Cells in a low oxygen, or hypoxic, microenvironment must have the ability to sense oxygen levels in the nucleus in order to maintain oxygen homeostasis by gene regulation. Hypoxia inducible factor-1 (HIF-1) serves as a molecular bridge between the sensation and utilization of oxygen, and thus functions as a key player in oxygen homeostasis. HIF-1 is a heterodimeric transcription factor and is composed of two subunits, the oxygen-sensitive HIF-1α and constitutively expressed HIF-1β. HIF-1 regulates the expression of a broad range of genes that facilitate acclimation to low oxygen conditions by changes in protein levels in circulation, metabolism, and proliferation. Appropriate temporal and spatial activation of HIF-1 is crucial not only in developmental and physiological processes, characterized by programmed cellular proliferation, but also in pathophysiological conditions such as tumorigenesis, which exhibit unregulated cellular proliferation. However, many contradictory reports as to the role of HIF-1 in the regulation of cellular proliferation have been put forward in recent years. In this review, our first aim is to summarize the current knowledge of oxygen-dependent HIF-1 activation mechanisms based on its structure. Then we will describe the proposed mechanisms through which HIF-1 regulates cellular proliferation of different cell types, including tumor cells as well as non-transformed, nonimmortalized cells under normoxic and hypoxic conditions.

Histone deacetylase (HDAC) inhibitors have garnered significant attention as cancer drugs. These therapeutic agents have recently been clinically validated with the market approval of vorinostat (SAHA, Zolinza) for treatment of cutaneous T-cell lymphoma. Like vorinostat, most of the small-molecule HDAC inhibitors in clinical development are hydroxamic acids, whose inhibitory activity stems from their ability to coordinate the catalytic Zn²⁺ in the active site of HDACs. We sought to identify novel, nonhydroxamate-based HDAC inhibitors with potentially distinct pharmaceutical properties via an ultra-high throughput small molecule biochemical screen against the HDAC activity in a HeLa cell nuclear extract. An α-mercaptoketone series was identified and chemically optimized. The lead compound, KD5170, exhibits HDAC inhibitory activity with an IC₅₀ of 0.045 μmol/L in the screening biochemical assay and an EC₅₀ of 0.025 μmol/L in HeLa cell–based assays that monitor histone H3 acetylation. KD5170 also exhibits broad spectrum classes I and II HDAC inhibition in assays using purified recombinant human isoforms. KD5170 shows significant antiproliferative activity against a variety of human tumor cell lines, including the NCI-60 panel. Significant tumor growth inhibition was observed after p.o. dosing in human HCT-116 (colorectal cancer), NCI-H460 (non–small cell lung carcinoma), and PC-3 (prostate cancer) s.c. xenografts in nude mice. In addition, a significant increase in antitumor activity and time to end-point occurred when KD5170 was combined with docetaxel in xenografts of the PC-3 prostate cancer cell line. The biological and pharmaceutical profile of KD5170 supports its continued preclinical and clinical development as a broad spectrum anticancer agent. [Mol Cancer Ther 2008;7(5):1054–65]

This paper describes a hypothesized learning progression for how secondary students understand interdependent relationships in ecosystems, a key concept in the field of ecology and for public understanding of science. In this study, a hypothetical learning progression was developed and empirically investigated using Rasch modeling of data from 1366 students in a large, diverse, urban school district. We found that the empirical evidence supported the general structure of the hypothesized learning progression for relationships in ecosystems. There were notable exceptions, and we describe the ways in which we altered the items and the learning progression to address empirical inconsistencies with our a priori conceptions. The assessment items developed through this study are immediately available online for formative assessment purposes, and the learning progression can support teachers’ thinking about students’ understanding of ecosystems. In particular, the upper reach of the learning progression offers a more complete description of the ways in which students might develop their understanding of complex interactions in ecosystems, beyond what is currently offered in the literature and standards documents about students’ understanding.

Inhibition of Inducible Nitric Oxide Synthase Expression by a Novel Small Molecule Activator of the Unfolded Protein Response

This article describes an innovative intervention used within a professional learning experience (PLE) for early-career high school science teachers. The intervention aimed to develop participants’ conceptual understanding of climate change while supporting engagement in learning via scientific practices through use of epistemic instructional activities. Participants were 18 teachers from 16 different public schools across the US, all serving historically underserved student populations. The intervention consisted of a sequence of three learning experiences, each of which engaged participants in learning through a unique epistemic tool or activity. We describe each activity and offer examples of our developed materials. Additionally, we use qualitative coding to analyze teacher-produced artifacts to evaluate the intervention. Results show: 1) a data analysis epistemic activity supported learner attention to variation in climate data; 2) an explanation-focused epistemic activity supported integration of several concepts within social constructions of mechanistic explanations; and 3) a claims evaluation epistemic activity supported participants’ linking of concepts about variation to mechanistic explanations of climate change, as well as their understanding of argumentation in general. We suggest that other educators could benefit from adapting our intervention to meet the needs of their contexts. Supplemental data for this article is available online at https://doi.org/10.1080/10899995.2021.1986785 .