Understanding the differentiation, expansion, recruitment and suppressive activities of myeloid-derived suppressor cells in cancers

There has been a great interest in myeloid-derived suppressor cells (MDSCs) due to their biological functions in tumor-mediated immune escape by suppressing antitumor immune responses. These cells arise from altered myelopoiesis in response to the tumor-derived factors. The most recognized function of MDSCs is suppressing anti-tumor immune responses by impairing T cell functions, and these cells are the most important players in cancer dissemination and metastasis. Therefore, understanding the factors and the mechanism of MDSC differentiation, expansion, and recruitment into the tumor microenvironment can lead to its control. However, most of the studies only defined MDSCs with no further characterization of granulocytic and monocytic subsets. In this review, we discuss the mechanisms by which specific MDSC subsets contribute to cancers. A better understanding of MDSC subset development and the specific molecular mechanism is needed to identify treatment targets. The understanding of the specific molecular mechanisms responsible for MDSC accumulation would enable more precise therapeutic targeting of these cells

The detection of oxygen in the low-density intergalactic medium

The abundances of metals in the intergalactic medium (IGM) can be used to constrain the amount of star formation at high redshift and the spectral shape of the ionizing background radiation. For both purposes it is essential to measure the abundances in regions of low density, away from local sources of metals and ionizing photons. Here we report the first detection of OVI in the low-density IGM at high redshift. We perform a pixel-by-pixel search for OVI absorption in eight high quality quasar spectra spanning the redshift range z = 2.0-4.5. At 2 ~< z ~< 3, we clearly detect OVI in the form of a positive correlation between the HI Ly-alpha optical depth and the optical depth in the corresponding OVI pixel, down to an HI optical depth of 0.1. This is an order of magnitude lower in HI optical depth than the best CIV measurements can probe and constitutes the first clear detection of metals in underdense gas. The non-detection of OVI at z > 3 is consistent with the enhanced photoionization from a hardening of the UV background below z ~ 3 but could also be caused by the high level of contamination from Ly series lines.Comment: 5 pages, 2 figures. Reference added to match published versio

Mg2+ Effect on Argonaute and RNA Duplex by Molecular Dynamics and Bioinformatics Implications

RNA interference (RNAi), mediated by small non-coding RNAs (e.g., miRNAs, siRNAs), influences diverse cellular functions. Highly complementary miRNA-target RNA (or siRNA-target RNA) duplexes are recognized by an Argonaute family protein (Ago2), and recent observations indicate that the concentration of Mg2+ ions influences miRNA targeting of specific mRNAs, thereby modulating miRNA-mRNA networks. In the present report, we studied the thermodynamic effects of differential [Mg2+] on slicing (RNA silencing cycle) through molecular dynamics simulation analysis, and its subsequent statistical analysis. Those analyses revealed different structural conformations of the RNA duplex in Ago2, depending on Mg2+ concentration. We also demonstrate that cation effects on Ago2 structural flexibility are critical to its catalytic/functional activity, with low [Mg2+] favoring greater Ago2 flexibility (e.g., greater entropy) and less miRNA/mRNA duplex stability, thus favoring slicing. The latter finding was supported by a negative correlation between expression of an Mg2+ influx channel, TRPM7, and one miRNA’s (miR-378) ability to downregulate its mRNA target, TMEM245. These results imply that thermodynamics could be applied to siRNA-based therapeutic strategies, using highly complementary binding targets, because Ago2 is also involved in RNAi slicing by exogenous siRNAs. However, the efficacy of a siRNA-based approach will differ, to some extent, based on the Mg2+ concentration even within the same disease type; therefore, different siRNA-based approaches might be considered for patient-to-patient needs

Increasing trends in hospital care burden of atrial fibrillation in Korea, 2006 through 2015

ObjectiveTemporal changes in the healthcare burden of atrial fibrillation (AF) are less well known in rapidly ageing Asian countries. We examined trends in hospitalisations, costs, treatment patterns and outcomes related to AF in Korea.MethodsUsing the National Health Insurance Service (NHIS) database involving the entire adult Korean population (n=41 701 269 in 2015), we analysed a nationwide AF cohort representing 931 138 patients with AF. We studied all hospitalisations due to AF from 2006 to 2015.ResultsOverall, hospitalisations for AF increased by 420% from 767 to 3986 per 1 million Korean population from 2006 to 2015. Most admissions occurred in patients aged ≥70 years, and the most frequent coexisting conditions were hypertension, heart failure and chronic obstructive pulmonary disease. Hospitalisations mainly due to major bleeding and AF control increased, whereas hospitalisations mainly due to ischaemic stroke and myocardial infarction decreased. The total cost of care increased even after adjustment for inflation from €68.4 million in 2006 to €388.4 million in 2015, equivalent to 0.78% of the Korean NHIS total expenditure. Overall in-hospital mortality decreased from 7.5% in 2006 to 4.3% in 2015. The in-hospital mortality was highest in patients ≥80 years of age (7.7%) and in patients with chronic kidney disease (7.4%).ConclusionsAF hospitalisations have increased exponentially over the past 10 years in Korea, in association with an increase in comorbid chronic diseases. Mortality associated with AF hospitalisations decreased during the last decade, but hospitalisation costs have markedly increased.</jats:sec

Perampanel Affects Up-Stream Regulatory Signaling Pathways of GluA1 Phosphorylation in Normal and Epileptic Rats

To elucidate the pharmacological properties of perampanel [2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile, a novel non-competitive antagonist of AMPA receptor], we investigated its effects on the up-stream regulatory pathways of GluA1 phosphorylation including protein kinase C (PKC), Ca2+-calmodulin-dependent protein kinase II (CAMKII), protein kinase A (PKA), extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), protein phosphatase (PP) 1, PP2A, and PP2B in normal and pilocarpine-induced epileptic rat model using Western blot analysis. In normal animals, perampanel affected GluA1 expression/phosphorylation, PKC, CAMKII, PKA, ERK1/2, JNK, and PPs activities. In epileptic rats, perampanel effectively inhibited spontaneous seizure activities. Perampanel enhanced phospho (p)-GluA1-S831 and -S845 ratios (phosphoprotein/total protein), while it reduced GluA1 expression. Perampanel also increased pCAMKII and pPKA ratios, which phosphorylate GluA1-S831 and -S845 site, respectively. Perampanel elevated pJNK and pPP2B ratios, which phosphorylates and dephosphorylates both GluA1-S831 and -S845 sits. Perampanel also increased pERK1/2 ratio in epileptic animals, while U0126 (an ERK1/2 inhibitor) did not affect pGluA1 ratios. Perampanel did not influence PKC, PP1, and PP2A expression levels and their phosphorylation ratios. In addition, perampanel did not have a detrimental impact on cognitive abilities of epileptic and normal rats in Morris water maze test. These findings suggest that perampanel may regulate AMPA receptor functionality via not only blockade of AMPA receptor but also the regulations of multiple molecules (CAMKII, PKA, JNK, and pPP2B)-mediated GluA1 phosphorylations without negative effects on cognition, although the effects of perampanel on PKC, PP1, and PP2A activities were different between normal and epileptic rats

Detection of PIWI and piRNAs in the mitochondria of mammalian cancer cells

AbstractPiwi-interacting RNAs (piRNAs) are 26–31 nt small noncoding RNAs that are processed from their longer precursor transcripts by Piwi proteins. Localization of Piwi and piRNA has been reported mostly in nucleus and cytoplasm of higher eukaryotes germ-line cells, where it is believed that known piRNA sequences are located in repeat regions of nuclear genome in germ-line cells. However, localization of PIWI and piRNA in mammalian somatic cell mitochondria yet remains largely unknown. We identified 29 piRNA sequence alignments from various regions of the human mitochondrial genome. Twelve out 29 piRNA sequences matched stem-loop fragment sequences of seven distinct tRNAs. We observed their actual expression in mitochondria subcellular fractions by inspecting mitochondrial-specific small RNA-Seq datasets. Of interest, the majority of the 29 piRNAs overlapped with multiple longer transcripts (expressed sequence tags) that are unique to the human mitochondrial genome. The presence of mature piRNAs in mitochondria was detected by qRT-PCR of mitochondrial subcellular RNAs. Further validation showed detection of Piwi by colocalization using anti-Piwil1 and mitochondria organelle-specific protein antibodies

Dream360: Diverse and Immersive Outdoor Virtual Scene Creation via Transformer-Based 360 Image Outpainting

360 images, with a field-of-view (FoV) of 180x360, provide immersive and realistic environments for emerging virtual reality (VR) applications, such as virtual tourism, where users desire to create diverse panoramic scenes from a narrow FoV photo they take from a viewpoint via portable devices. It thus brings us to a technical challenge: `How to allow the users to freely create diverse and immersive virtual scenes from a narrow FoV image with a specified viewport?' To this end, we propose a transformer-based 360 image outpainting framework called Dream360, which can generate diverse, high-fidelity, and high-resolution panoramas from user-selected viewports, considering the spherical properties of 360 images. Compared with existing methods, e.g., [3], which primarily focus on inputs with rectangular masks and central locations while overlooking the spherical property of 360 images, our Dream360 offers higher outpainting flexibility and fidelity based on the spherical representation. Dream360 comprises two key learning stages: (I) codebook-based panorama outpainting via Spherical-VQGAN (S-VQGAN), and (II) frequency-aware refinement with a novel frequency-aware consistency loss. Specifically, S-VQGAN learns a sphere-specific codebook from spherical harmonic (SH) values, providing a better representation of spherical data distribution for scene modeling. The frequency-aware refinement matches the resolution and further improves the semantic consistency and visual fidelity of the generated results. Our Dream360 achieves significantly lower Frechet Inception Distance (FID) scores and better visual fidelity than existing methods. We also conducted a user study involving 15 participants to interactively evaluate the quality of the generated results in VR, demonstrating the flexibility and superiority of our Dream360 framework.Comment: 11 pages, accepted to IEEE VR 202