indian Ridge in the Indian Ocean. Aphotopontius limatulus Humes, 1987, previously known only from the East Pacific, is included. The other seven species are new, as follows: Aphotopontius kiost n. sp., A. muricatus n. sp., Benthoxynus constrictus n. sp., Stygiopontius spinifer n. sp., S. horridus n. sp., S. geminus n. sp., and S. quadripaxillifer n. sp. The copepodid I stage of S. horridus n. sp. is also described. This is the first record on copepods living on hydrothermal vent fields in the Indian Ocean.

Summary Legionella pneumophila is an intracellular pathogen that requires nutrients from the host for its replication. It has been shown that replicating L. pneumophila prefers amino acids as main sources of carbon and energy. The homeostasis of amino acids in eukaryotic cells is regulated by the transcription factor EB (TFEB), which translocates into the nucleus and activates genes for autophagy and lysosomal biogenesis. Here we show that the Legionella effector SetA causes a robust nuclear translocation of TFEB when exogenously expressed in mammalian cells and that the translocation is dependent on the glucosyltransferase activity of SetA. We further show that SetA directly glucosylates TFEB at multiple sites. Our findings of TFEB glucosylation by SetA may suggest an alternative strategy for exploiting host nutrients in addition to the control of host mTORC1 signaling by L. pneumophila. Our results provide further insight into the molecular mechanism of the delicate TFEB nuclear shuttling., Graphical Abstract, Highlights • The Legionella effector SetA causes robust nuclear enrichment of TFEB • SetA directly glucosylates TFEB at multiple Ser/Thr sites • Glucosylation of the S138 site by SetA prevents TFEB nuclear export • Glucosylation near the S211 site of TFEB disrupts the binding between TFEB and 14-3-3, Molecular Biology; Microbiology

This study was carried out as part of a baseline long-term environmental project in the proposed mining areas for an environmental impact assessment of future mining in the Clarion-Clipperton Fracture Zone (CCFZ). The community structure and distributional pattern of meiobenthos were investigated in the deep-sea bottom of the Clarion-Clipperton Fracture Zone of the northeastern Pacific in July 1998, 1999, 2001, 2003 and August 2004, 2005. Twenty one meiobenthic groups were found at the stations in the study area. The most abundant meiobenthos comprised nematodes followed by benthic foraminiferans and harpacticoid copepods. The maximum density of meiobenthos was 306 ind/10 cm2 at the station located at 11°N (water depth, 4833 m), and the minimum density was 6 ind/10 cm2 at the station located at 14°N (water depth, 5037 m). Oligotrophic conditions in the CCFZ seem to directly reflect the lower standing stocks of meiobenthos in the CCFZ compared to other deep-sea plains of similar depth. The latitudinal distribution pattern of meiobenthos in the study area seemed to be related with surface water primary productivity, which was connected to the water circulation pattern of the Pacific Ocean near the Equator, diverging at 8oN latitude and converging at 5°N. The horizontal distribution of meiobenthic organisms in the study area showed high densities at the stations within 135–136°W. The densities of meiobenthic organismas within the CCFZ were high at stations with few manganese nodules on the sediment surface at low-latitude sites. In 1998, the observed relative high values of meiobenthic abundance were at stations from 5° to 6°N. Other stations from 7° to 10°N showed no significant fluctuations during the interannual sampling periods. It is considered that the inter-annual fluctuation of meiobenthos abundance is intimately related with a regime shift that may have occurred in the north Pacific between 1998 and 1999, the El Nino period. Vertical distribution of meiobenthic organisms showed the highest individual numbers in the surface sediment layers of 0∼2 cm depth and a steep decreasing trend as sediment becomes deeper at the stations of high latitude located in 16∼17°N. Size distribution analyses showed that organisms that fit into the sieve mesh size of 0.063 mm were abundant.