The molecular gas kinematics in the host galaxy of non-repeating FRB 180924B

Fast radio bursts (FRBs) are millisecond-duration transients with large dispersion measures. The origin of FRBs is still mysterious. One of the methods to comprehend FRB origin is to probe the physical environments of FRB host galaxies. Mapping molecular-gas kinematics in FRB host galaxies is critical because it results in star formation that is likely connected to the birth of FRB progenitors. However, most previous works of FRB host galaxies have focused on its stellar component. Therefore, we, for the first time, report the molecular gas kinematics in the host galaxy of the non-repeating FRB 180924B at $z= 0.3216$. Two velocity components of the CO (3-2) emission line are detected in its host galaxy with the Atacama Large Millimeter/submillimeter Array (ALMA): the peak of one component ($-155.40$ km s$^{-1}$) is near the centre of the host galaxy, and another ($-7.76$ km s$^{-1}$) is near the FRB position. The CO (3-2) spectrum shows asymmetric profiles with A$_{\rm peak}$ $=2.03\pm 0.39$, where A$_{\rm peak}$ is the peak flux density ratio between the two velocity components. The CO (3-2) velocity map also indicates an asymmetric velocity gradient from $-180$ km s$^{-1}$ to 8 km s$^{-1}$. These results indicate a disturbed kinetic structure of molecular gas in the host galaxy. Such disturbed kinetic structures are reported for repeating FRB host galaxies using HI emission lines in previous works. Our finding indicates that non-repeating and repeating FRBs could commonly appear in disturbed kinetic environments, suggesting a possible link between the gas kinematics and FRB progenitors.Comment: 5 pages, 4 figures, Accepted for publication in MNRAS, https://www.youtube.com/watch?v=CldxLE7Pdwk&t=1

Phyllanthus urinaria Induces Apoptosis in Human Osteosarcoma 143B Cells via Activation of Fas/FasL- and Mitochondria-Mediated Pathways

Phyllanthus urinaria (P. urinaria), in this study, was used for the treatment of human osteosarcoma cells, which is one of the tough malignancies with few therapeutic modalities. Herein, we demonstrated that P. urinaria inhibited human osteosarcoma 143B cells growth through an apoptotic extrinsic pathway to activate Fas receptor/ligand expression. Both intracellular and mitochondrial reactive oxygen species were increased to lead to alterations of mitochondrial membrane permeability and Bcl-2 family including upregulation of Bid, tBid, and Bax and downregulation of Bcl-2. P. urinaria triggered an intrinsic pathway and amplified the caspase cascade to induce apoptosis of 143B cells. However, upregulation of both intracellular and mitochondrial reactive oxygen species and the sequential membrane potential change were less pronounced in the mitochondrial respiratory-defective 143Bρ0 cells compared with the 143B cells. This study offers the evidence that mitochondria are essential for the anticancer mechanism induced by P. urinaria through both extrinsic and intrinsic pathways

Galaxy source counts at 7.7 μ\mum, 10 μ\mum and 15 μ\mum with the James Webb Space Telescope

We present mid-infrared galaxy number counts based on the Early Release Observations obtained by the James Webb Space Telescope (JWST) at 7.7-, 10- and 15-$\mu$m (F770W, F1000W and F1500W, respectively) bands of the Mid-Infrared Instrument (MIRI). Due to the superior sensitivity of JWST, the 80 percent completeness limits reach 0.32, 0.79 and 2.0 $\mu$Jy in F770W, F1000W and F1500W filters, respectively, i.e., $\sim$100 times deeper than previous space infrared telescopes such as Spitzer or AKARI. The number counts reach much deeper than the broad bump around $0.05\sim0.5$ mJy due to polycyclic aromatic hydrocarbon (PAH) emissions. An extrapolation towards fainter flux from the evolutionary models in the literature agrees amazingly well with the new data, where the extrapolated faint-end of infrared luminosity functions combined with the cosmic star-formation history to higher redshifts can reproduce the deeper number counts by JWST. Our understanding of the faint infrared sources has been confirmed by the observed data due to the superb sensitivity of JWST.Comment: 6 pages, 8 figures. Accepted for publication in MNRA

Serotonin receptor HTR6-mediated mTORC1 signaling regulates dietary restriction-induced memory enhancement

Dietary restriction (DR; sometimes called calorie restriction) has profound beneficial effects on physiological, psychological, and behavioral outcomes in animals and in humans. We have explored the molecular mechanism of DR-induced memory enhancement and demonstrate that dietary tryptophan-a precursor amino acid for serotonin biosynthesis in the brain-and serotonin receptor 5-hydroxytryptamine receptor 6 (HTR6) are crucial in mediating this process. We show that HTR6 inactivation diminishes DR-induced neurological alterations, including reduced dendritic complexity, increased spine density, and enhanced long-term potentiation (LTP) in hippocampal neurons. Moreover, we find that HTR6-mediated mechanistic target of rapamycin complex 1 (mTORC1) signaling is involved in DR-induced memory improvement. Our results suggest that the HTR6-mediated mTORC1 pathway may function as a nutrient sensor in hippocampal neurons to couple memory performance to dietary intake

Combination of D-dimer level and neutrophil to lymphocyte ratio predicts long-term clinical outcomes in acute coronary syndrome after percutaneous coronary intervention

Background: High D-dimer (DD) is associated with short-term adverse outcomes in patients with acute coronary syndrome (ACS). In ACS patients who underwent percutaneous coronary intervention (PCI), however, the value of DD (or combined with neutrophil to lymphocyte ratio [NLR]) to predict long-term major adverse cardiovascular events (MACEs) has not been fully evaluated. Methods: Patients diagnosed with ACS and receiving PCI were included. The primary outcome was MACEs. Cox proportional hazards regression and logistic regression was used to illustrate the relationship between clinical risk factors, biomarkers and MACEs. Survival models were developed based on significant factors and evaluated by the Concordance-index (C-index). Results: The final study cohort was comprised of 650 patients (median age, 64 years; 474 males), including 98 (15%) with MACEs during a median follow-up period of 40 months. According to the cut-off value of DD and NLR, the patients were separated into four groups: high DD or nonhigh DD with high or nonhigh NLR. After adjusting for confounding variables, DD (adjusted hazard ratio [aHR]: 2.39, 95% confidence interval [CI]: 1.52–3.76) and NLR (aHR: 2.71, 95% CI: 1.78–4.11) were independently associated with long-term MACEs. Moreover, patients with both high DD and NLR had a significantly higher risk in MACEs when considering patients with nonhigh DD and NLR as reference (aHR: 6.19, 95% CI: 3.30–11.61). The area under curve (AUC) increased and reached 0.70 in differentiating long-term MACEs when DD and NLR were combined, and survival models incorporating the two exhibited a stronger predictive power (C-index: 0.75). Conclusions: D-dimer (or combined with NLR) can be used to predict long-term MACEs in ACS patients undergoing PCI

YC-1 [3-(5Ј-Hydroxymethyl-2Ј-furyl)-1-benzyl Indazole] Inhibits Neointima Formation in Balloon-Injured Rat Carotid through Suppression of Expressions and Activities of Matrix Metalloproteinases 2 and 9

ABSTRACT Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, and postrevascularization production of vascular smooth muscle cells may play key roles in development of arterial restenosis. We investigated the inhibitory effect of 3-(5Ј-hydroxymethyl-2Ј-furyl)-1-benzyl indazole (YC-1), a benzyl indazole compound, on MMP-2 and MMP-9 activity in a ballooninjury rat carotid artery model. Injury was induced by inserting a balloon catheter through the common carotid artery; after 14 days, histopathological analysis using immunostaining and Western blotting revealed significant restenosis with neointimal formation that was associated with enhanced protein expression of MMP-2 and MMP-9. However, these effects were dosedependently reduced by orally administered YC-1 (1-10 mg/ kg). In addition, gelatin zymography demonstrated that increased MMP-2 and MMP-9 activity was diminished by YC-1 treatment. On the other hand, YC-1 inhibited hydrolysis of the fluorogenic quenching substrate Mca-Pro-Leu-Gly-Leu-DpaAla-Arg-NH 2 by recombinant MMP-2 and MMP-9 with IC 50 values ϭ 2.07 and 8.20 M, respectively. Reverse transcription-polymerase chain reaction analysis of MMP-2 and MMP-9 mRNA revealed that YC-1 significantly inhibited mRNA levels of MMPs. Finally, for the YC-1 treatment group, we did not observe elevation of cGMP levels using enzyme-linked immunosorbent assay, suggesting that YC-1 inhibition of neointimal formation is not through a cGMP-elevating pathway. These data show YC-1 suppression of neointimal formation is dependent on its influence on MMP-2 and MMP-9 protein, mRNA expression, and activity, but not through a cGMP-elevating effect. YC-1 shows therapeutic potential for treatment of restenosis after angioplasty. During the past 20 years, one focus of cardiovascular pharmaceutical research has been the development of drugs that inhibit intimal hyperplasia. Despite many attempts, no clinical trial has proven that there is an effective pharmacological solution to the problem Matrix metalloproteinases (MMPs) are a family of structurally related zinc-endopeptidases that degrade components of extracellular matrix associated with vascular remodeling during vascular injury-induced neointima formatio

Dehydrocostuslactone Suppresses Angiogenesis In Vitro and In Vivo through Inhibition of Akt/GSK-3β and mTOR Signaling Pathways

The traditional Chinese medicine component dehydrocostuslactone (DHC) isolated from Saussurea costus (Falc.) Lipschitz, has been shown to have anti-cancer activity. Angiogenesis is an essential process in the growth and progression of cancer. In this study, we demonstrated, for the first time, the anti-angiogenic mechanism of action of DHC to be via the induction of cell cycle progression at the G0/G1 phase due to abrogation of the Akt/glycogen synthase kinase-3β (GSK-3β)/cyclin D1 and mTOR signaling pathway. First, we demonstrated that DHC has an anti-angiogenic effect in the matrigel-plug nude mice model and an inhibitory effect on human umbilical vein endothelial cell (HUVEC) proliferation and capillary-like tube formation in vitro. DHC caused G0/G1 cell cycle arrest, which was associated with the down-regulation of cyclin D1 expression, leading to the suppression of retinoblastoma protein phosphorylation and subsequent inhibition of cyclin A and cdk2 expression. With respect to the molecular mechanisms underlying the DHC-induced cyclin D1 down-regulation, this study demonstrated that DHC significantly inhibits Akt expression, resulting in the suppression of GSK-3β phosphorylation and mTOR expression. These effects are capable of regulating cyclin D1 degradation, but they were significantly reversed by constitutively active myristoylated (myr)-Akt. Furthermore, the abrogation of tube formation induced by DHC was also reversed by overexpression of Akt. And the co-treatment with LiCl and DHC significantly reversed the growth inhibition induced by DHC. Taken together, our study has identified Akt/GSK-3β and mTOR as important targets of DHC and has thus highlighted its potential application in angiogenesis-related diseases, such as cancer

Design, Synthesis, Mechanisms of Action, and Toxicity of Novel 20( S )-Sulfonylamidine Derivatives of Camptothecin as Potent Antitumor Agents

Twelve novel 20-sulfonylamidine derivatives (9a–9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD50 56.2 mg/kg, i.p.) and 3 (LD50 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an anticancer clinical trial candidate

Prostate Cancer-Specific and Potent Antitumor Effect of a DD3-Controlled Oncolytic Virus Harboring the PTEN Gene

Prostate cancer is a major health problem for men in Western societies. Here we report a Prostate Cancer-Specific Targeting Gene-Viro-Therapy (CTGVT-PCa), in which PTEN was inserted into a DD3-controlled oncolytic viral vector (OV) to form Ad.DD3.E1A.E1B(Δ55)-(PTEN) or, briefly, Ad.DD3.D55-PTEN. The woodchuck post-transcriptional element (WPRE) was also introduced at the downstream of the E1A coding sequence, resulting in much higher expression of the E1A gene. DD3 is one of the most prostate cancer-specific genes and has been used as a clinical bio-diagnostic marker. PTEN is frequently inactivated in primary prostate cancers, which is crucial for prostate cancer progression. Therefore, the Ad.DD3.D55-PTEN has prostate cancer specific and potent antitumor effect. The tumor growth rate was almost completely inhibited with the final tumor volume after Ad.DD3.D55-PTEN treatment less than the initial volume at the beginning of Ad.DD3.D55-PTEN treatment, which shows the powerful antitumor effect of Ad.DD3.D55-PTEN on prostate cancer tumor growth. The CTGVT-PCa construct reported here killed all of the prostate cancer cell lines tested, such as DU145, 22RV1 and CL1, but had a reduced or no killing effect on all the non-prostate cancer cell lines tested. The mechanism of action of Ad.DD3.D55-PTEN was due to the induction of apoptosis, as detected by TUNEL assays and flow cytometry. The apoptosis was mediated by mitochondria-dependent and -independent pathways, as determined by caspase assays and mitochondrial membrane potential