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Abstract Invasive breast cancer (BrCa) is predicted to affect 1 in 9 women in a lifetime;1 in 32 will die from this disease. The most aggressive forms of BrCa, basal-like/triple-negative phenotype (TNBC), are challenging to treat and result in higher mortality due high number of metastatic cases. There is a paucity of options for TNBC treatment, which highlights the need for additional innovative treatment approaches. NIH-III mice were injected in the abdominal mammary fat pad with luciferase-expressing derivative of the human TNBC cell line, MDA-MB-231 cells. Animals were gavage-fed with nitrofen at the doses of 1, 3 or 6 mg/kg/alternate days. However, several structural properties/components of nitrofen raise concerns, including its high lipophilicity (cLogP of nearly 5) and a potential toxophore in the form of a nitroarene group. Therefore, we developed analogues of nitrofen which lack the nitro group and/or have replaced the diaryl ether linker with a diarylamine that could allow modulation of polarity. In vitro anti-invasiveness activity of nitrofen analogues were evaluated by quantitative determination of invasion of MDA-MB-231-Luciferase cells through Matrigel using a Boyden chamber. Our in vivo data show that nitrofen efficiently blocks TNBC tumor metastasis. In vitro data suggest that this is not due to cytotoxicity, but rather is due to impairment of invasive capacity of the cells. Further, using an in vitro model of EMT, we show that nitrofen interferes with the process of EMT and promotes mesenchymal to epithelial transformation. In addition, we show that three of the nitrofen analogues significantly reduced invasive potential of TNBC cells, which may, at least partially, be attributed to the analogues’ ability to promote mesenchymal to epithelial-like transformation of TNBC cells. Our study shows that nitrofen, and more importantly its analogues, are significantly effective in limiting the invasive potential of TNBC cell lines with minimal cytotoxic effect. Further, we demonstrate that nitrofen its analogues, are very effective in reversing mesenchymal phenotype to a more epithelial-like phenotype. This may be significant for the treatment of patients with mesenchymal-TNBC tumor subtype who are well known to exhibit high resistance to chemotherapy.

Here, we demonstrate that reductions in the depth of inlets or estuary channels can be used to reduce or prevent coastal flooding. A validated hydrodynamic model of Jamaica Bay, New York City (NYC), is used to test nature-based adaptation measures in ameliorating flooding for NYC's two largest historical coastal flood events. In addition to control runs with modern bathymetry, three altered landscape scenarios are tested: (1) increasing the area of wetlands to their 1879 footprint and bathymetry, but leaving deep shipping channels unaltered; (2) shallowing all areas deeper than 2 m in the bay to be 2 m below Mean Low Water; (3) shallowing only the narrowest part of the inlet to the bay. These three scenarios are deliberately extreme and designed to evaluate the leverage each approach exerts on water levels. They result in peak water level reductions of 0.3%, 15%, and 6.8% for Hurricane Sandy, and 2.4%, 46% and 30% for the Category-3 hurricane of 1821, respectively (bay-wide averages). These results suggest that shallowing can provide greater flood protection than wetland restoration, and it is particularly effective at reducing "fast-pulse" storm surges that rise and fall quickly over several hours, like that of the 1821 storm. Nonetheless, the goal of flood mitigation must be weighed against economic, navigation, and ecological needs, and practical concerns such as the availability of sediment.

Objective: This study sought to investigate whether the size of the target used in the horizontal vHIT has an effect on the saccade profile of healthy subjects, and to expand upon previous work linking age to the existence of small vHIT saccades.Methods: Forty eight participants were recruited between 18 and 77 years of age, with no history of vestibular, oculomotor or neurological conditions and a visual acuity of at least 0.3 LogMAR. Participants underwent four consecutive horizontal vHIT trials using the standard target size and three smaller targets. VOR gain and metrics for saccadic incidence, peak eye velocity and latency were then extracted from results.Results: Target size was a statistically significant influence on saccade metrics. As target size increased, saccadic incidence decreased while peak eye velocity and latency increased. However, a potential order effect was also discovered, and once this was corrected for the remaining effect of target size was small and is likely clinically insignificant. The effect of age was much stronger than target size; increasing age was strongly positively correlated with saccadic incidence and showed a medium size correlation with peak velocity, though not with saccadic latency.Conclusion: While this study suggests that target size may have a statistically significant impact on the vHIT saccade profile of normal subjects, age has a greater influence on the incidence and size of small vHIT saccades.

Diversified development of educational strategies has been increasingly growing in the field of teacher education to address the challenges in residential-based learning brought by the virtual classroom setting. Necessarily, the application of game-based learning (GBL) is viewed to significantly contribute to complementing the students' learning deficiencies. Hence, this study was conducted to increase concept retention among pre-service physical educators (PSPEs) through a game-based assessment strategy called moneypoly game. This descriptive-qualitative collaborative action research study comprised 48 student-participants enrolled in the professional education course, "Curriculum and Assessment in Physical Education and Health Education for K to 12", at a teacher education institution in Central Luzon, Philippines during the first semester of the academic year 2022-2023. Educational activities related to the moneypoly game were implemented multiple times during the face-to-face class sessions. Subsequently, open-ended reflective questionnaires were administered to obtain authentic and valid data to capture the increment of concept retention among the PSPEs. Adhering to Braun and Clarke's Thematic Analysis technique, students' responses were themed via qualitative analysis software powered by MAXQDA Analytics Pro 2022. Findings revealed three (3) emerging themes that helped learners retain long-term memory of the lessons' concepts. This includes (1) learners' experiences in the moneypoly game that strengthen their concept retention, (2) contributing factors to students' constant participation, and (3) significant recommendations to improve the game-based assessment strategy in the next cycle. These characteristics of the moneypoly game influenced the way that students learned and remembered information. This led to the perception that the intervention generated multiform driving forces for the learners' all-encompassing learning. The exploration and utilization of GBL could be applied to other areas of discipline to corroborate the findings made in this study. [ABSTRACT FROM AUTHOR]

The parameters that modulate the functional capacity of secondary Th1 effector cells are poorly understood. In this study, we employ a serial adoptive transfer model system to show that the functional differentiation and secondary memory potential of secondary CD4+ effector T cells are dependent on the inflammatory environment of the secondary challenge. Adoptive transfer of TCR transgenic lymphocytic choriomeningitis virus (LCMV) Glycoprotein-specific SMARTA memory cells into LCMV-immune hosts, followed by secondary challenge with Listeria monocytogenes recombinantly expressing a portion of the LCMV Glycoprotein (Lm-gp61), resulted in the rapid emergence of SMARTA secondary effector cells with heightened functional avidity (as measured by their ability to make IFNγ in response to ex vivo restimulation with decreasing concentrations of peptide), limited contraction after pathogen clearance and stable maintenance secondary memory T cell populations. In contrast, transfer of SMARTA memory cells into naïve hosts prior to secondary Lm-gp61 challenge, which resulted in a more extended infectious period, resulted in poor functional avidity, increased death during the contraction phase and poor maintenance of secondary memory T cell populations. The modulation of functional avidity during the secondary Th1 response was independent of differences in antigen load or persistence. Instead, the inflammatory environment strongly influenced the function of the secondary Th1 response, as inhibition of IL-12 or IFN-I activity respectively reduced or increased the functional avidity of secondary SMARTA effector cells following rechallenge in a naïve secondary hosts. Our findings demonstrate that secondary effector T cells exhibit inflammation-dependent differences in functional avidity and memory potential, and have direct bearing on the design of strategies aimed at boosting memory T cell responses.

Selective clonal deletion in the CD4(+) T cell compartment during the transition from effector to memory is accompanied by enhanced expression of the pro-apoptotic Bcl-2 family member Bim. Here, we show that Bim deficiency enables the survival of poorly functional Th1 responders that are normally eliminated during contraction. However, rescued bim(-/-) CD4(+) "memory" T cells continued to demonstrate deficient effector functions, poor sensitivity to antigen and an inability to respond to secondary challenge. Our results demonstrate that Bim activity plays a key role in shaping the CD4(+) memory T cell repertoire, ensuring the emergence of highly functional CD4(+) memory T cells and the elimination of Th1 effector cells with sub-optimal function. We propose that Bim is a key mediator of T cell death in the absence of appropriate TCR-driven activation and differentiation.

The Columbia River is a major source of and conduit for Pacific Northwest economic activity, and is one of the more heavily modified rivers in North America. Understanding human and climate‐induced changes in its hydrologic properties is, therefore, vital. Long streamflow records are essential to determining how runoff has changed over time, and Columbia River daily streamflow record at The Dalles began in 1878. To understand and separate anthropogenic and climate effects, however, it is also necessary to have a basin‐scale estimate of virgin or naturalized flow. The United States Geological Survey has calculated a monthly averaged adjusted river flow at The Dalles for 1879–1999 that accounts for the effects of flow regulation. The Bonneville Power Administration has estimated the monthly averaged virgin flow at The Dalles, i.e. the flow in the absence of both flow regulation and irrigation depletion for 1929–89. We have estimated the monthly virgin flow of the Columbia River at The Dalles from records of irrigated area for the missing early years, i.e. for the period 1879–1928. In addition, to allow hindcasting of a virgin flow sediment transport for the system, a daily virgin flow index with realistic higher moments and spectral properties has been calculated. Examination of the virgin flow record shows that climate change since the late 19th century has decreased annual average flow volume by > 7%; irrigation depletion has reduced the flow by another ∼7%. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]