Hypoxia has been proposed as an important microenvironmental factor in the development of tissue fibrosis; however, the underlying mechanisms are not well defined. To examine the role of hypoxia-inducible factor-1 (HIF-1), a key mediator of cellular adaptation to hypoxia, in the development of fibrosis in mice, we inactivated Hif-1alpha in primary renal epithelial cells and in proximal tubules of kidneys subjected to unilateral ureteral obstruction (UUO) using Cre-loxP-mediated gene targeting. We found that Hif-1alpha enhanced epithelial-to-mesenchymal transition (EMT) in vitro and induced epithelial cell migration through upregulation of lysyl oxidase genes. Genetic ablation of epithelial Hif-1alpha inhibited the development of tubulointerstitial fibrosis in UUO kidneys, which was associated with decreased interstitial collagen deposition, decreased inflammatory cell infiltration, and a reduction in the number of fibroblast-specific protein-1-expressing (FSP-1-expressing) interstitial cells. Furthermore, we demonstrate that increased renal HIF-1alpha expression is associated with tubulointerstitial injury in patients with chronic kidney disease. Thus, we provide clinical and genetic evidence that activation of HIF-1 signaling in renal epithelial cells is associated with the development of chronic renal disease and may promote fibrogenesis by increasing expression of extracellular matrix-modifying factors and lysyl oxidase genes and by facilitating EMT.

We report the observation of gravitational waves from two compact binary coalescences in LIGO's and Virgo's third observing run with properties consistent with neutron star-black hole (NSBH) binaries. The two events are named GW200105_162426 and GW200115_042309, abbreviated as GW200105 and GW200115; the first was observed by LIGO Livingston and Virgo and the second by all three LIGO-Virgo detectors. The source of GW200105 has component masses -+ 8.9 1.5 1.2 and 130 Gpc yr 69 112 3 1 under the assumption of a broader distribution of component masses.

Abstract-We recently reported that angiotensin II (Ang II) induced IL-6 mRNA expression in cardiac fibroblasts, which played an important role in Ang II-induced cardiac hypertrophy in paracrine fashion. The present study investigated the regulatory mechanism of Ang II-induced IL-6 gene expression, focusing especially on reactive oxygen species (ROS)-mediated signaling in cardiac fibroblasts. Ang II increased intracellular ROS in cardiac fibroblasts, and the increase was completely inhibited by the AT-1 blocker candesartan and the NADH/NADPH oxidase inhibitor diphenyleneiodonium (DPI). We first confirmed that antioxidant N-acetylcysteine, superoxide scavenger Tiron, and DPI suppressed Ang II-induced IL-6 expression. Because we observed that exogenous H 2 O 2 also increased IL-6 mRNA, the signaling pathways downstream of Ang II and exogenous H 2 O 2 were compared. Ang II, as well as exogenous H 2 O 2 , activated ERK, p38 MAPK, and JNK, which were significantly inhibited by N-acetylcysteine and DPI. In contrast with exogenous H 2 O 2 , however, Ang II did not influence phosphorylation and degradation of IB-␣/␤ or nuclear translocation of p65, nor did it increase NF-B promoter activity. PD98059 and SB203580 inhibited Ang II-induced IL-6 expression. Truncation and mutational analysis of the IL-6 gene promoter showed that CRE was an important cis-element in Ang II-induced IL-6 gene expression. NF-B-binding site was important for the basal expression of IL-6, but was not activated by Ang II. Ang II phosphorylated CREB through the ERK and p38 MAPK pathway in a ROS-sensitive manner. Collectively, these data indicated that Ang II stimulated ROS production via the AT1 receptor and NADH/NADPH oxidase, and that these ROS mediated activation of MAPKs, which culminated in IL-6 gene expression through a CRE-dependent, but not NF-B-dependent, pathway in cardiac fibroblasts. Key Words: angiotensin II Ⅲ interleukin-6 Ⅲ reactive oxygen species Ⅲ mitogen-activated protein kinase Ⅲ cardiac fibroblast C linical, experimental, and genetic data have demonstrated that the renin angiotensin system is linked to the pathogenesis of a variety of cardiac diseases. Expression of angiotensin II (Ang II), the key effector molecule of the renin angiotensin system, is increased under various pathophysiological conditions and stimulates cardiomyocyte hypertrophy and interstitial fibrosis coinciding with accumulation of extracellular matrix. Recent reports had shown that Ang II stimulates membrane-bound NAD(P)H oxidase, which generates reactive oxygen species (ROS) in a variety of nonphagocytic cells. 1 ROS may act as a second messenger that regulates various intracellular signal transduction cascades and the activity of various transcription factors. NF-B and AP-1 are the best characterized transcription factors to be influenced by the cellular oxidation-reduction (redox) state. 2,3 The primary target of activation of NF-B by ROS appears to be the phosphorylation and subsequent degradation of IB. 4 Another well-characterized redox sensitive signali...

We analyze the data of the gravitational microlensing survey carried out by the Microlensing Observations in Astrophysics (MOA) group during 2000 toward the Galactic bulge (GB). Our observations are designed to detect efficient high-magnification events with faint source stars and short-timescale events, by increasing the sampling rate up to $6 times per night and using Difference Image Analysis (DIA). We detect 28 microlensing candidates in 12 GB fields corresponding to 16 deg 2 . We use Monte Carlo simulations to estimate our microlensing event detection efficiency, where we construct the I-band extinction map of our GB fields in order to find dereddened magnitudes. We find a systematic bias and large uncertainty in the measured value of the timescale t E,out in our simulations. They are associated with blending and unresolved sources, and are allowed for in our measurements. We compute an optical depth ¼ 2:59 þ0:84 À0:64 Â 10 À6 toward the GB for events with timescales 0:3 < t E < 200 days. We consider disk-disk lensing, and obtain an optical depth bulge ¼ 3:36 þ1:11 À0:81 Â 10 À6 ½0:77=ð1 À f disk Þ for the bulge component assuming a 23% stellar contribution from disk stars. These observed optical depths are consistent with previous measurements by the MACHO and OGLE groups, and still higher than those predicted by existing Galactic models. We present the timescale distribution of the observed events, and find there are no significant short events of a few days, in spite of our high detection efficiency for short-timescale events down to t E $ 0:3 days. We find that half of all our detected events have high magnification (>10). These events are useful for studies of extrasolar planets.