Application of Transcriptome-Based Gene Set Featurization for Machine Learning Model to Predict the Origin of Metastatic Cancer.

Identifying the primary site of origin of metastatic cancer is vital for guiding treatment decisions, especially for patients with cancer of unknown primary (CUP). Despite advanced diagnostic techniques, CUP remains difficult to pinpoint and is responsible for a considerable number of cancer-related fatalities. Understanding its origin is crucial for effective management and potentially improving patient outcomes. This study introduces a machine learning framework, ONCOfind-AI, that leverages transcriptome-based gene set features to enhance the accuracy of predicting the origin of metastatic cancers. We demonstrate its potential to facilitate the integration of RNA sequencing and microarray data by using gene set scores for characterization of transcriptome profiles generated from different platforms. Integrating data from different platforms resulted in improved accuracy of machine learning models for predicting cancer origins. We validated our method using external data from clinical samples collected through the Kangbuk Samsung Medical Center and Gene Expression Omnibus. The external validation results demonstrate a top-1 accuracy ranging from 0.80 to 0.86, with a top-2 accuracy of 0.90. This study highlights that incorporating biological knowledge through curated gene sets can help to merge gene expression data from different platforms, thereby enhancing the compatibility needed to develop more effective machine learning prediction models.

Trends in Common Ownership among Insurers in Medicare Part D.

BACKGROUND: Recent studies document the rising prevalence of common ownership by institutional investors in specific industries. Those investors offer products, such as mutual and index funds, to trade securities on behalf of others and often own shares of multiple firms in the same industry to diversify portfolios. However, at present, few studies focus on common ownership trends in health care. OBJECTIVES: This paper examines institutional investors' common ownership in the major insurers offering plans in the Medicare Part D stand-alone prescription drug plan (PDP) market between 2013 and 2020. RESEARCH DESIGN: Using data from the Securities and Exchange Commission (SEC) database and the Center for Research in Securities Prices, we compute the percentages of outstanding shares of each insurer owned by institutional investors. Data visualization and network analysis are employed to assess the trends in common ownership among major insurers. RESULTS: We document a high prevalence of and substantial increase in shared institutional investors in the PDP market. From 2013 to 2020, the degree of common ownership increased by 7% on average, and the common ownership network became more connected. Common ownership also varies across the 34 PDP regions depending on their reliance on listed insurers, that are traded in the stock exchange, offering stand-alone PDPs. CONCLUSIONS: High and rising common ownership in the Medicare Part D PDP market raises policy questions about potential effects on plan offerings, premiums, and quality for consumers.

Comparison of Metabarcoding and Microscopy Methodologies to Analyze Diatom Communities in Five Estuaries Along the Southern Coast of the Korean Peninsula.

The study of microalgal communities is critical for understanding aquatic ecosystems. These communities primarily comprise diatoms (Heterokontophyta), with two methods commonly used to study them: Microscopy and metabarcoding. However, these two methods often deliver different results; thus, their suitability for analyzing diatom communities is frequently debated and evaluated. This study used these two methods to analyze the diatom communities in identical water samples and compare the results. The taxonomy of the species constituting the diatom communities was confirmed, and both methods showed that species belonging to the orders Bacillariales and Naviculales (class Bacillariophyceae) are the most diverse. In the lower taxonomic levels (family, genus, and species), microscopy tended to show a bias toward detecting diatom species (Nitzschia frustulum, Nitzschia inconspicua, Nitzschia intermedia, Navicula gregaria, Navicula perminuta, Navicula recens, Navicula sp.) belonging to the Bacillariaceae and Naviculaceae families. The results of the two methods differed in identifying diatom species in the communities and analyzing their structural characteristics. These results are consistent with the fact that diatoms belonging to the genera Nitzschia and Navicula are abundant in the communities; furthermore, only the Illumina MiSeq data showed the abundance of the Melosira and Entomoneis genera. The results obtained from microscopy were superior to those of Illumina MiSeq regarding species-level identification. Based on the results obtained via microscopy and Illumina MiSeq, it was revealed that neither method is perfect and that each has clear strengths and weaknesses. Therefore, to analyze diatom communities effectively and accurately, these two methods should be combined.

Anti-proliferative activity of A. Oxyphylla and its bioactive constituent nootkatone in colorectal cancer cells.

BACKGROUND: A. oxyphylla extract is known to possess a wide range of pharmacological activites. However, the molecular mechanism of A. oxyphylla and its bioactive compound nootkatone in colorectal cancer is unknown. METHODS: Our study aims to examine the role of A. oxyphylla and its bioactive compound nootkatone, in tumor suppression using several in vitro assays. RESULTS: Both A. oxyphylla extract and nootkatone exhibited antiproliferative activity in colorectal cancer cells. A. oxyphylla displayed antioxidant activity in colorectal cancer cells, likely mediated via induction of HO-1. Furthermore, expression of pro-apoptotic protein NAG-1 and cell proliferative protein cyclin D1 were increased and decreased respectively in the presence of A. oxyphylla. When examined for anticancer activity, nootkatone treatment resulted in the reduction of colony and spheroid formation. Correspondingly, nootkatone also led to increased NAG-1 expression and decreased cyclin D1 expression. The mechanism by which nootkatone suppresses cyclin D1 involves protein level regulation, whereas nootkatone increases NAG-1 expression at the transcriptional level. In addition to having PPARγ binding activity, nootkatone also increases EGR-1 expression which ultimately results in enhanced NAG-1 promoter activity. CONCLUSION: In summary, our findings suggest that nootkatone is an anti-tumorigenic compound harboring antiproliferative and pro-apoptotic activity.

Nitrogen Stimulates Microcystis-Dominated Blooms More than Phosphorus in River Conditions That Favor Non-Nitrogen-Fixing Genera.

Despite the implementation of intensive phosphorus reduction measures, periodic outbreaks of cyanobacterial blooms in large rivers remain a problem in Korea, raising the need for more effective solutions to reduce their occurrence. This study sought to evaluate whether phosphorus or nitrogen limitation is an effective approach to control cyanobacterial (Microcystis) blooms in river conditions that favor this non-nitrogen-fixing genus. These conditions include nutrient enrichment, high water temperature, and thermal stratification during summer. Mesocosm bioassays were conducted to investigate the limiting factors for cyanobacterial blooms in a river reach where severe Microcystis blooms occur annually. We evaluated the effect of five different nitrogen (3, 6, 9, 12, and 15 mg/L) and phosphorus (0.01, 0.02, 0.05, 0.1, and 0.2 mg/L) concentrations on algae growth. The results indicate that nitrogen treatments stimulated cyanobacteria (mostly Microcystis aeruginosa) more than phosphorus. Interestingly, phosphorus additions did not stimulate cyanobacteria, although it did stimulate Chlorophyceae and Bacillariophyceae. We conclude that phosphorus reduction might have suppressed the growth of Chlorophyceae and Bacillariophyceae more than that of cyanobacteria; therefore, nitrogen or at least both nitrogen and phosphorus control appears more effective than phosphorus reductions alone for reducing cyanobacteria in river conditions that are favorable for non-nitrogen-fixing genera.

Revealing nonclassicality beyond Gaussian states via a single marginal distribution.

A standard method to obtain information on a quantum state is to measure marginal distributions along many different axes in phase space, which forms a basis of quantum-state tomography. We theoretically propose and experimentally demonstrate a general framework to manifest nonclassicality by observing a single marginal distribution only, which provides a unique insight into nonclassicality and a practical applicability to various quantum systems. Our approach maps the 1D marginal distribution into a factorized 2D distribution by multiplying the measured distribution or the vacuum-state distribution along an orthogonal axis. The resulting fictitious Wigner function becomes unphysical only for a nonclassical state; thus the negativity of the corresponding density operator provides evidence of nonclassicality. Furthermore, the negativity measured this way yields a lower bound for entanglement potential-a measure of entanglement generated using a nonclassical state with a beam-splitter setting that is a prototypical model to produce continuous-variable (CV) entangled states. Our approach detects both Gaussian and non-Gaussian nonclassical states in a reliable and efficient manner. Remarkably, it works regardless of measurement axis for all non-Gaussian states in finite-dimensional Fock space of any size, also extending to infinite-dimensional states of experimental relevance for CV quantum informatics. We experimentally illustrate the power of our criterion for motional states of a trapped ion, confirming their nonclassicality in a measurement-axis-independent manner. We also address an extension of our approach combined with phase-shift operations, which leads to a stronger test of nonclassicality, that is, detection of genuine non-Gaussianity under a CV measurement.

Anticancer Effects of Cold Atmospheric Plasma in Canine Osteosarcoma Cells.

Osteosarcoma is known to be one of the frequently occurring cancers in dogs. Its prognosis is usually very poor, with a high incidence of lung metastasis. Although radiation therapy has become a major therapeutic choice for canine osteosarcoma, the high costs and unexpected side effects prevent some patients from considering this treatment. Cold atmospheric plasma (CAP) is an ionized gas with high energy at low temperatures, and it produces reactive oxygen species that mediate many signaling pathways. Although many researchers have used CAP as an anticancer therapeutic approach in humans, its importance has been neglected in veterinary medicine. In this study, D-17 and DSN canine osteosarcoma cell lines were treated with CAP to observe its anticancer activity. By high-content screening and flow cytometry, CAP-treated cells showed growth arrest and apoptosis induction. Moreover, the osteosarcoma cells exhibited reduced migration and invasion activity when treated with CAP. Overall, CAP exerted an anticancer effect on canine osteosarcoma cell lines. CAP may have the potential to be used as a novel modality for treating cancer in veterinary medicine.

Competitive inhibition by NAG-1/GDF-15 NLS peptide enhances its anti-cancer activity.

Non-steroidal anti-inflammatory drug activated gene-1 (NAG-1), also known as growth differentiation factor 15 (GDF15), is a TGF-ß (transforming growth factor beta) superfamily protein with a distinctive secretion pathway. NAG-1 is associated with multiple diseases including cancer, wherein it plays a role in both pro- and anti-cancer activities. We previously reported that NAG-1 is translocated to different subcellular compartments and its activity depends on its localization. In this paper, we report that the transfection of a novel peptide corresponding to the nuclear localization signal (NLS) of NAG-1 blocks its translocation to the nucleus. Further, accumulation of NAG-1 in the cytoplasm decreased mitochondrial membrane potential, thus implying apoptosis induction as a consequence. Overall, our results indicate that the novel peptide derived from NAG-1 NLS sequence is a promising tool for enhancing the anti-tumorigenic activity of NAG-1.

Highly Controlled Nanoporous Ag Electrode by Vaporization Control of 2-Ethoxyethanol for a Flexible Supercapacitor Application.

Controlling the surface morphology of the electrode on the nanoscale has been studied extensively because the surface morphology of a material directly leads to the functionalization in various fields of studies. In this study, we designed a simple and cost-effective method to fine-tune the surface morphology and create controlled nanopores on the silver electrode by utilizing 2-ethoxyethanol and two successive heat treatments. High electrical conductivity and mechanical robustness of nanoporous silver corroborate its prospect to be employed in various applications requiring a certain degree of flexibility. As a proof-of-concept, a high-performance supercapacitor was fabricated by electrodepositing MnO2. This method is expected to be useful in various electronic applications as well as energy storage devices.

Testing nonclassicality and non-gaussianity in phase space.

We theoretically propose and experimentally demonstrate a nonclassicality test of a single-mode field in phase space, which has an analogy with the nonlocality test proposed by Banaszek and Wódkiewicz [Phys. Rev. Lett. 82, 2009 (1999)]. Our approach to deriving the classical bound draws on the fact that the Wigner function of a coherent state is a product of two independent distributions as if the orthogonal quadratures (position and momentum) in phase space behave as local realistic variables. Our method detects every pure nonclassical Gaussian state, which can also be extended to mixed states. Furthermore, it sets a bound for all Gaussian states and their mixtures, thereby providing a criterion to detect a genuine quantum non-Gaussian state. Remarkably, our phase-space approach with invariance under Gaussian unitary operations leads to an optimized test for a given non-Gaussian state. We experimentally show how this enhanced method can manifest quantum non-Gaussianity of a state by simply choosing phase-space points appropriately, which is essentially equivalent to implementing a squeezing operation on a given state.

Plasmonic waveguide ring resonators with 4 nm air gap and λ0(2)/15,000 mode-area fabricated using photolithography.

Plasmonic air-gap disk resonators with 3.5 µm diameter and a 4 nm thick, 40 nm wide air gap for a mode area of only λ0(2)/15,000 were fabricated using photolithography only. The resonant modes were clearly identified using tapered fiber coupling method at the resonant wavelengths of 1280-1620 nm. We also demonstrate the advantage of the air-gap structure by using the resonators as label-free biosensors with a sensitivity of 1.6 THz/nm.

Evolutionary Spread of Distinct O-methyltransferases Guides the Discovery of Unique Isoaspartate-Containing Peptides, Pamtides.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a structurally diverse class of natural products with a distinct biosynthetic logic, the enzymatic modification of genetically encoded precursor peptides. Although their structural and biosynthetic diversity remains largely underexplored, the identification of novel subclasses with unique structural motifs and biosynthetic pathways is challenging. Here, it is reported that peptide/protein L-aspartyl O-methyltransferases (PAMTs) present in several RiPP subclasses are highly homologous. Importantly, it is discovered that the apparent evolutionary transmission of the PAMT gene to unrelated RiPP subclasses can serve as a basis to identify a novel RiPP subclass. Biochemical and structural analyses suggest that homologous PAMTs convert aspartate to isoaspartate via aspartyl-O-methyl ester and aspartimide intermediates, and often require cyclic or hairpin-like structures for modification. By conducting homology-based bioinformatic analysis of PAMTs, over 2,800 biosynthetic gene clusters (BGCs) are identified for known RiPP subclasses in which PAMTs install a secondary modification, and over 1,500 BGCs where PAMTs function as a primary modification enzyme, thereby defining a new RiPP subclass, named pamtides. The results suggest that the genome mining of proteins with secondary biosynthetic roles can be an effective strategy for discovering novel biosynthetic pathways of RiPPs through the principle of "guilt by association".

Peanut sprout tea extract inhibits lung metastasis of 4T1 murine mammary carcinoma cells by suppressing the crosstalk between cancer cells and macrophages in BALB/c mice.

BACKGROUND/OBJECTIVES: As peanuts germinate, the content of the components beneficial to health, such as resveratrol, increases within the peanut sprout. This study examined whether the ethanol extract of peanut sprout tea (PSTE) inhibits breast cancer growth and metastasis. MATERIALS/METHODS: After orthotopically injecting 4T1 cells into BALB/c mice to induce breast cancer, 0, 30, or 60 mg/kg body weight/day of PSTE was administered orally. Angiogenesis-related protein expression in the tumors and the degree of metastasis were analyzed. 4T1 and RAW 264.7 cells were co-cultured, and reverse transcription polymerase chain reaction was performed to measure the crosstalk between breast cancer cells and macrophages. RESULTS: PSTE reduced tumor growth and lung metastasis. In particular, PSTE decreased matrix metalloproteinase-9, platelet endothelial cell adhesion molecule-1, vascular endothelial growth factor-A, F4/80, CD11c, macrophage mannose receptor, macrophage colony-stimulating factor, and monocyte chemoattractant protein 1 expression in the tumors. Moreover, PSTE prevented 4T1 cell migration, invasion, and macrophage activity in RAW 264.7 cells. PSTE inhibited the crosstalk between 4T1 cells and RAW 264.7 cells and promoted the macrophage M1 subtype while inhibiting the M2 subtype. CONCLUSIONS: These results suggest that PSTE blocks breast cancer growth and metastasis to the lungs. This may be because the PSTE treatment inhibits the crosstalk between mammary cancer cells and macrophages and inhibits the differentiation of macrophages into the M2 subtype.

NAG-1/GDF-15 Transgenic Female Mouse Shows Delayed Peak Period of the Second Phase Nociception in Formalin-induced Inflammatory Pain.

Non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1), also known as growth differentiation factor-15 (GDF-15), is associated with cancer, diabetes, and inflammation, while there is limited understanding of the role of NAG-1 in nociception. Here, we examined the nociceptive behaviors of NAG-1 transgenic (TG) mice and wild-type (WT) littermates. Mechanical sensitivity was evaluated by using the von Frey filament test, and thermal sensitivity was assessed by the hot-plate, Hargreaves, and acetone tests. c-Fos, glial fibrillary acidic protein (GFAP), and ionized calcium binding adaptor molecule-1 (Iba-1) immunoreactivity was examined in the spinal cord following observation of the formalin-induced nociceptive behaviors. There was no difference in mechanical or thermal sensitivity for NAG-1 TG and WT mice. Intraplantar formalin injection induced nociceptive behaviors in both male and female NAG-1 TG and WT mice. The peak period in the second phase was delayed in NAG-1 TG female mice compared with that of WT female mice, while there was no difference in the cumulative time of nociceptive behaviors between the two groups of mice. Formalin increased spinal c-Fos immunoreactivity in both TG and WT female mice. Neither GFAP nor Iba-1 immunoreactivity was increased in the spinal cord of TG and WT female mice. These findings indicate that NAG-1 TG mice have comparable baseline sensitivity to mechanical and thermal stimulation as WT mice and that NAG-1 in female mice may have an inhibitory effect on the second phase of inflammatory pain. Therefore, it could be a novel target to inhibit central nervous system response in pain.

Analytical and Physical Investigation on Source Resistance in InxGa1-xAs Quantum-Well High-Electron-Mobility Transistors.

We present a fully analytical model and physical investigation on the source resistance (RS) in InxGa1-xAs quantum-well high-electron mobility transistors based on a three-layer TLM system. The RS model in this work was derived by solving the coupled quadratic differential equations for each current component with appropriate boundary conditions, requiring only six physical and geometrical parameters, including ohmic contact resistivity (ρc), barrier tunneling resistivity (ρbarrier), sheet resistances of the cap and channel regions (Rsh_cap and Rsh_ch), side-recessed length (Lside) and gate-to-source length (Lgs). To extract each model parameter, we fabricated two different TLM structures, such as cap-TLM and recessed-TLM. The developed RS model in this work was in excellent agreement with the RS values measured from the two TLM devices and previously reported short-Lg HEMT devices. The findings in this work revealed that barrier tunneling resistivity already played a critical role in reducing the value of RS in state-of-the-art HEMTs. Unless the barrier tunneling resistivity is reduced considerably, innovative engineering on the ohmic contact characteristics and gate-to-source spacing would only marginally improve the device performance.

Tolfenamic acid negatively regulates YAP and TAZ expression in human cancer cells.

Several diseases are associated with improper regulation of the Hippo pathway, which plays an important role in cell proliferation and cancer metastasis. Overactivation of the YAP and TAZ proteins accelerates cell proliferation, invasion, and migration during tumorigenesis. Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug (NSAID) that exhibits activity against various types of cancer. In this study, we observed that TA decreased YAP and TAZ protein levels in cancer cells. TA increased the phosphorylation of YAP and TAZ, leading to the degradation of YAP and TAZ in the cytoplasm and nucleus. TA predominantly affected multiple phosphodegron sites in the YAP and TAZ and lowered 14-3-3ß protein expression, causing YAP and TAZ to enter the ubiquitination pathway. Proteins that affect YAP and TAZ regulation, such as NAG-1 and several YAP/TAZ E3 ligases, were not involved in TA-mediated YAP/TAZ degradation. In summary, our results indicate that TA affects phosphodegron sites on YAP/TAZ, demonstrating a novel effect of TA in tumorigenesis.

The Prokaryotic Microalga Limnothrix redekei KNUA012 to Improve Aldehyde Decarbonylase Expression for Use as a Biological Resource.

The prokaryotic microalga Limnothrix redekei KNUA012 isolated from a freshwater bloom sample from Lake Hapcheon, Hapcheon-gun, South Korea, was investigated for its potential as a biofuel feedstock. Microalgae produce straight-chain alkanes/alkenes from acyl carrier protein-linked fatty acyls via aldehyde decarbonylase (AD; EC 1.2.1.3), which can convert aldehyde intermediates into various biofuel precursors, such as alkanes and free fatty acids. In L. redekei KNUA012, long-chain ADs can convert fatty aldehyde intermediates into alkanes. After heterologous AD expression in Escherichia coli (pET28-AD), we identified an AD in L. redekei KNUA012 that can synthesize various alkanes, such as pentadecane (C15H32), 8-heptadecene (C17H34), and heptadecane (C17H36). These alkanes can be directly used as fuels without transesterification. Biodiesel constituents including dodecanoic acid (C13H26O2), tetradecanoic acid (C15H30O2), 9-hexa decenoic acid (C17H32O2), palmitoleic acid (C17H32O2), hexadecanoic acid (C17H34O2), 9-octadecenoic acid (C19H36O2), and octadecanoic acid (C19H38O2) are produced by L. redekei KNUA012 as the major fatty acids. Our findings suggest that Korean domestic L. redekei KNUA012 is a promising resource for microalgae-based biofuels and biofuel feedstock.

Novel thrombospondin-1 transcript exhibits distinctive expression and activity in thyroid tumorigenesis.

Thrombospondin 1 (TSP1) is known for its cell-specific functions in cancer progression, such as proliferation and migration. It contains 22 exons that may potentially produce several different transcripts. Here, we identified TSP1V as a novel TSP1-splicing variant produced by intron retention (IR) in human thyroid cancer cells and tissues. We observed that TSP1V functionally inhibited tumorigenesis contrary to TSP1 wild-type, as identified in vivo and in vitro. These activities of TSP1V are caused by inhibiting phospho-Smad and phospho-focal adhesion kinase. Reverse transcription polymerase chain reaction and minigene experiments revealed that some phytochemicals/non-steroidal anti-inflammatory drugs enhanced IR. We further found that RNA-binding motif protein 5 (RBM5) suppressed IR induced by sulindac sulfide treatment. Additionally, sulindac sulfide reduced phospho-RBM5 levels in a time-dependent manner. Furthermore, trans-chalcone demethylated TSP1V, thereby preventing methyl-CpG-binding protein 2 binding to TSP1V gene. In addition, TSP1V levels were significantly lower in patients with differentiated thyroid carcinoma than in those with benign thyroid nodule, indicating its potential application as a diagnostic biomarker in tumor progression.

Tat-RAN attenuates brain ischemic injury in hippocampal HT-22 cells and ischemia animal model.

Oxidative stress plays a key role in the pathogenesis of neuronal injury, including ischemia. Ras-related nuclear protein (RAN), a member of the Ras superfamily, involves in a variety of biological roles, such as cell division, proliferation, and signal transduction. Although RAN reveals antioxidant effect, its precise neuroprotective mechanisms are still unclear. Therefore, we investigated the effects of RAN on HT-22 cell which were exposed to H2O2-induced oxidative stress and ischemia animal model by using the cell permeable Tat-RAN fusion protein. We showed that Tat-RAN transduced into HT-22 cells, and markedly inhibited cell death, DNA fragmentation, and reactive oxygen species (ROS) generation under oxidative stress. This fusion protein also controlled cellular signaling pathways, including mitogen-activated protein kinases (MAPKs), NF-κB, and apoptosis (Caspase-3, p53, Bax and Bcl-2). In the cerebral forebrain ischemia animal model, Tat-RAN significantly inhibited both neuronal cell death, and astrocyte and microglia activation. These results indicate that RAN significantly protects against hippocampal neuronal cell death, suggesting Tat-RAN will help to develop the therapies for neuronal brain diseases including ischemic injury.

Introducing EzTaxon-e: a prokaryotic 16S rRNA gene sequence database with phylotypes that represent uncultured species.

Despite recent advances in commercially optimized identification systems, bacterial identification remains a challenging task in many routine microbiological laboratories, especially in situations where taxonomically novel isolates are involved. The 16S rRNA gene has been used extensively for this task when coupled with a well-curated database, such as EzTaxon, containing sequences of type strains of prokaryotic species with validly published names. Although the EzTaxon database has been widely used for routine identification of prokaryotic isolates, sequences from uncultured prokaryotes have not been considered. Here, the next generation database, named EzTaxon-e, is formally introduced. This new database covers not only species within the formal nomenclatural system but also phylotypes that may represent species in nature. In addition to an identification function based on Basic Local Alignment Search Tool (blast) searches and pairwise global sequence alignments, a new objective method of assessing the degree of completeness in sequencing is proposed. All sequences that are held in the EzTaxon-e database have been subjected to phylogenetic analysis and this has resulted in a complete hierarchical classification system. It is concluded that the EzTaxon-e database provides a useful taxonomic backbone for the identification of cultured and uncultured prokaryotes and offers a valuable means of communication among microbiologists who routinely encounter taxonomically novel isolates. The database and its analytical functions can be found at http://eztaxon-e.ezbiocloud.net/.