Search for: All records

Abstract Androgen-independent prostate cancers, correlated with heightened aggressiveness and poor prognosis, are caused by mutations or deletions in the androgen receptor (AR) or expression of truncated variants of AR that are constitutively activated. Currently, drugs and drug candidates against AR target the steroid-binding domain to antagonize or degrade AR. However, these compounds cannot therapeutically access largely intrinsically disordered truncated splice variants of AR, such as AR-V7, that only possess the DNA binding domain and are missing the ligand binding domain. Targeting intrinsically disordered regions within transcription factors has remained challenging and is considered “undruggable”. Herein, we leveraged a cysteine-reactive covalent ligand library in a cellular screen to identify degraders of AR and AR-V7 in androgen-independent prostate cancer cells. We identified a covalent compound EN1441 that selectively degrades AR and AR-V7 in a proteasome-dependent manner through direct covalent targeting of an intrinsically disordered cysteine C125 in AR and AR-V7. EN1441 causes significant and selective destabilization of AR and AR-V7, leading to aggregation of AR/AR-V7 and subsequent proteasome-mediated degradation. Consistent with targeting both AR and AR-V7, we find that EN1441 completely inhibits total AR transcriptional activity in androgen-independent prostate cancer cells expressing both AR and AR-V7 compared to AR antagonists or degraders that only target the ligand binding domain of full-length AR, such as enzalutamide and ARV-110. Our results put forth a pathfinder molecule EN1441 that targets an intrinsically disordered cysteine within AR to destabilize, degrade, and inhibit both AR and AR-V7 in androgen-independent prostate cancer cells and highlights the utility of covalent ligand discovery approaches in directly targeting, destabilizing, inhibiting, and degrading classically undruggable transcription factor targets. 

Abstract BackgroundUsing simulations in science instruction can help make abstract topics more concrete and boost students' understanding. AimsThe current research examined whether using a simulation as an exploratory learning activity before an accompanying lecture has additional learning and motivational benefits compared to a more common lecture‐then‐simulation approach. SamplesParticipants (Experiment 1,N = 168; Experiment 2,N = 357) were undergraduate students in several sections of a first‐year chemistry course. MethodsStudents were randomly assigned to explore a simulation on atomic structure either before a lecture (explore‐first condition) or after the lecture (instruct‐first condition). In Experiment 1, the simulation activity time was limited (15 min) and the activity varied in whether self‐explanation (‘why’) prompts were included. In Experiment 2, the activity time was lengthened (20 min), and only ‘why’ prompts were used. After the activity and lecture, students completed a survey and posttest. ResultsIn Experiment 1, students in the explore‐first condition scored lower on posttest conceptual knowledge scores and reported lower curiosity compared to students in the instruct‐first condition. Scores for basic facts and transfer knowledge, and self‐reported situational interest, self‐efficacy, and competence, were equal between conditions. No effects of prompt condition were found. In Experiment 2, with longer activity time, the results reversed. Students in the explore‐first condition scored equally on basic facts and higher on conceptual knowledge and transfer measures, while also reporting higher curiosity, situational interest, self‐efficacy, competence, and cognitive engagement. ConclusionWhen properly designed, placing simulations before—rather than after—lecture can deepen learning, motivation, and competence. 

Abstract Environmental stimuli trigger rapid transcriptional reprogramming of gene networks. These responses occur in the context of the local chromatin landscape, but the contribution of organ-specific dynamic chromatin modifications in responses to external signals remains largely unexplored. We treated tomato seedlings with a supply of nitrate and measured the genome-wide changes of four histone marks, the permissive marks H3K27ac, H3K4me3, and H3K36me3 and repressive mark H3K27me3, in shoots and roots separately, as well as H3K9me2 in shoots. Dynamic and organ-specific histone acetylation and methylation were observed at functionally relevant gene loci. Integration of transcriptomic and epigenomic datasets generated from the same organ revealed largely syngenetic relations between changes in transcript levels and histone modifications, with the exception of H3K27me3 in shoots, where an increased level of this repressive mark is observed at genes activated by nitrate. Application of a machine learning approach revealed organ-specific rules regarding the importance of individual histone marks, as H3K36me3 is the most successful mark in predicting gene regulation events in shoots, while H3K4me3 is the strongest individual predictor in roots. Our integrated study substantiates a view that during plant environmental responses, the relationships between histone code dynamics and gene regulation are highly dependent on organ-specific contexts. 

Abstract The design of high‐entropy single‐atom catalysts (HESAC) with 5.2 times higher entropy compared to single‐atom catalysts (SAC) is proposed, by using four different metals (FeCoNiRu‐HESAC) for oxygen reduction reaction (ORR). Fe active sites with intermetallic distances of 6.1 Å exhibit a low ORR overpotential of 0.44 V, which originates from weakening the adsorption of OH intermediates. Based on density functional theory (DFT) findings, the FeCoNiRu‐HESAC with a nitrogen‐doped sample were synthesized. The atomic structures are confirmed with X‐ray photoelectron spectroscopy (XPS), X‐ray absorption (XAS), and scanning transmission electron microscopy (STEM). The predicted high catalytic activity is experimentally verified, finding that FeCoNiRu‐HESAC has overpotentials of 0.41 and 0.37 V with Tafel slopes of 101 and 210 mVdec⁻¹at the current density of 1 mA cm⁻²and the kinetic current densities of 8.2 and 5.3 mA cm⁻², respectively, in acidic and alkaline electrolytes. These results are comparable with Pt/C. The FeCoNiRu‐HESAC is used for Zinc–air battery applications with an open circuit potential of 1.39 V and power density of 0.16 W cm⁻². Therefore, a strategy guided by DFT is provided for the rational design of HESAC which can be replaced with high‐cost Pt catalysts toward ORR and beyond. 

This WIP paper presents new research on exploratory learning, an educational technique that reverses the order of standard lecture-based instruction techniques. In exploratory learning, students are presented with a novel activity first, followed by instruction. Exploratory learning has been observed to benefit student learning in foundational math and science courses such as calculus, physics, and statistics; however, it has yet to be applied to engineering topics such as programming. In two studies, we tested the effectiveness of exploratory learning in the programming unit of a first-year undergraduate engineering course. We designed a new activity to help students learn about different python error types, ensuring that it would be suitable for exploration. Then we implemented two different orders (the traditional instruct-first versus exploratory learning’s explore-first) across the six sections of the course. In Study 1 (N=406), we did not detect a difference between the instruct-first and explore-first conditions. In Study 2 (N=411), we added more scaffolding to the activity. Students who received the traditional order of instruction followed by the activity scored significantly higher on the assessment. These findings contradict the exploratory learning benefits typically shown, shedding light on potential boundary conditions to this effect. 

Plants are constantly exposed to volatile organic compounds (VOCs) that are released during plant-plant communication, within-plant self-signaling, and plant-microbe interactions. Therefore, understanding VOC perception and downstream signaling is vital for unraveling the mechanisms behind information exchange in plants, which remain largely unexplored. Using the hormone-like function of volatile terpenoids in reproductive organ development as a system with a visual marker for communication, we demonstrate that a petunia karrikin-insensitive receptor, PhKAI2ia, stereospecifically perceives the (−)-germacrene D signal, triggering a KAI2-mediated signaling cascade and affecting plant fitness. This study uncovers the role(s) of the intermediate clade of KAI2 receptors, illuminates the involvement of a KAI2ia-dependent signaling pathway in volatile communication, and provides new insights into plant olfaction and the long-standing question about the nature of potential endogenous KAI2 ligand(s).