2,528 research outputs found
The Co-expression of ROR1 and FZD2 in WNT5B Signaling in Osteosarcoma
Osteosarcoma is the most common primary bone malignancy. There is currently no targeted therapy, so standard treatment involves surgical resection along with chemotherapy. There is a large subset of osteosarcoma that has a high expression of WNT5B, which is linked to a worse overall survival probability. The WNT5B pathway in osteosarcoma is not known, so we wanted to find out what receptors it signals through. We came up with two candidates, ROR1 and FZD2, then tested our hypothesis using immunohistochemistry. We first optimized the antigen retrieval step and ROR1 primary antibody for our immunohistochemistry protocol then proceeded to test our hypothesis. We found that when WNT5B is present in the tumor, ROR1 and FZD2 are also present, likewise, when WNT5B is absent ROR1 and FZD2 are also absent. We also noticed that these proteins are all confined to the tumor itself, not the stroma. Lastly, we saw that WNT5B, ROR1 and FZD2 appear to be in the same locations in each sample, suggesting a potential signaling relationship. We hope to one day use these receptors as druggable targets to disrupt the WNT5B pathway in patients that have osteosarcoma with WNT5B overexpression
Internet neutrality debate is delayed in Argentina
Los cambios en Internet y las complejidades para su regulación se derivan de su carácter abierto, libre, global, descentralizado y des-territorializado. Por ello resulta clave analizar las tendencias regulatorias por las oportunidades y desafíos que supone para el diseño de las políticas de comunicación. Dada la creciente importancia de Internet para el ejercicio de la libertad de expresión y en la circulación de los bienes culturales, uno de los ejes del debate internacional se centra en el principio de la neutralidad de la red, que implica garantizar el acceso a los usuarios, la antidiscriminación en la circulación de los contenidos y la interoperabilidad de las redes. Desde un abordaje de la economía política de la comunicación, el artículo tiene como objetivo analizar las legislaciones y proyectos vigentes ligadas al desarrollo de Internet en Argentina, que se plantean por acción u omisión del Estado, a partir de la identificación de dos tensiones: el interés público versus el interés corporativo y la libertad de expresión versus el control del acceso. E indaga en qué medida se articula el principio de neutralidad de la red en las regulaciones emergentes para lo cual se identifican los actores clave y se evalúa el impacto de los intereses afectados.The transformations and the difficulties to regulate Internet take place because of being open, free, global, descentralized and des territorialized. Accordingly, it is important to analize the regulatories bias in order to elaborate communication policies. Since the key role that Internet is playing on the freedom of expression and the circulation of culture products, the worldwide debate is focused on the neutrality net. This is oriented to guarantee consumer’s access to networks, the non-discrimmination between different kind of contents and applications, and the interoperability between different nets. Within political economy of communication´s approach, this paper aims to analize the laws and bills over the development of Internet in Argentina, that are proposed by action or omission from governments. This study highlates two tensions: public interest versus corporate interest and the freedom of expression versus control access. Lastly, it inquires into the enforcement of the neutrality net on the emergent regulations, identifying the main actors and assessing the impact on their interests.Facultad de Periodismo y Comunicación Socia
Internet neutrality debate is delayed in Argentina
Los cambios en Internet y las complejidades para su regulación se derivan de su carácter abierto, libre, global, descentralizado y des-territorializado. Por ello resulta clave analizar las tendencias regulatorias por las oportunidades y desafíos que supone para el diseño de las políticas de comunicación. Dada la creciente importancia de Internet para el ejercicio de la libertad de expresión y en la circulación de los bienes culturales, uno de los ejes del debate internacional se centra en el principio de la neutralidad de la red, que implica garantizar el acceso a los usuarios, la antidiscriminación en la circulación de los contenidos y la interoperabilidad de las redes. Desde un abordaje de la economía política de la comunicación, el artículo tiene como objetivo analizar las legislaciones y proyectos vigentes ligadas al desarrollo de Internet en Argentina, que se plantean por acción u omisión del Estado, a partir de la identificación de dos tensiones: el interés público versus el interés corporativo y la libertad de expresión versus el control del acceso. E indaga en qué medida se articula el principio de neutralidad de la red en las regulaciones emergentes para lo cual se identifican los actores clave y se evalúa el impacto de los intereses afectados.The transformations and the difficulties to regulate Internet take place because of being open, free, global, descentralized and des territorialized. Accordingly, it is important to analize the regulatories bias in order to elaborate communication policies. Since the key role that Internet is playing on the freedom of expression and the circulation of culture products, the worldwide debate is focused on the neutrality net. This is oriented to guarantee consumer’s access to networks, the non-discrimmination between different kind of contents and applications, and the interoperability between different nets. Within political economy of communication´s approach, this paper aims to analize the laws and bills over the development of Internet in Argentina, that are proposed by action or omission from governments. This study highlates two tensions: public interest versus corporate interest and the freedom of expression versus control access. Lastly, it inquires into the enforcement of the neutrality net on the emergent regulations, identifying the main actors and assessing the impact on their interests.Facultad de Periodismo y Comunicación Socia
BRCA1 Forms a Functional Complex with γ-H2AX as a Late Response to Genotoxic Stress
Following genotoxic stress, the histone H2AX becomes phosphorylated at serine 139 by the ATM/ATR family of kinases. The tumor suppressor BRCA1, also phosphorylated by ATM/ATR kinases, is one of several proteins that colocalize with phospho-H2AX (γ-H2AX) at sites of active DNA repair. Both the precise mechanism and the purpose of BRCA1 recruitment to sites of DNA damage are unknown. Here we show that BRCA1 and γ-H2AX form an acid-stable biochemical complex on chromatin after DNA damage. Maximal association of BRCA1 with γ-H2AX correlates with reduced global γ-H2AX levels on chromatin late in the repair process. Since BRCA1 is known to have E3 ubiquitin ligase activity in vitro, we examined H2AX for evidence of ubiquitination. We found that H2AX is ubiquitinated at lysines 119 and 119 in vivo and that blockage of 26S proteasome function stabilizes γ-H2AX levels within cells. When BRCA1 levels were reduced, ubiquitination of H2AX was also reduced, and the cells retained higher levels of phosphorylated H2AX. These results indicate that BRCA1 is recruited into stable complexes with γ-H2AX and that the complex is involved in attenuation of the γ-H2AX repair signal after DNA damage
Forest Cover Changes in Tropical South and Central America from 1990 to 2005 and Related Carbon Emissions and Removals.
This paper outlines the methods and results for monitoring forest change and resulting carbon emissions for the 1990-2000 and 200-2005 periods carried out over tropical Central and South America. To produce our forest change estimates we used a systematic sample of medium resolution satellite data processed to forest change maps covering 1230 sites of 20 km by 20 km, each located at the degree confluence. Biomass data were spatially associated to each individual sample site so that annual carbon emissions could be estimated. For our study area we estimate that forest cover in the study area had fallen from 763 Mha (s.e. 10 Mha) in 1990 to 715 Mha (s.e. 10 Mha) in 2005. During the same period other wooded land (i.e., non-forest woody vegetation) had fallen from 191 Mha (s.e. 5.5 Mha) to 184 Mha (s.e. 5.5 Mha). This equates to an annual gross loss of 3.74 Mha·y−1 of forests (0.50% annually) between 1990 and 2000, rising to 4.40 Mha·y−1 in the early 2000s (0.61% annually), with Brazil accounting for 69% of the total losses. The annual carbon emissions from the combined loss of forests and other wooded land were calculated to be 482 MtC·y−1 (s.e. 29 MtC·y−1) for the 1990s, and 583 MtC·y−1 (s.e. 48 MtC·y−1) for the 2000 to 2005 period. Our maximum estimate of sinks from forest regrowth in tropical South America is 92 MtC·y−1. These estimates of gross emissions correspond well with the national estimates reported by Brazil, however, they are less than half of those reported in a recent study based on the FAO country statistics, highlighting the need for continued research in this area
DPAGT1 Inhibitors of Capuramycin Analogues and Their Antimigratory Activities of Solid Tumors
Capuramycin displays a narrow spectrum of antibacterial activity by targeting bacterial translocase I (MraY). In our program of development of new N-acetylglucosaminephosphotransferase1 (DPAGT1) inhibitors, we have identified that a capuramycin phenoxypiperidinylbenzylamide analogue (CPPB) inhibits DPAGT1 enzyme with an IC₅₀ value of 200 nM. Despite a strong DPAGT1 inhibitory activity, CPPB does not show cytotoxicity against normal cells and a series of cancer cell lines. However, CPPB inhibits migrations of several solid cancers including pancreatic cancers that require high DPAGT1 expression in order for tumor progression. DPAGT1 inhibition by CPPB leads to a reduced expression level of Snail but does not reduce E-cadherin expression level at the IC₅₀ (DPAGT1) concentration. CPPB displays a strong synergistic effect with paclitaxel against growth-inhibitory action of a patient-derived pancreatic adenocarcinoma, PD002: paclitaxel (IC₅₀: 1.25 μM) inhibits growth of PD002 at 0.0024–0.16 μM in combination with 0.10–2.0 μM CPPB (IC₅₀: 35 μM)
DPAGT1 Inhibitors of Capuramycin Analogues and Their Antimigratory Activities of Solid Tumors
Capuramycin displays a narrow spectrum of antibacterial activity by targeting bacterial translocase I (MraY). In our program of development of new N-acetylglucosaminephosphotransferase1 (DPAGT1) inhibitors, we have identified that a capuramycin phenoxypiperidinylbenzylamide analogue (CPPB) inhibits DPAGT1 enzyme with an IC₅₀ value of 200 nM. Despite a strong DPAGT1 inhibitory activity, CPPB does not show cytotoxicity against normal cells and a series of cancer cell lines. However, CPPB inhibits migrations of several solid cancers including pancreatic cancers that require high DPAGT1 expression in order for tumor progression. DPAGT1 inhibition by CPPB leads to a reduced expression level of Snail but does not reduce E-cadherin expression level at the IC₅₀ (DPAGT1) concentration. CPPB displays a strong synergistic effect with paclitaxel against growth-inhibitory action of a patient-derived pancreatic adenocarcinoma, PD002: paclitaxel (IC₅₀: 1.25 μM) inhibits growth of PD002 at 0.0024–0.16 μM in combination with 0.10–2.0 μM CPPB (IC₅₀: 35 μM)
WNT10B/β-catenin signalling induces HMGA2 and proliferation in metastatic triple-negative breast cancer
Wnt/β-catenin signalling has been suggested to be active in basal-like breast cancer. However, in highly aggressive metastatic triple-negative breast cancers (TNBC) the role of β-catenin and the underlying mechanism(s) for the aggressiveness of TNBC remain unknown. We illustrate that WNT10B induces transcriptionally active β-catenin in human TNBC and predicts survival-outcome of patients with both TNBC and basal-like tumours. We provide evidence that transgenic murine Wnt10b-driven tumours are devoid of ERα, PR and HER2 expression and can model human TNBC. Importantly, HMGA2 is specifically expressed during early stages of embryonic mammogenesis and absent when WNT10B expression is lost, suggesting a developmentally conserved mode of action. Mechanistically, ChIP analysis uncovered that WNT10B activates canonical β-catenin signalling leading to up-regulation of HMGA2. Treatment of mouse and human triple-negative tumour cells with two Wnt/β-catenin pathway modulators or siRNA to HMGA2 decreases HMGA2 levels and proliferation. We demonstrate that WNT10B has epistatic activity on HMGA2, which is necessary and sufficient for proliferation of TNBC cells. Furthermore, HMGA2 expression predicts relapse-free-survival and metastasis in TNBC patients
Wnt10b Deficiency Results in Age-Dependent Loss of Bone Mass and Progressive Reduction of Mesenchymal Progenitor Cells
Wnt10b is a canonical Wnt ligand expressed in developing bone and has been linked to mesenchymal progenitor functions in mice and humans. Because Wnt signaling has been shown to play an important role in progenitor maintenance in a variety of adult tissues, we examined bone deposition and growth rates throughout postnatal development in Wnt10b-null mice. Using bone histomorphometry and micro–computed tomographic (µCT) studies, we demonstrate that trabecular bone deposition is slightly enhanced in Wnt10b-null mice at 1 month of age, followed by progressive loss with age. Importantly, we find that Wnt10b is required for maintenance of adult bone density in multiple backgrounds of inbred mice and that both copies of the Wnt10b gene are required to maintain normal bone density in 6-month-old animals. We go on to show that the loss in trabecular bone in Wnt10b-null mice is associated with a reduction in the number of bone marrow–derived mesenchymal progenitors (MPCs) using in vitro colony-forming unit assays and marker analysis. Analysis of osteogenic gene expression in primary bone marrow stromal cells demonstrated reductions in expression of several osteoblast differentiation markers. Taken together, our results indicate that Wnt10b is uniquely required for maintenance of mesenchymal progenitor activity in adult bone. The results show the significance of studying individual Wnt ligands and their potentially unique contribution in the context of aging and disease. © 2010 American Society for Bone and Mineral Research
Impact of Federal, State, and Local Housing Policies on Disparities in Cardiovascular Disease in Black/African American Men and Women: From Policy to Pathways to Biology
Racist and discriminatory federal, state, and local housing policies significantly contribute to disparities in cardiovascular disease incidence and mortality for individuals that self-identify as Black or African American. Here we highlight three key housing policies – “redlining,” zoning, and the construction of highways – which have wrought a powerful, sustained, and destructive impact on cardiovascular health in Black/African American communities. Redlining and highway construction policies have restricted access to quality health care, increased exposure to carcinogens such as PM2.5, and increased exposure to extreme heat. At the root of these policy decisions are longstanding, toxic societal factors including racism, segregation, and discrimination, which also serve to perpetuate racial inequities in cardiovascular health. Here, we review these societal and structural factors and then link them with biological processes such as telomere shortening, allostatic load, oxidative stress, and tissue inflammation. Lastly, we focus on the impact of inflammation on the immune system and the molecular mechanisms by which the inflamed immune microenvironment promotes the formation of atherosclerotic plaques. We propose that racial residential segregation and discrimination increases tissue inflammation and cytokine production, resulting in dysregulated immune signaling, which promotes plaque formation and cardiovascular disease. This framework has the power to link structural racism not only to cardiovascular disease, but also to cancer
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