Objectives/Goals: Monensin is FDA approved for use in veterinary medicine. Recent studies pointed to its potent anticancer activity. Since de novo drug discovery process typically takes 10 to 15 years and requires an investment of approximately $1.3 to $3 billion, drug repositioning can bypass several steps in this process and increase the potential for success. Methods/Study Population: Cell viability assays were conducted on human MDA-MB-231, MDA-MB-468, and MCF10A breast cancer cell lines and mouse EO771 and 4T1 breast cancer cell lines. MDA-MB-231 cell line was used in all the studies unless specified otherwise. Time course levels of Bcl-2, Bak, p62, and LC3II were assessed via Western blotting with GAPDH as a loading control. Proteomics analysis was conducted by the IDEA National Resource for Quantitative Proteomics. Time course levels of major histocompatibility complex (MHC) I and II and calreticulin were evaluated using flow cytometry. At least three biological replicates have been conducted for each experiment. Results/Anticipated Results: Monensin and several of its novel analogs were potent toward human and mouse breast cancer cell lines. Furthermore, they induced apoptotic cell death as evidenced by Annexin V/PI assay, downregulation of Bcl-2, and upregulation of Bak in MDA-MB-231 cells. Proteomics analysis revealed that several molecular pathways related to MHC class I and II antigen presentation were significantly altered following treatment with these compounds. Additionally, monensin and its analogs significantly increased the expression of MHC class I and II. Our studies also showed that monensin and its analogs increase the surface calreticulin levels. Treatment of MDA-MB-231 cells with these compounds also resulted in an increase in p62 and LC3II expression, suggesting a disruption of the autophagic process. Discussion/Significance of Impact: These results suggest that monensin and its analogs not only exhibit anti-breast cancer cell activity but also modulate immune-related pathways. By disrupting autophagy and enhancing calreticulin levels, these compounds may potentiate antitumor immune responses, providing a promising avenue for drug repositioning in cancer therapy.

Measurement is the weak link between theory and empirical test. Complex concepts such as ideology, identity, and legitimacy are difficult to measure; yet, without measurement that matches theoretical constructs, careful empirical studies may not be testing that which they had intended. Item response theory (IRT) models offer promise by producing transparent and improvable measures of latent factors thought to underlie behavior. Unfortunately, those factors have no intrinsic substantive interpretations. Prior solutions to the substantive interpretation problem require exogenous information about the units, such as legislators or survey respondents, which make up the data; limit analysis to one latent factor; and/or are difficult to generalize. We propose and validate a solution, IRT-M, that produces multiple, potentially correlated, generalizable, latent dimensions, each with substantive meaning that the analyst specifies before analysis to match theoretical concepts. We offer an R package and step-by-step instructions in its use, via an application to survey data.

The California Department of Public Health (CDPH) reviewed 109 cases of healthcare personnel (HCP) with laboratory-confirmed mpox to understand transmission risk in healthcare settings. Overall, 90% of HCP with mpox had nonoccupational exposure risk factors. One occupationally acquired case was associated with sharps injury while unroofing a patient’s lesion for diagnostic testing.

Virtue epistemology is among the dominant influences in mainstream epistemology today. An important commitment of one strand of virtue epistemology – responsibilist virtue epistemology – is that it must provide regulative normative guidance for good thinking. Recently, a number of virtue epistemologists (most notably Baehr) have held that virtue epistemology not only can provide regulative normative guidance, but moreover that we should reconceive the primary epistemic aim of all education as the inculcation of the intellectual virtues. Baehr's picture contrasts with another well-known position – that the primary aim of education is the promotion of critical thinking. In this paper – that we hold makes a contribution to both philosophy of education and epistemology and, a fortiori, epistemology of education – we challenge this picture. We outline three criteria that any putative aim of education must meet and hold that it is the aim of critical thinking, rather than the aim of instilling intellectual virtue, that best meets these criteria. On this basis, we propose a new challenge for intellectual virtue epistemology, next to the well-known empirically driven ‘situationist challenge’. What we call the ‘pedagogical challenge’ maintains that the intellectual virtues approach does not have available a suitably effective pedagogy to qualify the acquisition of intellectual virtue as the primary aim of education. This is because the pedagogic model of the intellectual virtues approach (borrowed largely from exemplarist thinking) is not properly action-guiding. Instead, we hold that, without much further development in virtue-based theory, logic and critical thinking must still play the primary role in the epistemology of education.

We propose a fully spatio-temporal approach for identifying spatially varying modes of oscillation in fluid dynamics simulation output by means of multitaper frequency–wavenumber spectral analysis. One-dimensional spectrum estimation has proven to be a valuable tool in the analysis of turbulence data applied spatially to determine the rate of energy transport between spatial scales, or temporally to determine frequencies of oscillatory flows. It also allows for the quantitative comparison of flow characteristics between two scenarios using a standard basis. It has the limitation, however, that it neglects coupling between spatial and temporal structures. Two-dimensional frequency–wavenumber spectral analysis allows one to decompose waveforms into standing or travelling variety. The extended higher-dimensional multitaper method proposed here is shown to have improved statistical properties over conventional non-parametric spectral estimators, and is accompanied by confidence intervals which estimate their uncertainty. Multitaper frequency–wavenumber analysis is applied to a canonical benchmark problem, namely, a direct numerical simulation of von Kármán vortex shedding off a square wall-mounted cylinder with two inflow scenarios with matching momentum-thickness Reynolds numbers $Re_{\unicode[STIX]{x1D703}}\approx 1000$ at the obstacle. Frequency–wavenumber analysis of a two-dimensional section of these data reveals that although both the laminar and turbulent inflow scenarios show a turbulent $-5/3$ cascade in wavenumber ($\unicode[STIX]{x1D708}$ ) and frequency ($f$ ), the flow characteristics differ in that there is a significantly more prominent discrete harmonic oscillation near $(f,\unicode[STIX]{x1D708})=(0.2,0.21)$ in wavenumber and frequency in the laminar inflow scenario than the turbulent scenario. This frequency–wavenumber pair corresponds to a travelling wave with velocity near one near the centre path of the vortex street.

The chemistry of water in the Cambrian-Ordovician aquifer in six midwestern states has been studied as part of the Northern Midwest Regional Aquifer-System Analysis of the U.S. Geological Survey. Dissolved-solids concentrations generally increase perpendicular to the direction of regional groundwater flow, from less than 400 mg/liter in southeast Minnesota, southwest Wisconsin, and northeast Iowa to more than 10,000 mg/liter in northwest Missouri. Isotopic ratios of hydrogen and oxygen are significantly depleted from north to south, with an areal distribution approximately parallel to the distribution of dissolved solids. For example, δ18O in southern Iowa and northern Missouri is about 6 parts per thousand lighter than δ18O of modern recharge water in Minnesota and Wisconsin. Covariance between δ18O and δD of the groundwater, similar to that of modern precipitation, suggests that the differences in isotopic ratios between groundwater and modern recharge water reflect meteoric signatures of water during past recharge events rather than geochemical processes such as isotopic exchange with aquifer materials. The pronounced parallelism between the distribution of isotopes and dissolved solids over large areas probably reflects largescale recharge of Pleistocene glacial meltwater into the aquifer system, which probably had a paleoflow system with a gradient from northeast to southwest rather than from northwest to southeast.

Two new conulariid species, Conularia clarkei Babcock and C. paraguayensis Babcock from the Vargas Peña Shale, are the first Silurian conulariids to be described from Paraguay. They increase to three the number of Silurian species to be described from South America. The concept of Conularia Miller in Sowerby, 1820, is emended. It includes as junior synonyms Conularia (Plectoconularia) Bouček, 1939, Diconularia Sinclair, 1952, and Yangoconularia Xu and Li, 1985. The age of the Vargas Peña Shale has long been disputed, but conclusions based on organic-walled microfossils indicate an Early Silurian (Llandoverian) age for the unit.

This article reviews the interdisciplinary field of interpersonal neurobiology and its view of developmental trauma and wellbeing. Issues related to the mind, brain and relationships are discussed along with a working definition of both the mind and mental health.