Global Signature Research Articles

BRAFV600E Induction in Thyrocytes Triggers Important Changes in the miRNAs Content and the Populations of Extracellular Vesicles Released in Thyroid Tumor Microenvironment.

Papillary thyroid cancer (PTC) is the most common endocrine malignancy for which diagnosis and recurrences still challenge clinicians. New perspectives to overcome these issues could come from the study of extracellular vesicle (EV) populations and content. Here, we aimed to elucidate the heterogeneity of EVs circulating in the tumor and the changes in their microRNA content during cancer progression. Using a mouse model expressing BRAFV600E, we isolated and characterized EVs from thyroid tissue by ultracentrifugations and elucidated their microRNA content by small RNA sequencing. The cellular origin of EVs was investigated by ExoView and that of deregulated EV-microRNA by qPCR on FACS-sorted cell populations. We found that PTC released more EVs bearing epithelial and immune markers, as compared to the healthy thyroid, so that changes in EV-microRNAs abundance were mainly due to their deregulated expression in thyrocytes. Altogether, our work provides a full description of in vivo-derived EVs produced by, and within, normal and cancerous thyroid. We elucidated the global EV-microRNAs signature, the dynamic loading of microRNAs in EVs upon BRAFV600E induction, and their cellular origin. Finally, we propose that thyroid tumor-derived EV-microRNAs could support the establishment of a permissive immune microenvironment.

Isotopic constraints on selenium degassing from basaltic magma and near-surface capture by fumarolic deposits: Implications for Se redistribution onto the Earth's surface

Volcanic emanations from cooling basaltic lava represent a diffuse and relatively poorly constrained source of metallic and non-metallic compounds to the Earth's surface. These compounds become incorporated in fumarolic minerals and redeposit at the surface of lava flows before entering the environmental cycle. The semi-volatile and chalcophile element selenium (Se) can be either vital or toxic to animals and humans. Thus, understanding the pathways of Se capture and relative concentrations in fumaroles is imperative for estimating their contributions to soils and aquifers in volcanically active regions, with implications for animal and human health. In this study, we report Se concentrations and Se stable isotope composition in a sample suite comprising degassed and undegassed basaltic rocks and various fumarolic deposits (thenardite, Na-K sulfate, gypsum, fluoride, and native sulfur) fed from degassing lava flows at Piton de la Fournaise volcano, Réunion Island. Erupted basaltic lavas (136–58 ng·g−1 Se) lost up to more than half of their pre-eruptive Se due to subaerial degassing and retained a heavier isotope composition (δ82/76Se = 0.11 ± 0.17‰, 2 s.d.) compared to less undegassed volcanic glass (138 ng·g−1 Se and δ82/76Se = −0.19 ± 0.04‰, 2 s.e.). Fumarolic deposits that formed over a temperature range of ~800–100 °C and captured Se from the degassing lava show higher to very high Se concentrations ranging from 0.54 μg·g−1 to 1578 μg·g−1 and significant Se isotope fractionation (δ82/76Se = +0.6 to −2.08‰). We propose two separate models that can explain the relative concentration and Se isotope composition of the deposits: 1) A compound oxidation state-dependent Se incorporation into the various fumarolic minerals, or 2) Temperature-dependent Rayleigh condensation from a cooling gas triggered by compound saturation. The Rayleigh condensation model can entirely explain the Se concentration and isotope composition of the fumaroles and predicts that up to 80% of the Se released from the lava is likely to be captured by precipitation to form solid phases within the lava pile, most dramatically in the coldest deposits below the sublimation temperature of SeO2 (< 315 °C). In contrast, mineral-dependent isotope pathways cannot fully explain our data, including the lighter Se isotope compositions in the more oxidized compounds compared to more reduced ones. Such a mineralogical effect cannot be excluded but further investigations and experimental studies are required in order to scrutinize and invoke its role. Finally, the environmental impact of these degassing-induced secondary products will be dependent on the relative compound water solubilities resulting in either Se mobilization towards aquifers or accumulation onto developing soils and plants. Such studies could prove useful for developing risk assessments in volcanically active regions on our planet, and for reaching a better understanding of the global continent-ocean Se isotope budget and signature.

The independent prognostic value of global epigenetic alterations: An analysis of single-cell ATAC-seq of circulating leukocytes from trauma patients followed by validation in whole blood leukocyte transcriptomes across three etiologies of critical illness.

SummaryBackgroundWhile bulk and single cell transcriptomic patterns in circulating leukocytes from trauma patients have been reported, how these relate to changes in open chromatin patterns remain unstudied. Here, we investigated whether single-cell ATAC-seq would provide further resolution of transcriptomic patterns that align with patient outcomes.MethodsWe performed scATAC-seq on peripheral blood mononuclear cells from four trauma patients at <4 h, 24 h, 72 h post-injury and four matched healthy controls, and extracted the features associated with the global epigenetic alterations. Three large-scale bulk transcriptomic datasets from trauma, burn and sepsis patients were used to validate the scATAC-seq derived signature, explore patient epigenetic heterogeneity (Epigenetic Groups: EG_hi vs. EG_lo), and associate patterns with clinical outcomes in critical illness.FindingsPatient subsets with gene expression patterns in blood leukocytes representative of a high global epigenetic signature (EG_hi) had worse outcomes across three etiologies of critical illness. EG_hi designation contributed independent of the known immune leukocyte transcriptomic responses to patient prognosis (Trauma: HR=0.62 [95% CI: 0.43–0.89, event set as recovery], p=0.01, n=167; Burns: HR=4.35 [95% CI: 0.816–23.2, event set as death], p=0.085, n=121; Sepsis: HR=1.60 [95% CI: 1.10–2.33, event set as death], p=0.013, n=479; Cox proportional hazards regression).InterpretationThe inclusion of gene expression patterns that associate with global epigenetic changes in circulating leukocytes improves the resolution of transcriptome-based patient classification in acute critical illnesses. Early detection of both the global epigenetic signature and the known immune transcriptomic patterns associates with the worse prognosis in trauma, burns and sepsis.

Inferring dark matter substructure with astrometric lensing beyond the power spectrum

Astrometry—the precise measurement of positions and motions of celestial objects—has emerged as a promising avenue for characterizing the dark matter population in our Galaxy. By leveraging recent advances in simulation-based inference and neural network architectures, we introduce a novel method to search for global dark matter-induced gravitational lensing signatures in astrometric datasets. Our method based on neural likelihood-ratio estimation shows significantly enhanced sensitivity to a cold dark matter population and more favorable scaling with measurement noise compared to existing approaches based on two-point correlation statistics. We demonstrate the real-world viability of our method by showing it to be robust to non-trivial modeled as well as unmodeled noise features expected in astrometric measurements. This establishes machine learning as a powerful tool for characterizing dark matter using astrometric data.

The landscape of human tissue and cell type specific expression and co-regulation of senescence genes

BackgroundCellular senescence is a complex stress response that impacts cellular function and organismal health. Multiple developmental and environmental factors, such as intrinsic cellular cues, radiation, oxidative stress, oncogenes, and protein accumulation, activate genes and pathways that can lead to senescence. Enormous efforts have been made to identify and characterize senescence genes (SnGs) in stress and disease systems. However, the prevalence of senescent cells in healthy human tissues and the global SnG expression signature in different cell types are poorly understood.MethodsThis study performed an integrative gene network analysis of bulk and single-cell RNA-seq data in non-diseased human tissues to investigate SnG co-expression signatures and their cell-type specificity.ResultsThrough a comprehensive transcriptomic network analysis of 50 human tissues in the Genotype-Tissue Expression Project (GTEx) cohort, we identified SnG-enriched gene modules, characterized SnG co-expression patterns, and constructed aggregated SnG networks across primary tissues of the human body. Our network approaches identified 51 SnGs highly conserved across the human tissues, including CDKN1A (p21)-centered regulators that control cell cycle progression and the senescence-associated secretory phenotype (SASP). The SnG-enriched modules showed remarkable cell-type specificity, especially in fibroblasts, endothelial cells, and immune cells. Further analyses of single-cell RNA-seq and spatial transcriptomic data independently validated the cell-type specific SnG signatures predicted by the network analysis.ConclusionsThis study systematically revealed the co-regulated organizations and cell type specificity of SnGs in major human tissues, which can serve as a blueprint for future studies to map senescent cells and their cellular interactions in human tissues.

First light: switching on stars at the dawn of time

The Era of the First Stars is one of the last unknown frontiers for exploration: a poorly understood billion years missing from our cosmological timeline. We have now developed several methods for finally filling in the lost billion years of the history of our Universe: stellar archaeology, detecting primordial hydrogen using 21 cm cosmological emission, and observing the earliest galaxies, most recently using the James Webb Space Telescope. This review will summarise why the first stars and galaxies are unique and worthy of observation, and the methods employed by the groundbreaking telescopes aiming to detect them. Abbreviations: LOFAR: low frequency array; SKA: square kilometre array; MWA: Murchison widefield array; EDGES: experiment to detect the global EoR signature; EoR: epoch of reionisation; JWST: James Webb space telescope.

HERA Phase I Limits on the Cosmic 21 cm Signal: Constraints on Astrophysics and Cosmology during the Epoch of Reionization

Abstract Recently, the Hydrogen Epoch of Reionization Array (HERA) has produced the experiment’s first upper limits on the power spectrum of 21 cm fluctuations at z ∼ 8 and 10. Here, we use several independent theoretical models to infer constraints on the intergalactic medium (IGM) and galaxies during the epoch of reionization from these limits. We find that the IGM must have been heated above the adiabatic-cooling threshold by z ∼ 8, independent of uncertainties about IGM ionization and the radio background. Combining HERA limits with complementary observations constrains the spin temperature of the z ∼ 8 neutral IGM to 27 K 〈 T ¯ S 〉 630 K (2.3 K 〈 T ¯ S 〉 640 K) at 68% (95%) confidence. They therefore also place a lower bound on X-ray heating, a previously unconstrained aspects of early galaxies. For example, if the cosmic microwave background dominates the z ∼ 8 radio background, the new HERA limits imply that the first galaxies produced X-rays more efficiently than local ones. The z ∼ 10 limits require even earlier heating if dark-matter interactions cool the hydrogen gas. If an extra radio background is produced by galaxies, we rule out (at 95% confidence) the combination of high radio and low X-ray luminosities of L r,ν /SFR &gt; 4 × 1024 W Hz−1 M ⊙ − 1 yr and L X /SFR &lt; 7.6 × 1039 erg s−1 M ⊙ − 1 yr. The new HERA upper limits neither support nor disfavor a cosmological interpretation of the recent Experiment to Detect the Global EOR Signature (EDGES) measurement. The framework described here provides a foundation for the interpretation of future HERA results.

Specific hypomethylation programs underpin B cell activation in early multiple sclerosis

Epigenetic changes have been consistently detected in different cell types in multiple sclerosis (MS). However, their contribution to MS pathogenesis remains poorly understood partly because of sample heterogeneity and limited coverage of array-based methods. To fill this gap, we conducted a comprehensive analysis of genome-wide DNA methylation patterns in four peripheral immune cell populations isolated from 29 MS patients at clinical disease onset and 24 healthy controls. We show that B cells from new-onset untreated MS cases display more significant methylation changes than other disease-implicated immune cell types, consisting of a global DNA hypomethylation signature. Importantly, 4,933 MS-associated differentially methylated regions in B cells were identified, and this epigenetic signature underlies specific genetic programs involved in B cell differentiation and activation. Integration of the methylome to changes in gene expression and susceptibility-associated regions further indicates that hypomethylated regions are significantly associated with the up-regulation of cell activation transcriptional programs. Altogether, these findings implicate aberrant B cell function in MS etiology.

Improvements to the Search for Cosmic Dawn Using the Long Wavelength Array

We present recent improvements to the search for the global Cosmic Dawn signature using the Long Wavelength Array station located on the Sevilleta National Wildlife Refuge in New Mexico, USA (LWA–SV). These improvements are both in the methodology of the experiment and the hardware of the station. An improved observing strategy along with more sophisticated temperature calibration and foreground modeling schemes have led to improved residual RMS limits. A large improvement over previous work using LWA–SV is the use of a novel achromatic beamforming technique which has been developed for LWA–SV. We present results from an observing campaign which contains 29 days of observations between March 10, 2021 and April 10, 2021. The reported residual RMS limits are six times above the amplitude of the potential signal reported by the Experiment to Detect the Global EoR Signature (EDGES) collaboration.

Effects of sea level and upwelling on development of a Miocene shallow-water tropical carbonate ramp system, Ponce, Puerto Rico

ABSTRACT A Miocene (Langhian–Tortonian, ca. 15–10 Ma) tropical ramp system exposed in southern Puerto Rico is characterized by shallow-water facies consisting of heterozoans, red algae, large benthic foraminifera (LBF), and corals, which occur as isolated corals, segment- and cluster-type reefs, and reworked accumulations. Photozoan association components are limited to corals (Montastraea, Porites, Goniopora, and Agaricia) and LBF (amphisteginids, soritids, gypsinids, miliolids) that have been documented to tolerate elevated nutrients, turbidity, and cooler water conditions. Similar shallow-water carbonate systems are found throughout the Caribbean, and this regional development is thought to have resulted from the well-documented upwelling in the Caribbean during the Miocene. Sea-level fluctuations also exerted a major control on facies distributions and shifts in the Puerto Rico ramp, including a vertical facies pattern that occurs in each of three sequences. Basal parts of sequences, deposited during sea-level rises, are dominantly composed of mollusks, echinoderms, red algae, LBF, bryozoans, and solitary corals that formed in low-energy seagrass-bed environments with local associated higher-energy shoal environments. Coral facies occur only in upper parts of sequences and formed in shallow-water, low- to high-energy environments closely associated with seagrass beds during late highstands and sea-level falls. A similar vertical facies pattern occurs in time-equivalent sequences elsewhere around the Caribbean. Strontium-isotope age data indicate two sequence boundaries reflecting sea-level falls formed at about 12.3 Ma and 11.1 Ma. Correlation with time-equivalent unconformities in other well-dated areas in the Caribbean and to sea-level lows on eustatic curves suggests a global signature for sequence development. The connection between the Caribbean and the Pacific along the Central American Seaway (CAS), impacted by local tectonic episodes and sea-level fluctuations during the Miocene, affected nutrient influx and upwelling in the Caribbean, which may be reflected in the vertical facies pattern in shallow-water carbonate sequences. Times of restricted connection during sea-level falls and lows resulted in reduced nutrients and upwelling, which may have been more conducive to coral development. Time-equivalent tropical carbonate systems in the Mediterranean and Indo-Pacific show similarities to those in the Caribbean, indicating influence of global processes (cooling, temperature gradients, oceanographic circulation). Differences between areas indicates the importance of local and regional controls, which in the Caribbean was dominantly the opening and closure of the CAS.

PATH-34. MOLECULAR AND CLINICAL HETEROGENEITY WITHIN SPINAL EPENDYMOMAS

Abstract Ependymomas encompass multiple clinically relevant tumor types based on localization, genetic alterations, as well as epigenetic and transcriptomic profiles. Distinct global DNA methylation signatures serve as the most powerful diagnostic tool to distinguish these types. The methylation class of spinal ependymomas (SP-EPN) comprises mostly WHO°II tumors with slow progression and incomplete surgical resection rate. Molecular data of SP-EPN are scarce and clear treatment recommendations are lacking although these neoplasms represent the most common intramedullary tumors in children and adults. The only known recurrent genetic events in SP-EPN are the loss of chromosome 22q and mutations of the NF2 gene. However, data on the frequency of NF2 mutations range from 16 % to 71 % and originate from small series that lack epigenetic or transcriptomic characterization. Furthermore, it remains unclear whether SP-EPN with germline or sporadic NF2 mutation or with NF2 wild type status display clinical and other molecular differences. Finally, the underlying genomic and transcriptomic changes of SP-EPN without NF2 mutations are fully unclear. To provide a comprehensive molecular profile of SP-EPN, we integrated genomic and epigenetic analyses and clinical data of 170 cases. Unsupervised hierarchical clustering and t-SNE analyses of methylation data revealed three distinct molecular SP-EPN subtypes. Of the three subtypes, only subtype 1 and subtype 2 contained tumors with NF2 mutations, either as previously known germline mutations or as sporadic mutations without evidence for a syndromic disease (p&amp;lt; 0.0001). Besides the lack of NF2 mutations, subtype 3 tumors showed a higher frequency of MGMT promoter methylation (p= 0.0015) and occurred in significantly older patients compared to tumors of subtypes 1 and 2 (p= 0.0038). Further investigations such as whole-exome sequencing, copy number variation profiling, gene expression analysis, and histological evaluation are ongoing and will add to the picture of molecular and clinical heterogeneity within SP-EPN.

Serum Proteomic Analyses Suggest That the HMGB1 and Other Inflammatory Pathways Are Operational in MBL and Are Less in Overt CLL

Background. CLL-like monoclonal B-ceII lymphocytosis (MBL) is considered a requisite precursor of CLL, with 1-2% of subjects annually progressing to CLL requiring therapy. The role of immune alterations leading to and operating in MBL and controlling progression to CLL is not well characterized. Since an increased frequency of immune-related conditions associated with immune dysfunction exists prior to CLL diagnosis (Landgren et al, Br J Haematol 2007 and Blood 2007; Andersen et al, Leukemia 2020), immune alterations likely exist in MBL. We have examined the serum protein profiles of MBL and CLL in search of clues linking immune dysfunction with malignant transformation.Objectives. 1. Characterize the serum proteomic profiles of MBL individuals, IGHV-mutated CLL (M-CLL) and IGHV-unmutated CLL (U-CLL) patients, and age-matched healthy controls (HC). 2. Compare the serum proteomic profiles between the groups. 3. Assess the effect of IGHV mutation status on serum proteomic profiles in CLL.Methods. A total of 12 MBL, 12 M-CLL, 12 U-CLL and 12 age-matched HC were studied. Patients were cared for at Northwell Health, New York (n=25) and Hospital del Mar, Barcelona (n=11). All patients were treatment naive except for one U-CLL patient who was treated one year beforehand. Serum samples were collected, and their protein levels measured employing SOMAmers (modified single-stranded DNA aptamers; SomaLogic) to quantify relative levels of 1,310 proteins. P-values <0.05 were used to define significantly different protein levels between groups. Ingenuity Pathway Analysis (IPA; QIAGEN) was employed to evaluate potential protein interactions and pathways. IPA pathways with P-value <0.05 and Z-score ≥2 or ≤-2 were considered to be activated or inhibited, respectively.Results. Overall, the levels of 862 proteins differed significantly between groups: MBL vs. HC: 10 downregulated (d) and 24 upregulated (u); M-CLL vs. HC: 206d and 6u; U-CLL vs. HC: 54d and 40u; M-CLL vs. MBL: 384d and 5u; U-CLL vs. MBL: 74d and 24u; and M-CLL vs. U-CLL: 35d and 0u. IPA highlighted a role for the pro-inflammatory HMGB1 pathway in several comparisons. First, an activated HMGB1 pathway was predicted in MBL compared to HC, together with activation of phagocytes, and an inhibition of the systemic immune suppressor TGF-β. Second and consistent with the former, U-CLL patients displayed an activated HMGB1 pathway compared to HC, along with other signs of immune stimulation (activated NFkB and Th1 pathways, maturation of dendritic cells, and inhibition of TGF-β) and leukemic progression (activated progression of tumor, and leukocyte extravasation). Third and contrary to the above, the HMGB1 pathway was inhibited when comparing M-CLL to HC, in line with a global immune suppression signature (inhibited PRR, GM-CSF, FcεRI, IL1, IL8, TNF, Th1, STAT3 and NFkB pathways, in addition to inhibited cell movement, viability and activation). Notably, inhibition of immune pathways was predicted for both M-CLL and U-CLL compared to MBL (diminished TNF and IL6 signaling, and reduced cell movement), although the greatest differences were seen for M-CLL vs. MBL comparison, including blockade of the HMGB1 pathway in M-CLL. Finally, the M-CLL vs. U-CLL comparison suggested inhibited INFγ, IL2, IL3, IL4, NFkB, and decreased T lymphocyte stimulation and movement of tumor cells in M-CLL patients.Conclusions. An increased pro-inflammatory signature with involvement of the HMGB1 pathway was identified in MBL and U-CLL compared with HC, whereas the opposite was seen for M-CLL. Since MBL most often exhibit mutated IGHV (91% of cases in our cohort), these findings suggest immune stimulation as a characteristic feature in the pre-leukemic and U-CLL leukemic stage that surprisingly is not operative in M-CLL. Consistent with this, M-CLL displayed a global immune suppression (HMGB1 pathway inhibition), whereas U-CLL exhibited signs of immune stimulation (HMGB1 pathway activation) compared to HC which may relate to distinct capabilities of the two subtypes to interact with the microenvironment. Lastly, the increased inflammatory signature identified in MBL, which are mainly IGHV-mutated, was lessened in CLL, mainly in M-CLL patients. This is consistent with a decreased influence of immune imbalance and the HMGB1 pathway associated with IGHV-mutated clonal expansions.Acknowledgments. GB is supported by a grant from Fundación Alfonso Martín Escudero. DisclosuresAllen: Alexon: Research Funding; Bristol Myers Squibb: Other: Equity Ownership; C4 Therapeutics: Other: Equity Ownership; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees. Rhodes: Conquer Cancer Foundation Young Investigator Award: Other: Grant/Research Support; AbbVie, Genentech, Pharmacyclics, TG Therapeutics: Other: Consultant.

Patient-derived xenograft culture-transplant system for investigation of human breast cancer metastasis

Metastasis is a fatal disease where research progress has been hindered by a lack of authentic experimental models. Here, we develop a 3D tumor sphere culture-transplant system that facilitates the growth and engineering of patient-derived xenograft (PDX) tumor cells for functional metastasis assays in vivo. Orthotopic transplantation and RNA sequencing (RNA-seq) analyses show that PDX tumor spheres maintain tumorigenic potential, and the molecular marker and global transcriptome signatures of native tumor cells. Tumor spheres display robust capacity for lentiviral engineering and dissemination in spontaneous and experimental metastasis assays in vivo. Inhibition of pathways previously reported to attenuate metastasis also inhibit metastasis after sphere culture, validating our approach for authentic investigations of metastasis. Finally, we demonstrate a new role for the metabolic enzyme NME1 in promoting breast cancer metastasis, providing proof-of-principle that our culture-transplant system can be used for authentic propagation and engineering of patient tumor cells for functional studies of metastasis.

Long-read sequencing-based in silico phage typing of vancomycin-resistant Enterococcus faecium

BackgroundVancomycin-resistant enterococci (VRE) are successful nosocomial pathogens able to cause hospital outbreaks. In the Netherlands, core-genome MLST (cgMLST) based on short-read sequencing is often used for molecular typing. Long-read sequencing is more rapid and provides useful information about the genome’s structural composition but lacks the precision required for SNP-based typing and cgMLST. Here we compared prophages among 50 complete E. faecium genomes belonging to different lineages to explore whether a phage signature would be usable for typing and identifying an outbreak caused by VRE. As a proof of principle, we investigated if long-read sequencing data would allow for identifying phage signatures and thereby outbreak-related isolates.ResultsAnalysis of complete genome sequences of publicly available isolates showed variation in phage content among different lineages defined by MLST. We identified phage present in multiple STs as well as phages uniquely detected within a single lineage. Next, in silico phage typing was applied to twelve MinION sequenced isolates belonging to two different genetic backgrounds, namely ST117/CT24 and ST80/CT16. Genomic comparisons of the long-read-based assemblies allowed us to correctly identify isolates of the same complex type based on global genome architecture and specific phage signature similarity.ConclusionsFor rapid identification of related VRE isolates, phage content analysis in long-read sequencing data is possible. This allows software development for real-time typing analysis of long-read sequencing data, which will generate results within several hours. Future studies are required to assess the discriminatory power of this method in the investigation of ongoing outbreaks over a longer time period.

Global Runoff Signatures Changes and Their Response to Atmospheric Environment, GRACE Water Storage, and Dams

Runoff signatures (RS), a special set of runoff indexes reflecting the hydrological process, have an important influence on many fields of both human and natural systems by flooding, drought, and available water resources. However, the global RS changes and their causes remain largely unknown. Here, we make a comprehensive investigation of RS changes and their response to total water storage anomalies (TWSA) from GRACE satellites, atmospheric circulation, and reservoir construction by using daily runoff data from 21,955 hydrological stations during 1975–2017. The global assessment shows that (1) in recent years, the global extreme flow signatures tend to decrease, while the low and average flow signatures are likely to increase in more regions; (2) the spatial patterns of trends are similar for different RS, suggesting that the runoff distribution tends to entirely upward in some regions, while downward in other regions; (3) the trends in RS are largely consistent with that in TWSA over most regions in North America and eastern South America during 1979–2017, indicating that the GRACE-based TWSA have great potential in hydrological monitoring and attribution; (4) atmospheric circulation change could partly explain the global spatiotemporal variation patterns of RS; (5) dams have important influences on reducing the high flow signature in the catchments including dams built during 1975–2017. This study provides a full picture of RS changes and their possible causes, which has important implications for water resources management and flood and drought disaster assessment.

Dynamic changes in tRNA modifications and abundance during T cell activation

The tRNA pool determines the efficiency, throughput, and accuracy of translation. Previous studies have identified dynamic changes in the tRNA (transfer RNA) supply and mRNA (messenger RNA) demand during cancerous proliferation. Yet dynamic changes may also occur during physiologically normal proliferation, and these are less well characterized. We examined the tRNA and mRNA pools of T cells during their vigorous proliferation and differentiation upon triggering their antigen receptor. We observed a global signature of switch in demand for codons at the early proliferation phase of the response, accompanied by corresponding changes in tRNA expression levels. In the later phase, upon differentiation, the response of the tRNA pool relaxed back to the basal level, potentially restraining excessive proliferation. Sequencing of tRNAs allowed us to evaluate their diverse base-modifications. We found that two types of tRNA modifications, wybutosine and ms2t6A, are reduced dramatically during T cell activation. These modifications occur in the anticodon loops of two tRNAs that decode "slippery codons," which are prone to ribosomal frameshifting. Attenuation of these frameshift-protective modifications is expected to increase the potential for proteome-wide frameshifting during T cell proliferation. Indeed, human cell lines deleted of a wybutosine writer showed increased ribosomal frameshifting, as detected with an HIV gag-pol frameshifting site reporter. These results may explain HIV's specific tropism toward proliferating T cells since it requires ribosomal frameshift exactly on the corresponding codon for infection. The changes in tRNA expression and modifications uncover a layer of translation regulation during T cell proliferation and expose a potential tradeoff between cellular growth and translation fidelity.

Ketamine induces EEG oscillations that may aid anesthetic state but not dissociation monitoring

ObjectiveKetamine is an anesthetic drug associated with dissociation. Decreased electroencephalogram alpha (8–13 Hz) and low-beta (13–20 Hz) oscillation power have been associated with ketamine-induced dissociation. We aimed to characterize surface electroencephalogram signatures that may serve as biomarkers for dissociation. MethodsWe analyzed data from a single-site, open-label, high-density surface electroencephalogram study of ketamine anesthesia (2 mg/kg, n = 15). We assessed dissociation longitudinally using the Clinician Administered Dissociation States Scale (CADSS) and administered midazolam to attenuate dissociation and enable causal inference. We analyzed electroencephalogram power and global coherence with multitaper spectral methods. Mixed effects models were used to assess whether power and global coherence signatures of ketamine could be developed into dissociation-specific biomarkers. ResultsCompared to baseline, ketamine unresponsiveness was associated with increased frontal power between 0.5 to 9.3 Hz, 12.2 to 16.6 Hz, and 24.4 to 50 Hz. As subjects transitioned into a responsive but dissociated state (mean CADSS ± SD, 22.1 ± 17), there was a decrease in power between 0.5 to 10.3 Hz and 11.7 to 50 Hz. Midazolam reduced dissociation scores (14.3 ± 11.6), decreased power between 4.4 to 11.7 Hz and increased power between 14.2 to 50 Hz. Our mixed-effects model demonstrated a quadratic relationship between time and CADSS scores. When models (frontal power, occipital power, global coherence) were reanalyzed with midazolam and electroencephalogram features as covariates, only midazolam was retained. ConclusionsKetamine is associated with structured electroencephalogram power and global coherence signatures that may enable principled anesthetic state but not dissociation monitoring. SignificanceA neurophysiological biomarker for dissociation may lead to a better understanding of neuropsychiatric disorders.

Seismological expression of the iron spin crossover in ferropericlase in the Earth\u2019s lower mantle

The two most abundant minerals in the Earth’s lower mantle are bridgmanite and ferropericlase. The bulk modulus of ferropericlase (Fp) softens as iron d-electrons transition from a high-spin to low-spin state, affecting the seismic compressional velocity but not the shear velocity. Here, we identify a seismological expression of the iron spin crossover in fast regions associated with cold Fp-rich subducted oceanic lithosphere: the relative abundance of fast velocities in P- and S-wave tomography models diverges in the ~1,400-2,000 km depth range. This is consistent with a reduced temperature sensitivity of P-waves throughout the iron spin crossover. A similar signal is also found in seismically slow regions below ~1,800 km, consistent with broadening and deepening of the crossover at higher temperatures. The corresponding inflection in P-wave velocity is not yet observed in 1-D seismic profiles, suggesting that the lower mantle is composed of non-uniformly distributed thermochemical heterogeneities which dampen the global signature of the Fp spin crossover.

Similar patterns of tropical precipitation and circulation changes under solar and greenhouse gas forcing

Theory and model evidence indicate a higher global hydrological sensitivity for the same amount of surface warming to solar as to greenhouse gas (GHG) forcing, but regional patterns are highly uncertain due to their dependence on circulation and dynamics. We analyse a multi-model ensemble of idealized experiments and a set of simulations of the last millennium and we demonstrate similar global signatures and patterns of forced response in the tropical Pacific, of higher sensitivity for the solar forcing. In the idealized simulations, both solar and GHG forcing warm the equatorial Pacific, enhance precipitation in the central Pacific, and weaken and shift the Walker circulation eastward. Centennial variations in the solar forcing over the last millennium cause similar patterns of enhanced equatorial precipitation and slowdown of the Walker circulation in response to periods with stronger solar forcing. Similar forced patterns albeit of considerably weaker magnitude are identified for variations in GHG concentrations over the 20th century, with the lower sensitivity explained by fast atmospheric adjustments. These findings differ from previous studies that have typically suggested divergent responses in tropical precipitation and circulation between the solar and GHG forcings. We conclude that tropical Walker circulation and precipitation might be more susceptible to solar variability rather than GHG variations during the last-millennium, assuming comparable global mean surface temperature changes.

CLRM-13. INTRAOPERATIVE MICRODIALYSIS: GLIOMA INTELLIGENCE FROM BEHIND ENEMY LINES

INTRODUCTIONGliomas present a formidable challenge for translational progress. Heterogeneity within and between tumors may demand empirically individualized and adaptive paradigms requiring rapid mechanistic feedback. We asked if tumor-associated metabolic biomarkers from glioma extracellular fluid could impart mechanistic “intelligence” reflecting intra- and inter-tumoral heterogeneity.METHODSFive live human gliomas (2 oligos; 2 IDH-WT GBMs; 1 IDH-mutant GBM), were evaluated in situ with high molecular weight (100kDA) intraoperative microdialysis using 3 disparately placed catheters. Isotonic 3% dextran perfusate was collected in 20 min (40mL) aliquots. CSF samples (n=21) were additionally evaluated from these and other patients with diverse brain tumors. The IDH-mutant glioma-associated oncometabolite D2-hydroxyglutarate (D2-HG) was quantified with targeted Liquid Chromotography-Mass Spectrometry (LC-MS). Over 200 metabolites were further evaluated via untargeted LC-MS using the Metabolon platform. Correlation, clustering, ROC and enrichment analyses were employed to identify correlations within and between patient samples.RESULTSCSF samples from patients with IDH-mutant gliomas contained over twenty-fold higher levels of D2-HG (median 4.1 mM, range 1.6-13.2, n=7) compared to those from IDH-wild type tumors (median 0.19 mM; range 0.89-0.35, n=14). Microdialysate from IDH-mutant gliomas contained 10-953mM D2-HG, 9-63x higher than paired CSF samples. Interestingly, IDH status failed to predict the global metabolic signature of microdialysate. Microdialysate samples clustered into 2 major metabolic phenotype clusters with IDH-WT and IDH-mutant gliomas in each cluster. A superimposed metabolic signature distinguishing enhancing from non-enhancing tumor, was conserved in both patient clusters. Amino acid and carnitine metabolism predominated in microdialysate signatures. TCA cycle and Warburg-associated metabolites were differentially enriched in CSF samples after prior therapy independent of tumor burden.CONCLUSIONSIntra-operative micro-dialysis may complement currently available “intelligence” regarding the phenotype, burden, and metabolism of live human gliomas and is feasible within standard-of-care surgical procedures. Future work will evaluate utility for pharmacodynamic feedback following novel early phase candidate therapies.