Global Signature Research Articles

Impact of CHIKV Replication on the Global Proteome of Aedes albopictus Cells.

Arboviruses are some of the important causative agents of mosquito-mediated viral diseases. These viruses are transmitted between vector and host during the blood meal. Upon viral entry, host replication machinery is hijacked, supporting new virus particle production and thereby allowing viral survival in the host. In this process, host proteins interact with viral proteins to either facilitate viral replication, or they may provide antiviral defense mechanisms. In this study, we analyzed the impact of chikungunya virus (CHIKV) infection on the global proteome of Dicer active Aedes albopictus cells during the early and late time points of infection. We utilized a bottom-up approach of global proteomics analysis, and we used label-free quantitative mass spectrometry to identify the global protein signatures of Ae. albopictus at two different time points upon CHIKV infection. The mass spectrometry data analysis of the early time point revealed that proteins belonging to pathways such as translation, RNA processing, and cellular metabolic processes were less in abundance, whereas those belonging to pathways such as cellular catabolic process and organic substance transport were significantly abundant. At later time points, proteins belonging to pathways such as cellular metabolic processes, primary metabolic process, organonitrogen compound metabolic process, and organic substance metabolic process were found to be decreased in their presence, whereas those belonging to pathways such as RNA processing, gene expression, macromolecule metabolic processing, and nitrogen compound metabolic processing were found to be abundant during CHIKV infection, indicating that modulation in gene expression favoring cell survival occurs at a later time point, suggesting a survival strategy of Aedes cells to counter prolonged CHIKV infection.

The Impact of Genetic Surfing on Neutral Genomic Diversity.

Range expansions have been common in the history of most species. Serial founder effects and subsequent population growth at expansion fronts typically lead to a loss of genomic diversity along the expansion axis. A frequent consequence is the phenomenon of "gene surfing," where variants located near the expanding front can reach high frequencies or even fix in newly colonized territories. Although gene surfing events have been characterized thoroughly for a specific locus, their effects on linked genomic regions and the overall patterns of genomic diversity have been little investigated. In this study, we simulated the evolution of whole genomes during several types of 1D and 2D range expansions differing by the extent of migration, founder events, and recombination rates. We focused on the characterization of local dips of diversity, or "troughs," taken as a proxy for surfing events. We find that, for a given recombination rate, once we consider the amount of diversity lost since the beginning of the expansion, it is possible to predict the initial evolution of trough density and their average width irrespective of the expansion condition. Furthermore, when recombination rates vary across the genome, we find that troughs are over-represented in regions of low recombination. Therefore, range expansions can leave local and global genomic signatures often interpreted as evidence of past selective events. Given the generality of our results, they could be used as a null model for species having gone through recent expansions, and thus be helpful to correctly interpret many evolutionary biology studies.

Expanded analysis of high-grade astrocytoma with piloid features identifies an epigenetically and clinically distinct subtype associated with neurofibromatosis type 1.

High-grade astrocytoma with piloid features (HGAP) is a recently recognized glioma type whose classification is dependent on its global epigenetic signature. HGAP is characterized by alterations in the mitogen-activated protein kinase (MAPK) pathway, often co-occurring with CDKN2A/B homozygous deletion and/or ATRX mutation. Experience with HGAP is limited and to better understand this tumor type, we evaluated an expanded cohort of patients (n = 144) with these tumors, as defined by DNA methylation array testing, with a subset additionally evaluated by next-generation sequencing (NGS). Among evaluable cases, we confirmed the high prevalence CDKN2A/B homozygous deletion, and/or ATRX mutations/loss in this tumor type, along with a subset showing NF1 alterations. Five of 93 (5.4%) cases sequenced harbored TP53 mutations and RNA fusion analysis identified a single tumor containing an NTRK2 gene fusion, neither of which have been previously reported in HGAP. Clustering analysis revealed the presence of three distinct HGAP subtypes (or groups = g) based on whole-genome DNA methylation patterns, which we provisionally designated as gNF1 (n = 18), g1 (n = 72), and g2 (n = 54) (median ages 43.5years, 47years, and 32years, respectively). Subtype gNF1 is notable for enrichment with patients with Neurofibromatosis Type 1 (33.3%, p = 0.0008), confinement to the posterior fossa, hypermethylation in the NF1 enhancer region, a trend towards decreased progression-free survival (p = 0.0579), RNA processing pathway dysregulation, and elevated non-neoplastic glia and neuron cell content (p < 0.0001 and p < 0.0001, respectively). Overall, our expanded cohort broadens the genetic, epigenetic, and clinical phenotype of HGAP and provides evidence for distinct epigenetic subtypes in this tumor type.

Deciphering multi-way interactions in the human genome

Chromatin architecture, a key regulator of gene expression, can be inferred using chromatin contact data from chromosome conformation capture, or Hi-C. However, classical Hi-C does not preserve multi-way contacts. Here we use long sequencing reads to map genome-wide multi-way contacts and investigate higher order chromatin organization in the human genome. We use hypergraph theory for data representation and analysis, and quantify higher order structures in neonatal fibroblasts, biopsied adult fibroblasts, and B lymphocytes. By integrating multi-way contacts with chromatin accessibility, gene expression, and transcription factor binding, we introduce a data-driven method to identify cell type-specific transcription clusters. We provide transcription factor-mediated functional building blocks for cell identity that serve as a global signature for cell types.

Proximity spin-orbit coupling in graphene on alloyed transition metal dichalcogenides

The negligible intrinsic spin-orbit coupling (SOC) in graphene can be enhanced by proximity effects in stacked heterostructures of graphene and transition metal dichalcogenides (TMDCs). The composition of the TMDC layer plays a key role in determining the nature and strength of the resultant SOC induced in the graphene layer. Here, we study the evolution of the proximity--induced SOC as the TMDC layer is deliberately defected. Alloyed $\mathrm{G}/{\mathrm{W}}_{\ensuremath{\chi}}{\mathrm{Mo}}_{1\ensuremath{-}\ensuremath{\chi}}{\mathrm{Se}}_{2}$ heterostructures with diverse compositions ($\ensuremath{\chi}$) and defect distributions are simulated using density functional theory. Comparison with continuum and tight-binding models allows both local and global signatures of the metal-atom alloying to be clarified. Our findings show that, despite some dramatic perturbation of local parameters for individual defects, the low-energy spin and electronic behavior follow a simple effective medium model which depends only on the composition ratio of the metallic species in the TMDC layer. Furthermore, we demonstrate that the topological state of such alloyed systems can be feasibly tuned by controlling this ratio.

Spatial organization and early signaling of the B-cell receptor in CLL.

Most chronic lymphocytic leukemia (CLL) clones express B-cell receptors (BcR) of both IgM/IgD isotypes; however, 5%–10% of CLL cases express isotype-switched immunoglobulin G (IgG). The early signaling and spatial patterning of the various BcRs at steady state and after activation are still fully unresolved. Herein, we show higher expression of the BcR signalosome elements and a more robust constitutive cell-intrinsic proximal BcR signaling in CLL with unmutated IGHV expressing IgM isotype (IgM U-CLL), compared with IGHV-mutated CLL (M-CLL) expressing either IgM or IgG isotypes. IgM in U-CLL is frequently located in the membrane plane in polarized patches, occasionally in caps, and sometimes inside the cells. Among M-CLL, IgM is scattered laterally in the membrane plane in a similar pattern as seen in normal B cells, whereas IgG is dispersed around the cell membrane in smaller clusters than in IgM U-CLL. Upon BcR engagement, both IgG and IgM expressing M-CLL showed attenuated signaling and only slight spatial reorganization dynamics of BcR microclusters and internalization, compared with the extensive reorganization and internalization of the BcR in IgM expressing U-CLL. The global gene signature of IgG M-CLL was closely related to that of IgM M-CLL rather than IgM U-CLL. Overall, we report fundamental differences in the basal composition, biochemical status, and spatial organization of the BcR in the three examined immunogenetic CLL subtypes that correlate with their clinical behavior. On the basis of our findings, IgG class-switched M-CLL likely represents the same disease as IgM M-CLL rather than a different biological and/or clinical entity.

Does Flash Flood Model Performance Increase with Complexity? Signature and Sensitivity-Based Comparison of Conceptual and Process-Oriented Models on French Mediterranean Cases

We compare three hydrological models of different complexities, GR4H (lumped, continuous), SMASH (distributed, continuous), and MARINE (distributed, event-based), for Mediterranean flash flood modeling. The objective was to understand how differently they simulate the catchment’s behavior, in terms of outlet discharge and internal dynamics, and how these can help to improve the relevance of the models. The methodology involved global sensitivity analysis, calibration/validation, and signature comparison at the event scale with good performances. For all models, we found transfer parameters to be sensitive in the case of Gardon and production parameters in the case of Ardeche. The non-conservative flow component of GR4H was found to be sensitive and could benefit the distributed models. At the event scale, the process-based MARINE model at finer resolution outperformed the two continuous hourly models at flood peak and its timing. SMASH, followed by GR4H, performed better in the volume of water exported. Using the operational surface model SIM2 to benchmark the soil moisture simulated by the three models, MARINE (initialized with SIM1) emerged as the most accurate. GR4H followed closely, while SMASH was the least accurate. Flexible modeling and regionalization should be developed based on multi-source signatures and worldwide physiographic databases.

Improved global wetland carbon isotopic signatures support post-2006 microbial methane emission increase

Atmospheric concentrations of methane, a powerful greenhouse gas, have strongly increased since 2007. Measurements of stable carbon isotopes of methane can constrain emissions if the isotopic compositions are known; however, isotopic compositions of methane emissions from wetlands are poorly constrained despite their importance. Here, we use a process-based biogeochemistry model to calculate the stable carbon isotopic composition of global wetland methane emissions. We estimate a mean global signature of −61.3 ± 0.7‰ and find that tropical wetland emissions are enriched by ~11‰ relative to boreal wetlands. Our model shows improved resolution of regional, latitudinal and global variations in isotopic composition of wetland emissions. Atmospheric simulation scenarios with the improved wetland isotopic composition suggest that increases in atmospheric methane since 2007 are attributable to rising microbial emissions. Our findings substantially reduce uncertainty in the stable carbon isotopic composition of methane emissions from wetlands and improve understanding of the global methane budget.

3‐D Atmospheric Modeling of the Global Budget of N2O and Its Isotopologues for 1980–2019: The Impact of Anthropogenic Emissions

AbstractNitrous oxide (N2O) is the third most important anthropogenic greenhouse gas and a major ozone‐depleting substance. Its main sources include anthropogenic activities (mostly agriculture) and natural emissions from ocean and soils. However, emission estimates for individual sources are highly variable due to uncertainties in N2O lifetime estimates and partitioning among sources. We derive annual global N2O emissions for 1990–2019 using NOAA Global Monitoring Laboratory (GML) surface N2O observations and the N2O lifetime calculated in the NASA GEOS‐5 chemistry climate model. The inferred global mean N2O emissions has gradually increased from ∼15.8 TgN/yr in the early 1990s to ∼17.8 TgN/yr in the 2010s. This implies that anthropogenic N2O emissions have grown rapidly from ∼6.7 TgN/yr in the 1990s to about ∼8.7 TgN/yr in the 2010s, a ∼30% increase. With specially designed N2O isotopic tracers in 3‐D GEOSCCM, we estimate that, on global average, stratospheric enrichment contributes about +7.7‰/yr, +7.6‰/yr, +8.0‰/yr to tropospheric δ15Nα, δ15Nβ, and δ18O budget, respectively. To balance the global mean isotopic signature for pre‐industrial terrestrial sources of δ15Nα ∼ 6.7‰, δ15Nβ ∼ −12.6‰, δ18O ∼ 35.4‰, our 3‐dimensional isotopic budget simulation using the GEOSCCM suggests global mean anthropogenic isotopic signatures in the recent decades are δ15Nα ∼ −18‰, δ15Nβ ∼ −20‰, δ18O ∼ 19‰. These anthropogenic isotopic estimates are significantly lighter than results from one‐box atmospheric model‐based estimates with the largest difference seen for δ15Nβ. More surface isotopic measurements are needed to better quantify the N2O isotopic signatures.

Common and Exclusive Features of Intestinal Intraepithelial γδ T Cells and Other γδ T Cell Subsets.

Murine peripheral lymph node TCR γδ T cells have been divided into type 1 and type 17 functional categories based on phenotypic and functional markers. Localized in the gut epithelial barrier, intestinal intraepithelial lymphocytes (iIEL) γδ T cells constitute a peculiar subset of T lymphocytes involved in intestinal homeostasis. However, whether iIEL γδ T cells obey the type 1/type 17 dichotomy is unclear. Using both global transcriptional signatures and expression of cell surface markers, we reveal that murine iIEL γδ T cells compose a distinct population, expressing ∼1000 specific genes, in particular genes that are responsible for cytotoxicity and regulatory functions. The expression of the transcription factor Helios is a feature of iIEL γδ T cells, distinguishing them from the other TCR γδ T subsets, including those present in the epithelia of other tissues. The marked expression of Helios is also shared by the other iIELs, TCRαβCD8αα lymphocytes present within the intestinal epithelium. Finally, we show that Helios expression depends in part on TGF-β signaling but not on the microbiota. Thus, our study proposes iIEL γδ T cells as a distinct subset and identifies novel markers to differentiate them from their peripheral counterparts.

Both YAP1-MAML2 and constitutively active YAP1 drive the formation of tumors that resemble NF2 mutant meningiomas in mice.

YAP1 is a transcriptional coactivator regulated by the Hippo signaling pathway, including NF2. Meningiomas are the most common primary brain tumors; a large percentage exhibit heterozygous loss of chromosome 22 (harboring the NF2 gene) and functional inactivation of the remaining NF2 copy, implicating oncogenic YAP activity in these tumors. Recently, fusions between YAP1 and MAML2 have been identified in a subset of pediatric NF2 wild-type meningiomas. Here, we show that human YAP1-MAML2-positive meningiomas resemble NF2 mutant meningiomas by global and YAP-related gene expression signatures. We then show that expression of YAP1-MAML2 in mice induces tumors that resemble human YAP1 fusion-positive and NF2 mutant meningiomas by gene expression. We demonstrate that YAP1-MAML2 primarily functions by exerting TEAD-dependent YAP activity that is resistant to Hippo signaling. Treatment with YAP-TEAD inhibitors is sufficient to inhibit the viability of YAP1-MAML2-driven mouse tumors ex vivo. Finally, we show that expression of constitutively active YAP1 (S127/397A-YAP1) is sufficient to induce similar tumors, suggesting that the YAP component of the gene fusion is the critical driver of these tumors. In summary, our results implicate YAP1-MAML2 as a causal oncogenic driver and highlight TEAD-dependent YAP activity as an oncogenic driver in YAP1-MAML2 fusion meningioma as well as NF2 mutant meningioma in general.

Abstract 1611: Temporal recapitulation of genome instability in an iPSC model of osteosarcoma

Abstract Osteosarcoma (OS) is characterized by widespread genomic instability, with cellular transformation associated with extensive structural (SV) and copy number variation (CNV). TP53 and RB1 mutations contribute to the initiation and maintenance of genome instability, which serves as a key driver of relapse. Significant effort has been made to model OS genome instability; however, current models have limited capacity to recapitulate genomic instability in real time. To model OS initiation and development, TP53 and RB1 mutations were installed in human iPSC using CRISPR/Cas9, followed by differentiation to mesenchymal (iMSC) and osteoblast (iOB) lineages in vitro. Functional assays of transformation were then conducted at intermediate stages of development for each genotype. Compared to isogenic WT controls, TP53-/- and TP53-/-/RB1-/- iOB exhibited increased proliferation, whereas anchorage independent growth was only observed in TP53-/-/RB1-/- iOB. Overexpression of cMYC and hRAS significantly increased the magnitude of these results in iOB. In contrast to iOB, TP53-/-/RB1-/- iMSC did not form colonies without cMYC and hRAS overexpression. To evaluate this phenomenon in vivo, iMSC and iOB were injected into the calcaneal bone of immunodeficient mice. Consistent with our in vitro observations, TP53-/-/RB1-/- and TP53-/-/RB1-/-+cMYC/hRAS iOB, and TP53-/-/RB1-/-+cMYC/hRAS iMSC gave rise to tumors. Histological evaluation of MSC-derived tumors revealed a largely undifferentiated pleomorphic phenotype, with a progressive increase in complexity in tumors derived from later stage iOB. Global gene expression signatures of xenografted tumors bore a striking similarity to OS patient samples compared to other pediatric tumors. In follow-on experiments, a progressive increase in cytogenetic abnormalities were observed in mutant but not WT iMSC, which became more pronounced in mutant iOB and correlated with a transformed phenotype. We are currently evaluating the temporal kinetics of this process, including through the use of low-coverage whole genome sequencing to elucidate the existence of recurrent patterns. These data highlight the utility of our iPSC approach as a novel model of OS, allowing for the first time the ability to study the evolution of genome instability in real time. We envision that this approach may uncover heretofore undiscovered common patterns underlying the seemingly chaotic nature of OS genomes, providing new opportunities for therapeutic intervention. Citation Format: Kelsie Lynn Becklin, Rebecca Madden, Lauren Mills, Nicole Thue, Nathan Carroll, Anthony DeFeo, Branden Moriarity, Beau Webber. Temporal recapitulation of genome instability in an iPSC model of osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1611.

Skin Aging in Long-Lived Naked Mole-Rats Is Accompanied by Increased Expression of Longevity-Associated and Tumor Suppressor Genes

Naked mole-rats (NMRs) (Heterocephalus glaber) are long-lived mammals that possess a natural resistance to cancer and other age-related pathologies, maintaining a healthy life span >30 years. In this study, using immunohistochemical and RNA-sequencing analyses, we compare skin morphology, cellular composition, and global transcriptome signatures between young and aged (aged 3‒4 vs. 19‒23 years, respectively) NMRs. We show that similar to aging in human skin, aging in NMRs is accompanied by a decrease in epidermal thickness; keratinocyte proliferation; and a decline in the number of Merkel cells, T cells, antigen-presenting cells, and melanocytes. Similar to that in human skin aging, expression levels of dermal collagens are decreased, whereas matrix metalloproteinase 9 and matrix metalloproteinase 11 levels increased in aged versus in young NMR skin. RNA-sequencing analyses reveal that in contrast to human or mouse skin aging, the transcript levels of several longevity-associated (Igfbp3, Igf2bp3, Ing2) and tumor-suppressor (Btg2, Cdkn1a, Cdkn2c, Dnmt3a, Hic1, Socs3, Sfrp1, Sfrp5, Thbs1, Tsc1, Zfp36) genes are increased in aged NMR skin. Overall, these data suggest that specific features in the NMR skin aging transcriptome might contribute to the resistance of NMRs to spontaneous skin carcinogenesis and provide a platform for further investigations of NMRs as a model organism for studying the biology and disease resistance of human skin.

Dupilumab for Atopic Dermatitis-From Clinical Trials to Molecular and Cellular Mechanisms.

Dupilumab is a monoclonal antibody that represents the first approved targeted biological therapy for adults, adolescents, and children older than 6 years with moderate-to-severe atopic dermatitis (AD). Dupilumab binds the shared chain of the interleukin-4 and interleukin-13 receptor blocking the downstream signaling of these cytokines. The clinical improvements induced by dupilumab were associated with remission of the dysregulated immune mechanisms linked with AD. Dupilumab reversed the epidermal barrier defects and improved the global molecular signature of AD. This review seeks to provide an overview on the development of dupilumab as the first target-specific biological treatment for AD, with a description of the clinical trials that have been performed in different age groups, their outcomes, and reported adverse effects. Novel aspects of dupilumab treatment, as well as the current knowledge on the molecular and cellular mechanisms underlying the treatment of AD with dupilumab, are summarized and discussed.

Impact of Protein Sources in a Guideline-Based Omnivorous Diet on Circulating Biogenic Amine Metabolites: A Randomized Controlled-Feeding Trial

ObjectivesAge is a risk factor for chronic diseases—the leading causes of death and disability. An omnivorous diet compared to a plant-based diet was shown to increase blood Trimethylamine-N-oxide (TMAO)—a biogenic amine biomarker for atherosclerosis that may also increase the risk for insulin resistance and certain cancers. Worldwide, pork and chicken are the most popular animal proteins, however, poultry is perceived as healthier. It is unknown if pork intake differentially modifies the TMAO-response than poultry which was investigated here using a non-inferiority study design to avoid any potential negative results. MethodsIn a randomized, active-controlled, 2-arm-crossover trial (NCT03539666), healthy adults (n = 38/arm, age ≥ 50 y) consumed 156 g/day of lean pork or white-meat chicken as the main protein source as part of an omnivorous diet based on the 2015 USDA dietary guidelines. The feeding arms were matched for food ingredients, nutrients, and energy. Overnight-fasted samples were collected before and after each diet phase. LC/MS with isotope-labeled internal standards and 16S-rDNA sequencing were used for metabolite and microbiome measurements, respectively. Univariate and multivariate data were analyzed using supervised and unsupervised machine learning algorithms in R. ResultsA non-inferiority of pork to poultry for a circulating TMAO-response (97.5% CI, linear mixed model) was observed for the first time. In addition, global biogenic amine signature (346 metabolites, 95% CI), microbiota-dependent essential TMAO precursor—trimethylamine (97.5% CI), three dietary TMAO substrates (choline, betaine, and L-carnitine) as well as the microbiota composition (95% CI) underlying the observed TMAO-response were not different between the two proteins. TMAO phenotype varied at baseline; a higher baseline circulating TMAO concentration associated with distinct microbiota profiles (all, FDR corrected p < 0.05) and greater TMAO-response (p = 0.0001) independent of the dietary proteins. ConclusionsLean pork does not exacerbate TMAO-risk in omnivores 50 years or older. With 95% of Americans being omnivorous and a third of them fast aging, lean pork increases dietary protein options that may help improve adherence to dietary recommendations for greater healthspan. Funding SourcesNational Pork Board, National Institute of Food & Agriculture

EEG Signals Index a Global Signature of Arousal Embedded in Neuronal Population Recordings.

Electroencephalography (EEG) has long been used to index brain states, from early studies describing activity in the presence and absence of visual stimulation to modern work employing complex perceptual tasks. These studies have shed light on brain-wide signals but often lack explanatory power at the single neuron level. Similarly, single neuron recordings can suffer from an inability to measure brain-wide signals accessible using EEG. Here, we combined these techniques while monkeys performed a change detection task and discovered a novel link between spontaneous EEG activity and a neural signal embedded in the spiking responses of neuronal populations. This "slow drift" was associated with fluctuations in the subjects' arousal levels over time: decreases in prestimulus α power were accompanied by increases in pupil size and decreases in microsaccade rate. These results show that brain-wide EEG signals can be used to index modes of activity present in single neuron recordings, that in turn reflect global changes in brain state that influence perception and behavior.

Global and Comparative Proteome Signatures in the Lens Capsule, Trabecular Meshwork, and Iris of Patients With Pseudoexfoliation Glaucoma.

Pseudoexfoliation (PXF) is characterized by the accumulation of the exfoliative material in the eye and high rates of blindness if left untreated. Pseudoexfoliation glaucoma (PXG) is generally diagnosed too late due to its asymptomatic nature, necessitating the development of new effective screening tools for the early diagnosis of the disease. Thus, the increasing prevalence of this disease due to an aging population has demanded the identification of suitable biomarkers for the early detection of the disease or detection of the onset of glaucoma in the eyes with PXF. We applied a proteomics strategy based on a high-throughput screening method for the determination of proteins involving PXF and PXG pathogenesis. The lens capsule (LC), iris, and trabecular meshwork (TM) samples with PXF and PXG were taken by surgical trabeculectomy, and control samples were taken from the donor corneal buttons obtained from the institutional eye bank to characterize the proteome profile. Peptides from the LC were analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). The protein of interest and cytokine/chemokine profiles were verified using immunohistochemistry and the bio-plex kit assay, respectively. There were a total of 1433 proteins identified in the human LC, of which 27 proteins were overexpressed and eight proteins were underexpressed in PXG compared with PXF. Overexpressed proteins such as fibromodulin, decorin, lysyl oxidase homolog 1, collagen alpha-1(I) chain, collagen alpha-3(VI) chain, and biglycan were the major components of the extracellular matrix (ECM) proteins involved in cell-matrix interactions or ECM proteoglycans and the assembly and cross-linking of collagen fibrils. The ECM composition and homeostasis are altered in glaucoma. Thus, quantitative proteomics is a method to discover molecular markers in the eye. Monitoring these events can help evaluate disease progression in future studies.

An E3 Ubiquitin Ligase Scaffolding Protein Is Proviral during Chikungunya Virus Infection in Aedes aegypti.

ABSTRACTChikungunya virus (CHIKV) is a reemerging alphavirus causing chikungunya disease (CHIKD) and is transmitted to humans by Aedes mosquitoes. The virus establishes an intricate balance of cellular interactions that ultimately helps in its replication and dodges cellular immune response. In an attempt to identify cellular host factors required during CHIKV replication in Aag2 cells, we performed global transcriptomics of CHIKV-infected Aag2 cells, and further, we compared this library with the Drosophila RNAi Screening Center (DRSC) database and identified transcripts that were regulated in Aedes aegypti during CHIKV infection. These analyses revealed specific pathways, such as ubiquitin-related pathways, proteolysis pathways, protein catabolic processes, protein modification, and cellular protein metabolic processes, involved during replication of the virus. Loss-of-function assays of selected candidates revealed their proviral or antiviral characteristics upon CHIKV infection in A. aegypti-derived Aag2 cells. Further validations identified that the ubiquitin proteasomal pathway is required for CHIKV infection in A. aegypti and that an important member of this family of proteins, namely, AeCullin-3 (Aedes ortholog of human cullin-3), is a proviral host factor of CHIKV replication in Aag2 cells.IMPORTANCE Arboviruses cause several diseases in humans and livestock. Vector control is the main strategy for controlling diseases transmitted by mosquitoes. In this context, it becomes paramount to understand how the viruses replicate in the vector for designing better transmission blocking strategies. We obtained the global transcriptome signature of A. aegypti cells during CHIKV infection, and in order to obtain the maximum information from these data sets, we further utilized the well-characterized Drosophila system and arrived upon a set of transcripts and their pathways that affect A. aegypti cells during CHIKV infection. These analyses and further validations reveal that important pathways related to protein degradation are actively involved during CHIKV infection in A. aegypti and are mainly proviral. Targeting these molecules may provide novel approaches for blocking CHIKV replication in A. aegypti.

Probing the primordial Universe with 21 cm line from cosmic dawn/epoch of reionization

Abstract In the most distant reaches of the Universe, the 21 cm hyperfine transition in neutral hydrogen provides one of the only available tracers of large-scale structure. A number of instruments have been working or are planned to measure the 21 cm line signals, and in particular, the Experiment to Detect the Global EoR Signature (EDGES) has recently reported the first detection of an absorption signal, which corresponds to the 21 cm line global signal at the epoch of reionization (EoR). The future large radio telescope, the Square Kilometre Array (SKA) will be able to deliver the high-precision measurement of the 21 cm line emission/absorption signals. In this paper, we review the current status for the 21 cm line global and fluctuation signals from EoR to the dark ages, and then summarize the recent studies of how we probe the primordial Universe particularly motivated by the recent EDGES result and future observations by SKA. We focus on two applications for constraining cosmology with the EDGES result: constraints on the primordial magnetic fields and those on the primordial power spectrum. We also discuss the potential of future SKA for probing the inflationary Universe, by discussing expected constraints on the primordial power spectrum, its adiabaticity, and primordial non-Gaussianities from future observations of 21 cm fluctuations.

Integrated analysis of transcriptomic datasets to identify placental biomarkers of spontaneous preterm birth

IntroductionPreterm birth (PTB) remains the leading cause of neonatal morbidity and mortality in the United States. The mechanisms underlying spontaneous PTB (SPTB) involve multiple physiological processes and molecular transformations at the level of the placenta. This study aimed to identify consistent molecular correlates in the placenta linked with SPTB by cross-examining publicly available transcriptomic datasets within two publicly available repositories. MethodsThe National Center for Biotechnology Information and the European Bioinformatics Institute were queried, and relevant datasets were independently normalized, and then merged based on similarity in design. Differentially expressed genes between SPTB and term delivery (TD) were identified using a fixed effects linear model (p < 0.0001) and were evaluated for enrichment of biological processes and pathways. In general, global signatures associated with SPTB were unique to each study. ResultsA total of three datasets were used in the meta-analysis to assess the placental transcriptome in SPTB (11 samples) as compared to TD (15 samples). We identified 174 differentially expressed genes consistently correlated with SPTB across all studies, including previously proposed and new candidate biomarkers of SPTB. Differentially expressed genes were significantly enriched for master regulatory pathways relevant to placental development and disease, including chromatin organization and cellular response to stress. DiscussionIdentification of differentially expressed genes and associated pathways across multiple studies may identify transcriptomic biomarkers that can be applied in clinical investigations of SPTB and provide researchers enhanced insight into the underlying etiologies of SPTB.