Cripowellins Pause Plasmodium falciparum Intraerythrocytic Development at the Ring Stage.

Cripowellins from Crinum erubescens are known pesticidal and have potent antiplasmodial activity. To gain mechanistic insights to this class of natural products, studies to determine the timing of action of cripowellins within the asexual intraerythrocytic cycle of Plasmodium falciparum were performed and led to the observation that this class of natural products induced reversible cytostasis in the ring stage within the first 24 h of treatment. The transcriptional program necessary for P. falciparum to progress through the asexual intraerythrocytic life cycle is well characterized. Whole transcriptome abundance analysis showed that cripowellin B "pauses" the transcriptional program necessary to progress through the intraerythrocytic life cycle coinciding with the lack of morphological progression of drug treated parasites. In addition, cripowellin B-treated parasites re-enter transcriptional progression after treatment was removed. This study highlights the use of cripowellins as chemical probes to reveal new aspects of cell cycle progression of the asexual ring stage of P. falciparum which could be leveraged for the generation of future antimalarial therapeutics.

ß-Carboline-3-carboxamide Antimalarials: Structure-Activity Relationship, ADME-Tox Studies, and Resistance Profiling.

The development of parasite resistance to both artemisinin derivatives and their partner drugs jeopardizes the effectiveness of the artemisinin combination therapy. Thus, the discovery of new antimalarial drugs, with new mechanisms of action, is urgently needed. We recently disclosed that ß-carboline 1a was orally efficacious in Plasmodium berghei-infected mice and that it showed low cross-resistance between susceptible Plasmodium falciparum and four different drug-resistant strains. In this report, we describe the synthesis and in vitro antimalarial evaluation of 91 new derivatives of 1a. The asexual blood stage growth inhibition data show a clear preference for a 3,4-dihalogenated, 3,5-dihalogenated, 3,4,5-trichloro-, or 4-trifluoromethyphenyl ring at the C1-position. The most potent compound, 3,4,5-trichlorophenyl-substituted 42a, is twice as potent as 1a. Six potent analogues were assessed for their drug-like properties, and four of these were subjected to in vitro barcoded cross-resistance profiling. Compounds 1a, 1m, 42a, and 42m showed no cross-resistance to 32 resistance mutations on the Dd2 genetic background and 10 resistance mutations on the 3D7 genetic background. These data suggest that compounds in this scaffold possess a novel mechanism of antimalarial action.

"Oh, that makes sense": Social Metacognition in Small-Group Problem Solving.

Stronger metacognition, or awareness and regulation of thinking, is related to higher academic achievement. Most metacognition research has focused at the level of the individual learner. However, a few studies have shown that students working in small groups can stimulate metacognition in one another, leading to improved learning. Given the increased adoption of interactive group work in life science classrooms, there is a need to study the role of social metacognition, or the awareness and regulation of the thinking of others, in this context. Guided by the frameworks of social metacognition and evidence-based reasoning, we asked: 1) What metacognitive utterances (words, phrases, statements, or questions) do students use during small-group problem solving in an upper-division biology course? 2) Which metacognitive utterances are associated with small groups sharing higher-quality reasoning in an upper-division biology classroom? We used discourse analysis to examine transcripts from two groups of three students during breakout sessions. By coding for metacognition, we identified seven types of metacognitive utterances. By coding for reasoning, we uncovered four categories of metacognitive utterances associated with higher-quality reasoning. We offer suggestions for life science educators interested in promoting social metacognition during small-group problem solving.

Revisiting Clickers: In-Class Questions Followed by At-Home Reflections Are Associated with Higher Student Performance on Related Exam Questions.

Clicker questions are a commonly used active learning technique that stimulates student interactions to help advance understanding of key concepts. Clicker questions are often administered with an initial vote, peer discussion, and a second vote, followed by broader classroom explanation. While clickers can promote learning, some studies have questioned whether students maintain this performance on later exams, highlighting the need to further understand how student answer patterns relate to their understanding of the material and to identify ways for clickers to benefit a broader range of students. Systematic requizzing of concepts during at-home assignments represents a promising mechanism to improve student learning. Thus, we paired clicker questions with at-home follow-up reflections to help students articulate and synthesize their understandings. This pairing of clickers with homework allowed us to decipher how student answer patterns related to their underlying conceptions and to determine if revisiting concepts provided additional benefits. We found that students answering both clicker votes correctly performed better on isomorphic exam questions and that students who corrected their answers after the first vote did not show better homework or exam performance than students who maintained an incorrect answer across both votes. Furthermore, completing the follow-up homework assignment modestly boosted exam question performance. Our data suggest that longer-term benefits of clickers and associated homework may stem from students having repeated opportunities to retrieve, refine, and reinforce emerging conceptions.

Enantiopure Benzofuran-2-carboxamides of 1-Aryltetrahydro-ß-carbolines Are Potent Antimalarials In Vitro.

The tetrahydro-ß-carboline scaffold has proven fertile ground for the discovery of antimalarial agents (e.g., MMV008138 (1) and cipargamin (2)). Similarity searching of a publicly disclosed collection of antimalarial hits for molecules resembling 1 drew our attention to N2-acyl tetrahydro-ß-carboline GNF-Pf-5009 ((±)-3b). Compound purchase, "analog by catalog", and independent synthesis of hits indicated the benzofuran-2-yl amide portion was required for in vitro efficacy against P. falciparum. Preparation of pure enantiomers demonstrated the pharmacological superiority of (R)-3b. Synthesis and evaluation of D- and F-ring substitution variants and benzofuran isosteres indicated a clear structure-activity relationship. Ultimately (R)-3b was tested in Plasmodium berghei-infected mice; unfavorable physicochemical properties may be responsible for the lack of oral efficacy.

Student, instructor, and observer agreement regarding frequencies of scientific teaching practices using the Measurement Instrument for Scientific Teaching-Observable (MISTO).

BACKGROUND: The Scientific Teaching (ST) pedagogical framework encompasses many of the best practices recommended in the literature and highlighted in national reports. Understanding the growth and impact of ST requires instruments to accurately measure the extent to which practitioners implement ST in their courses. Researchers have typically relied on students, instructors, or observers to document course teaching practices, but it remains unclear whether and how these perspectives differ from each other. To address this issue, we modified our previously published instrument to generate the Measurement Instrument for Scientific Teaching-Observable (MISTO), which can be completed by students, instructors, and observers, and we investigated the degree of similarity between these three perspectives across 70 undergraduate science courses at seven different institutions in the USA. RESULTS: We found that the full MISTO and Active Learning subcategory scores showed the highest correlations among the three perspectives, but the degree of correlation between perspectives varied for the other subcategories. Match scores between students and instructors were significantly higher than observer matches for the full MISTO and for the Active Learning, Inclusivity, and Responsiveness subcategories. CONCLUSIONS: We find that the level and type of agreement between perspectives varies across MISTO subcategories and that this variation likely stems from intrinsic differences in the course access and scoring decisions of the three perspectives. Building on this data, we recommend MISTO users consider their research goals, available resources, and potential artifacts that may arise when deciding which perspective best fits their needs in measuring classroom teaching practices.