Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1–FoxM1 complex

Genes encoding angiotensin-converting enzymes (Ace and Ace2) are essential for heart function regulation. Cardiac stress enhances Ace, but suppresses Ace2, expression in the heart, leading to a net production of angiotensin II that promotes cardiac hypertrophy and fibrosis. The regulatory mechanism that underlies the Ace2-to-Ace pathological switch, however, is unknown. Here we report that the Brahma-related gene-1 (Brg1) chromatin remodeler and forkhead box M1 (FoxM1) transcription factor cooperate within cardiac (coronary) endothelial cells of pathologically stressed hearts to trigger the Ace2-to-Ace enzyme switch, angiotensin I-to-II conversion, and cardiac hypertrophy. In mice, cardiac stress activates the expression of Brg1 and FoxM1 in endothelial cells. Once activated, Brg1 and FoxM1 form a protein complex on Ace and Ace2 promoters to concurrently activate Ace and repress Ace2, tipping the balance to Ace2 expression with enhanced angiotensin II production, leading to cardiac hypertrophy and fibrosis. Disruption of endothelial Brg1 or FoxM1 or chemical inhibition of FoxM1 abolishes the stress-induced Ace2-to-Ace switch and protects the heart from pathological hypertrophy. In human hypertrophic hearts, BRG1 and FOXM1 expression is also activated in endothelial cells; their expression levels correlate strongly with the ACE/ACE2 ratio, suggesting a conserved mechanism. Our studies demonstrate a molecular interaction of Brg1 and FoxM1 and an endothelial mechanism of modulating Ace/Ace2 ratio for heart failure therapy

On the direct insulator-quantum Hall transition in two-dimensional electron systems in the vicinity of nanoscaled scatterers.

A direct insulator-quantum Hall (I-QH) transition corresponds to a crossover/transition from the insulating regime to a high Landau level filling factor ν > 2 QH state. Such a transition has been attracting a great deal of both experimental and theoretical interests. In this study, we present three different two-dimensional electron systems (2DESs) which are in the vicinity of nanoscaled scatterers. All these three devices exhibit a direct I-QH transition, and the transport properties under different nanaoscaled scatterers are discussed.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Improving Conversational Passage Re-ranking with View Ensemble

This paper presents ConvRerank, a conversational passage re-ranker that employs a newly developed pseudo-labeling approach. Our proposed view-ensemble method enhances the quality of pseudo-labeled data, thus improving the fine-tuning of ConvRerank. Our experimental evaluation on benchmark datasets shows that combining ConvRerank with a conversational dense retriever in a cascaded manner achieves a good balance between effectiveness and efficiency. Compared to baseline methods, our cascaded pipeline demonstrates lower latency and higher top-ranking effectiveness. Furthermore, the in-depth analysis confirms the potential of our approach to improving the effectiveness of conversational search.Comment: SIGIR 202

Overexpression of Nuclear Protein Kinase CK2 α Catalytic Subunit (CK2α) as a Poor Prognosticator in Human Colorectal Cancer

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies but the current therapeutic approaches for advanced CRC are less efficient. Thus, novel therapeutic approaches are badly needed. The purpose of this study is to investigate the involvement of nuclear protein kinase CK2 α subunit (CK2α) in tumor progression, and in the prognosis of human CRC. METHODOLOGY/PRINCIPAL FINDINGS: Expression levels of nuclear CK2α were analyzed in 245 colorectal tissues from patients with CRC by immunohistochemistry, quantitative real-time PCR and Western blot. We correlated the expression levels with clinicopathologic parameters and prognosis in human CRC patients. Overexpression of nuclear CK2α was significantly correlated with depth of invasion, nodal status, American Joint Committee on Cancer (AJCC) staging, degree of differentiation, and perineural invasion. Patients with high expression levels of nuclear CK2α had a significantly poorer overall survival rate compared with patients with low expression levels of nuclear CK2α. In multi-variate Cox regression analysis, overexpression of nuclear CK2α was proven to be an independent prognostic marker for CRC. In addition, DLD-1 human colon cancer cells were employed as a cellular model to study the role of CK2α on cell growth, and the expression of CK2α in DLD-1 cells was inhibited by using siRNA technology. The data indicated that CK2α-specific siRNA treatment resulted in growth inhibition. CONCLUSIONS/SIGNIFICANCE: Taken together, overexpression of nuclear CK2α can be a useful marker for predicting the outcome of patients with CRC

Nanoscaled biphasic calcium phosphate modulates osteogenesis and attenuates LPS-induced inflammation

Micron-scale structure biphasic calcium phosphate (BCP) materials have demonstrated promising clinical outcomes in the field of bone tissue repair. However, research on biphasic calcium phosphate materials at the nanoscale level remains limited. In this study, we synthesize granular-shaped biphasic calcium phosphate nanomaterials with multiple desirable characteristics, including negatively charged surfaces, non-cytotoxicity, and the capability to penetrate cells, using a nanogrinding dispersion process with a polymeric carboxylic acid as the dispersant. Our results reveal that treating human osteoblasts with 0.5 μg/mL biphasic calcium phosphate nanomaterials results in a marked increase in alkaline phosphatase (ALP) activity and the upregulation of osteogenesis-related genes. Furthermore, these biphasic calcium phosphate nanomaterials exhibit immunomodulatory properties. Treatment of THP-1-derived macrophages with BCP nanomaterials decreases the expression of various inflammatory genes. Biphasic calcium phosphate nanomaterials also mitigate the elevated inflammatory gene expression and protein production triggered by lipopolysaccharide (LPS) exposure in THP-1-derived macrophages. Notably, we observe that biphasic calcium phosphate nanomaterials have the capacity to reverse the detrimental effects of LPS-stimulated macrophage-conditioned medium on osteoblastic activity and mineralization. These findings underscore the potential utility of biphasic calcium phosphate nanomaterials in clinical settings for the repair and regeneration of bone tissue. In conclusion, this study highlights the material properties and positive effects of biphasic calcium phosphate nanomaterials on osteogenesis and immune regulation, opening a promising avenue for further research on inflammatory osteolysis in patients undergoing clinical surgery

Characteristics of Summertime Volatile Organic Compounds in the Lower Free Troposphere: Background Measurements at Mt. Fuji

Air samples were collected at Mt. Fuji Research Station (FRS) for the measurements of volatile organic compounds (VOCs) in the summers of 2015 and 2016. In this study, 24 compounds were analyzed, of which only 12 halocarbons were quantified in 2015. The average total concentrations of target VOCs were 2.62 ± 1.38 and 2.99 ± 0.95 ppb in 2015 and 2016, respectively. The concentrations of individual VOCs ranged from a few ppt to a few ppb, indicating a highly inhomogeneous feature at the FRS. A cluster analysis of 3-day backward trajectories was performed for the sampling time. Except for the aromatic compounds, the VOCs showed relatively low concentrations in association with air masses originating from the coastal region in the low latitudes (15°N–35°N) of East Asia in 2015. By contrast, the clusters with elevated VOC concentrations mainly came from the high latitudes (35°N–60°N) of the Asian continent in 2016. No particular diurnal pattern was found for VOCs and CO, which might have resulted from suppressed mountain-valley winds at the FRS. Halocarbons regulated by the Montreal Protocol showed low variability and were in favorable agreement with background values at the Gosan station (GSN) and those reported in the literature. Other partially halogenated compounds with higher variability, such as CH_3Cl and CHCl_3, showed discrepancies at the FRS and GSN. 1,2-dichloroethane (R-150), 1,1-dichloroethane (R-150a), and 1,4-dichlorobenzene (p-DCB) were also measured at the FRS with concentrations of 24 ± 14, 38 ± 13, and 13 ± 10 ppt, respectively, in 2015. A close relationship between n-pentane and i-pentane with R^2 more than 0.85 was found in both 2015 and 2016. Low ratios of n/i-pentane ranging from 0.25 to 0.67 were observed in the free troposphere at the FRS, comparable to most mountain stations.http://purl.org/coar/resource_type/c_650

Cloud structure of three Galactic infrared dark star-forming regions from combining ground and space based bolometric observations

We have modified the iterative procedure introduced by Lin et al. (2016), to systematically combine the submm images taken from ground based (e.g., CSO, JCMT, APEX) and space (e.g., Herschel, Planck) telescopes. We applied the updated procedure to observations of three well studied Infrared Dark Clouds (IRDCs): G11.11-0.12, G14.225-0.506 and G28.34+0.06, and then performed single-component, modified black-body fits to derive $\sim$10$"$ resolution dust temperature and column density maps. The derived column density maps show that these three IRDCs exhibit complex filamentary structures embedding with rich clumps/cores. We compared the column density probability distribution functions (N-PDFs) and two-point correlation (2PT) functions of the column density field between these IRDCs with several OB cluster-forming regions. Based on the observed correlation and measurements, and complementary hydrodynamical simulations for a 10$^{4}$ $\rm M_{\odot}$ molecular cloud, we hypothesize that cloud evolution can be better characterized by the evolution of the (column) density distribution function and the relative power of dense structures as a function of spatial scales, rather than merely based on the presence of star-forming activity. Based on the small analyzed sample, we propose four evolutionary stages, namely: {\it cloud integration, stellar assembly, cloud pre-dispersal and dispersed-cloud.} The initial {\it cloud integration} stage and the final {\it dispersed cloud} stage may be distinguished from the two intermediate stages by a steeper than $-$4 power-law index of the N-PDF. The {\it cloud integration} stage and the subsequent {\it stellar assembly} stage are further distinguished from each other by the larger luminosity-to-mass ratio ($>$40 $\rm L_{\odot}/M_{\odot}$) of the latter

Novel artificial tricalcium phosphate and magnesium composite graft facilitates angiogenesis in bone healing

Bone grafting is the standard treatment for critical bone defects, but autologous grafts have limitations like donor site morbidity and limited availability, while commercial artificial grafts may have poor integration with surrounding bone tissue, leading to delayed healing. Magnesium deficiency negatively impacts angiogenesis and bone repair. Therefore, incorporating magnesium into a synthetic biomaterial could provide an excellent bone substitute. This study aims to evaluate the morphological, mechanical, and biological properties of a calcium phosphate cement (CPC) sponge composed of tetracalcium phosphate (TTCP) and monocalcium phosphate monohydrate (MCPM), which could serve as an excellent bone substitute by incorporating magnesium. This study aims to develop biomedical materials composed mainly of TTCP and MCPM powder, magnesium powder, and collagen. The materials were prepared using a wet-stirred mill and freeze-dryer methods. The particle size, composition, and microstructure of the materials were investigated. Finally, the biological properties of these materials, including 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay for biocompatibility, effects on bone cell differentiation by alkaline phosphatase (ALP) activity assay and tartrate-resistant acid phosphatase (TRAP) activity assay, and endothelial cell tube formation assay for angiogenesis, were evaluated as well. The data showed that the sub-micron CPC powder, composed of TTCP/MCPM in a 3.5:1 ratio, had a setting time shorter than 15 minutes and a compressive strength of 4.39±0.96 MPa. This reveals that the sub-micron CPC powder had an adequate setting time and mechanical strength. We found that the sub-micron CPC sponge containing magnesium had better biocompatibility, including increased proliferation and osteogenic induction effects without cytotoxicity. The CPC sponge containing magnesium also promoted angiogenesis. In summary, we introduced a novel CPC sponge, which had a similar property to human bone promoted the biological functions of bone cells, and could serve as a promising material used in bone regeneration for critical bone defects. [Abstract copyright: Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.