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A high-throughput chemical screen of primary human hepatocytes in combination with machine-learning algorithms for evaluation of imaging data identifies compounds that promote expansion of primary human hepatocytes and maturation from human iPS cells toward an adult-like hepatocyte phenotype. Cell-based therapies hold the potential to alleviate the growing burden of liver diseases. Such therapies require human hepatocytes, which, within the stromal context of the liver, are capable of many rounds of replication. However, this ability is lost ex vivo , and human hepatocyte sourcing has limited many fields of research for decades. Here we developed a high-throughput screening platform for primary human hepatocytes to identify small molecules in two different classes that can be used to generate renewable sources of functional human hepatocytes. The first class induced functional proliferation of primary human hepatocytes in vitro . The second class enhanced hepatocyte functions and promoted the differentiation of induced pluripotent stem cell–derived hepatocytes toward a more mature phenotype than what was previously obtainable. The identification of these small molecules can help address a major challenge affecting many facets of liver research and may lead to the development of new therapeutics for liver diseases.

How is art both distinct and different from the rest of human life, while also mattering in and for it? This central yet overlooked question in contemporary philosophy of art is at the heart of Georg Bertram's new aesthetic. Drawing on the resources of diverse philosophical traditions – analytic philosophy, French philosophy, and German post-Kantian philosophy – his book offers a systematic account of art as a human practice. One that remains connected to the whole of life.

Englerin A is a structurally unique natural product reported to selectively inhibit growth of renal cell carcinoma cell lines. A large scale phenotypic cell profiling experiment (CLiP) of englerin A on ¬over 500 well characterized cancer cell lines showed that englerin A inhibits growth of a subset of tumor cell lines from many lineages, not just renal cell carcinomas. Expression of the TRPC4 cation channel was the cell line feature that best correlated with sensitivity to englerin A, suggesting the hypothesis that TRPC4 is the efficacy target for englerin A. Genetic experiments demonstrate that TRPC4 expression is both necessary and sufficient for englerin A induced growth inhibition. Englerin A induces calcium influx and membrane depolarization in cells expressing high levels of TRPC4 or its close ortholog TRPC5. Electrophysiology experiments confirmed that englerin A is a TRPC4 agonist. Both the englerin A induced current and the englerin A induced growth inhibition can be blocked by the TRPC4/C5 inhibitor ML204. These experiments confirm that activation of TRPC4/C5 channels inhibits tumor cell line proliferation and confirms the TRPC4 target hypothesis generated by the cell line profiling. In selectivity assays englerin A weakly inhibits TRPA1, TRPV3/V4, and TRPM8 which suggests that englerin A may bind a common feature of TRP ion channels. In vivo experiments show that englerin A is lethal in rodents near doses needed to activate the TRPC4 channel. This toxicity suggests that englerin A itself is probably unsuitable for further drug development. However, since englerin A can be synthesized in the laboratory, it may be a useful chemical starting point to identify novel modulators of other TRP family channels.

In Alzheimer disease (AD), amyloid β peptide (Aβ) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Aβ binding to the V domain of RAGE and inhibited Aβ40- and Aβ42-induced cellular stress in RAGE-expressing cells in vitro and in the mouse brain in vivo. FPS-ZM1 was nontoxic to mice and readily crossed the blood-brain barrier (BBB). In aged APPsw/0 mice overexpressing human Aβ-precursor protein, a transgenic mouse model of AD with established Aβ pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating Aβ40 and Aβ42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited β-secretase activity and Aβ production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced Aβ40 and Aβ42 levels in brain markedly and normalized cognitive performance and cerebral blood flow responses in aged APPsw/0 mice. Our data suggest that FPS-ZM1 is a potent multimodal RAGE blocker that effectively controls progression of Aβ-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD.

Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for its antitumor activity. The activation of STING requires its high-order oligomerization, which could be induced by binding of the endogenous ligand, cGAMP, to the cytosolic ligand-binding domain. Here we report the discovery through functional screens of a class of compounds, named NVS-STGs, that activate human STING. Our cryo-EM structures show that NVS-STG2 induces the high-order oligomerization of human STING by binding to a pocket between the transmembrane domains of the neighboring STING dimers, effectively acting as a molecular glue. Our functional assays showed that NVS-STG2 could elicit potent STING-mediated immune responses in cells and antitumor activities in animal models. A cell-based phenotypic screen led to the discovery of compounds called NVS-STGs, which bind to the N-terminal domain of STING and act as a molecular glue to induce higher-order oligomerization and activation.

The delivery of drugs in a controllable fashion is a topic of intense research activity in both academia and industry because of its impact in healthcare. Implantable electronic interfaces for the body have great potential for positive economic, health, and societal impacts; however, the implantation of such interfaces results in inflammatory responses due to a mechanical mismatch between the inorganic substrate and soft tissue, and also results in the potential for microbial infection during complex surgical procedures. Here, we report the use of conducting polypyrrole (PPY)-based coatings loaded with clinically relevant drugs (either an anti-inflammatory, dexamethasone phosphate (DMP), or an antibiotic, meropenem (MER)). The films were characterized and were shown to enhance the delivery of the drugs upon the application of an electrochemical stimulus in vitro, by circa (ca.) 10–30% relative to the passive release from non-stimulated samples. Interestingly, the loading and release of the drugs was correlated with the physical descriptors of the drugs. In the long term, such materials have the potential for application to the surfaces of medical devices to diminish adverse reactions to their implantation in vivo.

Proteins modulate the majority of all biological functions and are primarily composed of highly organized secondary structural elements such as helices, turns and sheets. Many of these functions are affected by a small number of key proteinprotein contacts, often involving one or more of these well-defined structural elements. Given the ubiquitous nature of these protein recognition domains, their mimicry by peptidic and non-peptidic scaffolds has become a major focus of contemporary research. This review examines several key advances in secondary structure mimicry over the past several years, particularly focusing upon scaffolds that show not only promising projection of functional groups, but also a proven effect in biological systems.

Cardiovascular disease remains the leading cause of mortality among women globally, yet females, particularly those who are pregnant or postpartum, remain underrepresented in cardiovascular clinical trials. This study assessed enrollment trends of all-female participants, including pregnant and postpartum women, in cardiovascular trials registered on ClinicalTrials.gov from 2017 to 2023. Among the trials identified, there was no significant increase in studies exclusively enrolling women or those focused on pregnancy and postpartum populations. Most trials targeted obesity (58%) and hypertension (26%) in women aged 19–55 and were predominantly sponsored by universities in the United States. Interventions were largely limited to lifestyle and pharmacologic strategies. The lack of growth in inclusive trial design underscores persistent research gaps. Greater efforts are needed across policy, funding, and trial design to ensure equitable representation of all women, particularly during vulnerable physiological stages such as pregnancy and lactation, to improve evidence-based cardiovascular care.

Cyclic peptide natural products have evolved to exploit diverse protein targets, many of which control essential cellular processes. Inspired by a series of cyclic peptides with partially elucidated structures, we designed synthetic variants of ternatin, a cytotoxic and anti-adipogenic natural product whose molecular mode of action was unknown. The new ternatin variants are cytotoxic toward cancer cells, with up to 500-fold greater potency than ternatin itself. Using a ternatin photo-affinity probe, we identify the translation elongation factor-1A ternary complex (eEF1A·GTP·aminoacyl-tRNA) as a specific target and demonstrate competitive binding by the unrelated natural products, didemnin and cytotrienin. Mutations in domain III of eEF1A prevent ternatin binding and confer resistance to its cytotoxic effects, implicating the adjacent hydrophobic surface as a functional hot spot for eEF1A modulation. We conclude that the eukaryotic elongation factor-1A and its ternary complex with GTP and aminoacyl-tRNA are common targets for the evolution of cytotoxic natural products. Many plants, fungi, and bacteria have evolved to produce small molecules that have powerful effects on the cells of other living organisms, and can even kill them. These naturally produced compounds are often used as starting points for developing new drugs. One such class of compounds are the cyclic peptides, which can be relatively easily produced in the laboratory and are able to penetrate cells. Some cyclic peptides have also proved to be useful for treating cancer and immune diseases, so researchers are keen to identify others that have similar effects. One promising prospect, called ternatin, is produced by several species of fungi. In high doses, ternatin can kill mammalian cells, but it was not clear how it does so. To learn more, Carelli et al. searched a chemical database for cyclic peptides related to ternatin and identified several similar compounds that were reported to kill cancer cells. Inspired by the structures of these cyclic peptides, Carelli et al. synthesized modified versions of ternatin. One of these was 500 times more potent than ternatin, which means a much lower dose of the compound is still able to kill cancer cells. Further experiments showed that ternatin blocks the production of new proteins in cells. Specifically, ternatin binds to a complex that includes a protein called elongation factor-1A (eEF1A). Mutations in a particular region of eEF1A prevent ternatin from killing cells, suggesting a potential binding site for ternatin. The next challenge is to dissect the mechanism by which compounds binding to this site on eEF1A block protein synthesis and kill cells. A related challenge is to understand why certain cancer cells are hypersensitive to ternatin and other eEF1A inhibitors, while other cancer cells are relatively resistant. These questions are relevant to the development of eEF1A inhibitors as cancer treatments.

Approximately 30% of human cancers harbor oncogenic gain-of-function mutations in KRAS. Despite interest in KRAS as a therapeutic target, direct blockade of KRAS function with small molecules has yet to be demonstrated. Based on experiments that lower mRNA levels of protein kinases, KRAS-dependent cancer cells were proposed to have a unique requirement for the serine/threonine kinase STK33. Thus, it was suggested that small-molecule inhibitors of STK33 might have therapeutic benefit in these cancers. Here, we describe the development of selective, low nanomolar inhibitors of STK33’s kinase activity. The most potent and selective of these, BRD8899, failed to kill KRAS-dependent cells. While several explanations for this result exist, our data are most consistent with the view that inhibition of STK33’s kinase activity does not represent a promising anti-KRAS therapeutic strategy.