Extracellular NM23 Protein as a Therapeutic Target for Hematologic Malignancies

An elevated serum level of NM23-H1 protein is a poor prognostic factor in patients with various hematologic malignancies. The extracellular NM23-H1 protein promotes the in vitro growth and survival of acute myelogenous leukemia (AML) cells and inversely inhibits the in vitro survival of normal peripheral blood monocytes in primary culture at concentrations equivalent to the levels found in the serum of AML patients. The growth and survival promoting activity to AML cells is associated with cytokine production and activation of mitogen-activated protein kinases (MAPKs) and signal transducers and activators of transcription (STAT) signaling pathways. Inhibitors specific for MAPK signaling pathways inhibit the growth/survival-promoting activity of NM23-H1. These findings indicate a novel biological action of extracellular NM23-H1 and its association with poor prognosis. These results suggest an important role of extracellular NM23-H1 in the malignant progression of leukemia and a potential therapeutic target for these malignancies

Spatially-resolved Radio-to-Far-infrared SED of the Luminous Merger Remnant NGC 1614 with ALMA and VLA

We present the results of Atacama Large Millimeter/Submillimeter Array (ALMA) 108, 233, 352, and 691 GHz continuum observations and Very Large Array (VLA) 4.81 and 8.36 GHz observations of the nearby luminous merger remnant NGC 1614. By analyzing the beam (1".0 * 1".0) and uv (> 45 k{\lambda}) matched ALMA and VLA maps, we find that the deconvolved source size of lower frequency emission (< 108 GHz) is more compact (420 pc * 380 pc) compared to the higher frequency emission (> 233 GHz) (560 pc * 390 pc), suggesting different physical origins for the continuum emission. Based on an SED model for a dusty starburst galaxy, it is found that the SED can be explained by three components, (1) non-thermal synchrotron emission (traced in the 4.81 and 8.36 GHz continuum), (2) thermal free-free emission (traced in the 108 GHz continuum), and (3) thermal dust emission (traced in the 352 and 691 GHz continuum). We also present the spatially-resolved (sub-kpc scale) Kennicutt-Schmidt relation of NGC 1614. The result suggests a systematically shorter molecular gas depletion time in NGC 1614 (average {\tau}_gas of 49 - 77 Myr and 70 - 226 Myr at the starburst ring and the outer region, respectively) than that of normal disk galaxies (~ 2 Gyr) and a mid-stage merger VV 114 (= 0.1 - 1 Gyr). This implies that the star formation activities in U/LIRGs are efficiently enhanced as the merger stage proceeds, which is consistent with the results from high-resolution numerical merger simulations.Comment: 10 pages, 6 figures, accepted for publication in PAS

Morphological features of lipid droplet transition during porcine oocyte fertilisation and early embryonic development to blastocyst in vivo and in vitro

Lipid content in mammalian oocytes or embryos differs among species, with bovine and porcine oocytes and embryos showing large cytoplasmic droplets. These droplets are considered to play important roles in energy metabolism during oocyte maturation, fertilisation and early embryonic development, and also in the freezing ability of oocytes or embryos; however, their detailed distribution or function is not well understood. In the present study, changes in the distribution and morphology of porcine lipid droplets during in vivo and in vitro fertilisation, in contrast to parthenogenetic oocyte activation, as well as during their development to blastocyst stage, were evaluated by transmission electron microscopy (TEM). The analysis of semi-thin and ultra-thin sections by TEM showed conspicuous, large, electron-dense lipid droplets, sometimes associated with mitochondrial aggregates in the oocytes, irrespective of whether the oocytes had been matured in vivo or in vitro. Immediately after sperm penetration, the electron density of the lipid droplets was lost in both the in vivo and in vitro oocytes, the reduction being most evident in the oocytes developed in vitro. Density was restored in the pronculear oocytes, fully in the in vivo specimens but only partially in the in vitro ones. The number and size of the droplets seemed, however, to have decreased. At 2- to 4-cell and blastocyst stages, the features of the lipid droplets were almost the same as those of pronuclear oocytes, showing a homogeneous or saturated density in the in vivo embryos but a marbled or partially saturated appearance in the in vitro embryos. In vitro matured oocytes undergoing parthenogenesis had lipid droplets that resembled those of fertilised oocytes until the pronuclear stage. Overall, results indicate variations in both the morphology and amount of cytoplasmic lipid droplets during porcine oocyte maturation, fertilisation and early embryo development as well as differences between in vivo and in vitro development, suggesting both different energy status during preimplantation development in pigs and substantial differences between in vitro and in vivo development.</p

Spatially resolved CO SLED of the Luminous Merger Remnant NGC 1614 with ALMA

We present high-resolution (1".0) Atacama Large Millimeter/submillimeter Array (ALMA) observations of CO (1-0) and CO (2- 1) rotational transitions toward the nearby IR-luminous merger NGC 1614 supplemented with ALMA archival data of CO (3-2), and CO (6-5) transitions. The CO (6-5) emission arises from the starburst ring (central 590 pc in radius), while the lower-$J$ CO lines are distributed over the outer disk ($\sim$ 3.3 kpc in radius). Radiative transfer and photon dominated region (PDR) modeling reveal that the starburst ring has a single warmer gas component with more intense far-ultraviolet radiation field ($n_{\rm{H_2}}$ $\sim$ 10$^{4.6}$ cm$^{-3}$, $T_{\rm{kin}}$ $\sim$ 42 K, and $G_{\rm{0}}$ $\sim$ 10$^{2.7}$) relative to the outer disk ($n_{\rm{H_2}}$ $\sim$ 10$^{5.1}$ cm$^{-3}$, $T_{\rm{kin}}$ $\sim$ 22 K, and $G_{\rm{0}}$ $\sim$ 10$^{0.9}$). A two-phase molecular interstellar medium with a warm and cold ($>$ 70 K and $\sim$ 19 K) component is also an applicable model for the starburst ring. A possible source for heating the warm gas component is mechanical heating due to stellar feedback rather than PDR. Furthermore, we find evidence for non-circular motions along the north-south optical bar in the lower-$J$ CO images, suggesting a cold gas inflow. We suggest that star formation in the starburst ring is sustained by the bar-driven cold gas inflow, and starburst activities radiatively and mechanically power the CO excitation. The absence of a bright active galactic nucleus can be explained by a scenario that cold gas accumulating on the starburst ring is exhausted as the fuel for star formation, or is launched as an outflow before being able to feed to the nucleus.Comment: 20 pages, 19 figures, 2 tables, accepted for publication in Ap

Development to the blastocyst stage, the oxidative state, and the quality of early developmental stage of porcine embryos cultured in alteration of glucose concentrations in vitro under different oxygen tensions

BACKGROUND: Recent work has shown that glucose may induce cell injury through the action of free radicals generated by autooxidation or through hypoxanthine phosphoribosyltransferase inhibition. The effect of glucose during early in vitro culture (IVC) period of porcine embryos on their developmental competence, contents of reactive oxygen species (ROS) and glutathione (GSH), and the quality of the blastocysts yielded was examined. METHODS: In vitro matured and fertilized porcine oocytes were cultured for the first 2 days (Day 0 = day of fertilization) of IVC in NCSU-37 added with 1.5 to 20 mM glucose (Gluc-1.5 to -20 groups) or pyruvate and lactate (Pyr-Lac group). The embryos in all groups were cultured subsequently until Day 6 in NCSU-37 with 5.5 mM added glucose. The ROS and GSH level were measured at Day 1 and 2. DNA-fragmented nuclei and the total cell numbers in blastocyst were evaluated by TUNEL-staining at Day 6. RESULTS: Under 5% oxygen the blastocyst rates and total cell numbers in the blastocysts in all glucose groups were significantly lower than that in the Pyr-Lac group. Similar result in blastocyst rate was found under 20% oxygen (excluding the Gluc-10 group), but total cell numbers in the blastocysts was similar among the groups. At both oxygen tensions, the H2O2 levels of Day 1 embryos in all glucose groups were significantly higher than that in the Pyr-Lac group, while only the Gluc-1.5 group of Day 2 embryos showed a significantly higher H2O2 level than that in the Pyr-Lac group. The GSH contents of either Day 1 or Day 2 embryos developed under 5% oxygen were similar among the groups. Only the content of Day 2 embryos in 1.5 mM group was significantly lower than the embryos in the Pyr-Lac group under 20% oxygen. Total cell numbers in the blastocysts (except in the Gluc-20 group) were significantly lower in the embryos cultured under 20% oxygen than 5% oxygen. Only the Gluc-20 blastocysts developed under 5% oxygen showed significantly higher DNA fragmentation rate than those of Pyr-Lac blastocysts. CONCLUSION: These results show that a decrease in developmental ability of embryos cultured by use of glucose instead of pyruvate and lactate after the ferilization may be due to the rise in ROS generation in Day 1 embryos. Moreover, results from this study suggest that the concentration of glucose in the medium that can be used by the Day 1–2 embryos is limited to 3.5 mM and exposure to higher glucose concentrations does not improve embryo development

Intraocular Pressure Readings Obtained through Soft Contact Lenses using Four Types of Tonometer

To compare the reliability and accuracy of intraocular pressure (IOP) measured while wearing soft contact lenses (SCLs) using a non-contact tonometer (NCT), Goldmann applanation tonometer (GAT), iCare rebound tonometer (RBT) and the Tono-Pen XL. Twenty-six healthy subjects were examined. The IOP was measured using NCT, GAT, RBT, and the Tono-Pen XL, while the subjects wore SCLs −5.00 D, −0.50 D and +5.00 D. Bland–Altman plots and a regression analysis were used to compare the IOPs obtained with those instruments and the IOPs of the naked eyes measured using GAT (the standard IOPs in this study). The IOPs obtained by the Tono-Pen XL while the subjects were wearing −5.00 D, −0.50 D, and +5.00 D SCLs were significantly higher than those of the naked eyes obtained using GAT. RBT showed that the IOPs were similar to the GAT standard IOPs under all conditions. The IOPs measured with NCT and GAT while the subjects were wearing −5.00 D and −0.50 D SCLs were similar to the GAT standard IOPs. The IOPs obtained with RBT and NCT while the subjects were wearing −5.00 D and −0.50 D SCLs exhibited a good correlation with the standard IOPs. The NCT and RBT are best when measuring IOP through hydrogel SCLs

Suppression of Propionibacterium acnes

Purpose. Macrophages serve as sweepers of microbes and inflammation-derived wastes and regulators of inflammation. Some traditional Japanese medicines are reported to have adjuvant effects by modifying macrophages. Our aim was to characterize the actions of jumihaidokuto (JHT) for treatment of skin inflammations including acne vulgaris, in which Propionibacterium acnes has pathogenic roles. Methods. Dermatitis was induced in rat ears by intradermal injection of P. acnes. JHT or prednisolone (PDN) was given orally, and ear thickness and histology were evaluated. The effects of constituents and metabolites of JHT on monocytes were tested by cell-based assays using the human monocytic THP-1 cell. Results. JHT and PDN suppressed the ear thickness induced by P. acnes injection. Histological examinations revealed that JHT, but not PDN, promoted macrophage accumulation at 24 h after the injection. PDN suppressed the macrophage chemokine MCP-1 in the inflamed ears, while JHT did not affect it. The JHT constituents liquiritigenin and isoliquiritin increased expression of CD86 (type-1 macrophage marker) and CD192 (MCP-1 receptor) and enhanced phagocytosis by THP-1. Conclusions. JHT suppressed dermatitis, probably by enhancing type-1 macrophage functions, with an action different from PDN. JHT may be a beneficial drug in treatment of skin inflammation induced by P. acnes

A series of ENU-induced single-base substitutions in a long-range cis-element altering Sonic hedgehog expression in the developing mouse limb bud

AbstractMammal–fish-conserved-sequence 1 (MFCS1) is a highly conserved sequence that acts as a limb-specific cis-acting regulator of Sonic hedgehog (Shh) expression, residing 1 Mb away from the Shh coding sequence in mouse. Using gene-driven screening of an ENU-mutagenized mouse archive, we obtained mice with three new point mutations in MFCS1: M101116, M101117, and M101192. Phenotype analysis revealed that M101116 mice exhibit preaxial polydactyly and ectopic Shh expression at the anterior margin of the limb buds like a previously identified mutant, M100081. In contrast, M101117 and M101192 show no marked abnormalities in limb morphology. Furthermore, transgenic analysis revealed that the M101116 and M100081 sequences drive ectopic reporter gene expression at the anterior margin of the limb bud, in addition to the normal posterior expression. Such ectopic expression was not observed in the embryos carrying a reporter transgene driven by M101117. These results suggest that M101116 and M100081 affect the negative regulatory activity of MFCS1, which suppresses anterior Shh expression in developing limb buds. Thus, this study shows that gene-driven screening for ENU-induced mutations is an effective approach for exploring the function of conserved, noncoding sequences and potential cis-regulatory elements