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What might you do with a hat that had so many decorations dangling from the brim that you couldn't put it on? Lewis acids and bases are the molecular versions of hats and heads. Stephan reviews the surprising chemistry of so-called frustrated Lewis pairs (FLPs), which cannot form their natural complex together. Over the past decade, such systems (most often comprising a borane with a nitrogen or phosphorus partner) have been used to catalyze hydrogenation reactions, activate a number of other small molecules, and generally promote a wide range of cooperative chemical reactivity. Science , this issue p. 10.1126/science.aaf7229 The revelation that combinations of Lewis acids and bases for which dative bonding is impeded can activate dihydrogen led to the concept of “frustrated Lewis pairs” (FLPs). Over the past decade, a range of FLP systems and substrate molecules have precipitated a paradigm change in main-group chemistry and metal-free catalysis. The FLP motif has also found application in a growing body of chemical problems in organic synthesis, transition metal and free radical chemistry, materials, enzymatic models, and surface chemistry. The current state of FLP chemistry is assessed herein, and the outlook for the future considered.

Over the last decade, numerous histone acyl post-translational modifications (acyl-PTMs) have been discovered, of which the functional significance is still under intense study. Here, we use high-resolution mass spectrometry to accurately quantify eight acyl-PTMs in vivo and after in vitro enzymatic assays. We assess the ability of seven histone acetyltransferases (HATs) to catalyze acylations on histones in vitro using short-chain acyl-CoA donors, proving that they are less efficient towards larger acyl-CoAs. We also observe that acyl-CoAs can acylate histones through non-enzymatic mechanisms. Using integrated metabolomic and proteomic approaches, we achieve high correlation ( R 2  > 0.99) between the abundance of acyl-CoAs and their corresponding acyl-PTMs. Moreover, we observe a dose-dependent increase in histone acyl-PTM abundances in response to acyl-CoA supplementation in in nucleo reactions. This study represents a comprehensive profiling of scarcely investigated low-abundance histone marks, revealing that concentrations of acyl-CoAs affect histone acyl-PTM abundances by both enzymatic and non-enzymatic mechanisms. A number of histone lysine modifications related to acetylation have been identified, but their functional significance is unclear. Here, the authors use in vitro and in vivo assays to characterize eight acyl histone post-translational modifications and link their abundance with metabolism.

Histone acetylation is a ubiquitous hallmark of transcription, but whether the link between histone acetylation and transcription is causal or consequential has not been addressed. Using immunoblot and chromatin immunoprecipitation-sequencing in S. cerevisiae , here we show that the majority of histone acetylation is dependent on transcription. This dependency is partially explained by the requirement of RNA polymerase II (RNAPII) for the interaction of H4 histone acetyltransferases (HATs) with gene bodies. Our data also confirms the targeting of HATs by transcription activators, but interestingly, promoter-bound HATs are unable to acetylate histones in the absence of transcription. Indeed, HAT occupancy alone poorly predicts histone acetylation genome-wide, suggesting that HAT activity is regulated post-recruitment. Consistent with this, we show that histone acetylation increases at nucleosomes predicted to stall RNAPII, supporting the hypothesis that this modification is dependent on nucleosome disruption during transcription. Collectively, these data show that histone acetylation is a consequence of RNAPII promoting both the recruitment and activity of histone acetyltransferases. Histone acetylation is a ubiquitous hallmark of transcription. Here the authors provide evidence that the majority of histone acetylation is dependent on transcription, specifically due to the requirement of RNAPII for the recruitment and activity of histone acetyltransferases.

Histone acetyltransferases (HATs) are implicated as both oncogene and nononcogene dependencies in diverse human cancers. Acetyl-CoA-competitive HAT inhibitors have emerged as potential cancer therapeutics and the first clinical trial for this class of drugs is ongoing (NCT04606446). Despite these developments, the potential mechanisms of therapeutic response and evolved drug resistance remain poorly understood. Having discovered that multiple regulators of de novo coenzyme A (CoA) biosynthesis can modulate sensitivity to CBP/p300 HAT inhibition (PANK3, PANK4 and SLC5A6), we determined that elevated acetyl-CoA concentrations can outcompete drug-target engagement to elicit acquired drug resistance. This not only affects structurally diverse CBP/p300 HAT inhibitors, but also agents related to an investigational KAT6A/B HAT inhibitor that is currently in Phase 1 clinical trials. Altogether, this work uncovers CoA metabolism as an unexpected liability of anticancer HAT inhibitors and will therefore buoy future efforts to optimize the efficacy of this new form of targeted therapy. A resistance mechanism for a class of drugs targeting histone acetyltransferase inhibitors was identified where metabolic rewiring creates high concentrations of acetyl-CoA that outcompete drug-target engagement.

Hydrogen atom transfer (HAT) process is a powerful and effective strategy for activating C-H bonds followed by further functionalization. Intramolecular 1,n (n = 5 or 6)-HATs are common and frequently encountered in organic synthesis. However, intramolecular 1,n (n = 2 or 3)-HAT is very challenging due to slow kinetics. Compared to proton-shuttle process, which is well established for organic synthesis, hydrogen radical-shuttle (HRS) is unexplored. In this work, a HRS-enabled decarboxylative annulation of carbonyl compounds via photoredox catalysis for the synthesis of indanones is developed. This protocol features broad substrate scope, excellent functional group tolerance, internal hydrogen radical transfer, atom- and step-economy. Critical to the success of this process is the introduction of water, acting as both HRS and hydrogen source, which was demonstrated by mechanistic experiments and density functional theory (DFT) calculations. Importantly, this mechanistically distinctive HAT provides a complement to that of typical proton-shuttle-promoted, representing a breakthrough in hydrogen radical transfer, especially in the inherently challenging 1,2- or 1,3-HAT. Although hydrogen atom transfer is widely observed in synthetic organic chemistry, intramolecular hydrogen atom transfer between atoms separated by fewer than four bonds is kinetically slow. Here the authors show a method to form indanones, with hydrogen atoms shuttled across short distances by water.

Facial identity and expression play critical roles in our social lives. Faces are therefore frequently used as stimuli in a variety of areas of scientific research. Although several extensive and well-controlled databases of adult faces exist, few databases include children's faces. Here we present the Dartmouth Database of Children's Faces, a set of photographs of 40 male and 40 female Caucasian children between 6 and 16 years-of-age. Models posed eight facial expressions and were photographed from five camera angles under two lighting conditions. Models wore black hats and black gowns to minimize extra-facial variables. To validate the images, independent raters identified facial expressions, rated their intensity, and provided an age estimate for each model. The Dartmouth Database of Children's Faces is freely available for research purposes and can be downloaded by contacting the corresponding author by email.

In recent years, climate service has emerged as a new field to better connect climate data providers and users of climate change–related information. The aim is to transform climate–related information into customized, user-centered products. This transformation of data is increasingly sought after by decision-makers due to public and regulatory pressure. As one of the first institutions to provide climate services, the Climate Service Center Germany (GERICS) has collected a wide range of different experiences in the field of climate services. Based on this know-how, GERICS has identified three distinct roles—we call them hats—that the institute commonly assumes as a climate service provider: the facilitator, the developer, and the trendsetter. The definition and tasks related to each of these distinct hats is presented alongside examples. The key ingredient for the success of a service product heavily depends on successful user engagement. While wearing any of the three hats and depending on a project’s context as well as the project stage, GERICS makes use of several methods to codevelop services with users. Based on past experiences, four different styles of user engagement, distinguished by the degree of intensity of participation, were established: information, consultation, dialog, and partnership. The connection of the three hats and the four styles of user engagement creates a structure in which climate service providers operate. It may help other climate service providers to reflect upon the general outline of their services and enhance the effectiveness of their engagement with users in transdisciplinary research settings.

The yellow fever mosquito, Aedes aegypti, is distributed worldwide and transmits viruses that cause many diseases, including dengue, yellow fever, chikungunya, and zika. Epigenetic modifications such as acetylation of histones regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) control insect development. We recently reported that the Creb-binding protein (a HAT) regulates the metamorphosis of A. aegypti. However, the function of HDACs in A. aegypti is not known. In this study, we identified 10 genes coding for HDACs in A. aegypti and determined their function in larval development using RNA interference (RNAi). Knockdown of each HDAC has a distinct effect on the growth, development, and metamorphosis of A. aegypti. Knockdown of HDAC3 severely affected the larval survival, indicating its indispensable role in larval development. HDAC3 is highly expressed during the larval stages, and its messenger RNA (mRNA) levels correlate with the juvenile hormone (JH) titers. JH induces the expression of HDAC3 through its receptor, methoprenetolerant (Met). Knockdown of HDAC3 resulted in increased expression of proapoptotic genes involved in apoptosis of larval midgut cells. This consequently decreased midgut size and led to larval death. HDAC3 deacetylates histone H4 localized at the promoters of proapoptotic genes and suppresses their expression. In addition, a corepressor, SMRTER, is required for HDAC3-mediated suppression of proapoptotic genes. Interestingly, ecdysone attenuates HDAC3-mediated repression of proapoptotic genes. These data demonstrate that JH-induced HDAC3 is a key player in JH suppression of precocious larval cell death and metamorphosis in A. aegypti.