We introduced a perturbational single-cell RNA sequencing (scRNA-seq) dataset with 1.2 million cells spanning 88 perturbations across 10 primary and cancer cell lines. Using this dataset along with public perturbational omics data (held-out CMap and SciPlex signatures), we showed that DrugReflector robustly prioritizes compounds from transcriptional signatures even outside of its training context, consistently outperforming state-of-the-art approaches. Through two hematopoietic campaigns using single-cell atlas–defined cell state transitions as model inputs, we identified inducers of megakaryocyte and erythroid differentiation, achieving hit rates 10-fold higher than a random baseline. To assess generalizability, we additionally deployed DrugReflector in two distinct oncology indications, recovering clinical standards of care and modulators of known indication-specific pathways. To further characterize and leverage the transcriptional drivers of megakaryocyte induction, we created a time-course scRNA-seq dataset of hematopoietic stem and progenitor cells with paired flow cytometry readouts for a range of transcriptionally and phenotypically active compounds.

With all the advances in both the science of aging and artificial intelligence (AI), we are in a propitious position to accurately and precisely determine who is at high risk of developing Alzheimer's disease years before signs of even mild cognitive deficit. It takes at least 20 years for aggregates of misfolded β-amyloid and tau proteins to accumulate in the brain along with neuroinflammation that they incite. This provides a long window of opportunity to get ahead of the pathobiological process, both for prediction and prevention. A family history of Alzheimer's and the presence of genetic variants in the APOE4 (apolipoprotein E4) allele indicate an increased risk, as does a polygenic risk score that is based on the combined influence of many genetic variants. However, each of these clues provides little insight about when initial symptoms would likely present.

Proponents of the use of artificial intelligence (AI) in drug discovery predict that it is likely to make drug discovery and development faster and cheaper, particularly in preclinical stages before patents are filed (1). But AI use may also create tendencies to file "compound" patents on molecules that disclose little evidence of real-world testing, exacerbating an issue already of concern in more traditional (even if also computer-aided) drug development and patenting. Our preliminary analyses of an original dataset of compound patents on small-molecule drugs suggest that, compared with more traditional drug developers, "AI-native" developers perform less in vivo, in-depth testing before patenting. In light of the potential for such early patenting to dampen overall drug research and development, it is worth considering policies that encourage disclosure of more evidence for securing a patent and provide incentives for research on disclosed but unpatented structures.

Following its successes retrieving lunar samples from both the near and far sides of the Moon, China is planning an encore, sending a probe to snatch material from a near-Earth asteroid. The target of the Tianwen-2 mission, which is expected to launch by the end of the month, is a chunk of rock named 469219 Kamo'oalewa. It is one of just seven asteroids that fall into a little-understood class known as quasi-satellites of Earth--and it could also be the first known asteroid comprised of lunar material. That hypothesis could be confirmed by laboratory studies of fragments collected by Tianwen-2, which are due to be returned to Earth about 2.5 years after launch. "This is an ambitious mission to explore a fascinating object," says astrophysicist Amy Mainzer of the University of California, Los Angeles.

The World Health Organization (WHO) has sent an internal memo about potential problems with a major company's malaria tests after scientists reported issues with test sensitivity and warned it could delay patients' access to critical treatment. Abbott's Bioline rapid diagnostic tests (RDTs) for malaria are used by health workers around the world, particularly in remote areas where lab techniques such as microscopy and DNA detection aren't available. Investigations at several institutions in Southeast Asia suggest at least some of these RDTs fail to detect infections or show faint test lines for some positive cases. Daniel Ngamije Madandi, director of WHO's Global Malaria Programme (GMP), issued the memo to WHO's six regional offices on 30 April. It lists 11 "affected" lots from two Abbott RDTs--Pf/Pv and Pf/Pan--that were associated with "faint lines and false negative results" in reports from "multiple research groups." The memo follows a public notice by WHO in March that warned of reports of faint lines in malaria RDTs without mentioning particular brands or products.

A study that used artificial intelligence–generated content to "participate" in online discussions and test whether AI was more successful at changing people's minds than human-generated content has caused an uproar because of ethical concerns about the work. This week some of the unwitting research participants publicly asked the University of Zürich (UZH), where the researchers behind the experiment hold positions, to investigate and apologize. "I think people have a reasonable expectation to not be in scientific experiments without their consent," says Casey Fiesler, an expert on internet research ethics at the University of Colorado Boulder. A university statement emailed to Science says the researchers--who remain anonymous--have decided not to publish their results. The university will investigate the incident, the statement says.

On 28 March, Briony Swire-Thompson began seeing reports online that the National Institutes of Health (NIH) might cancel grants for research on misinformation. At first, she didn't think she would be affected. Swire-Thompson, a psychologist at Northeastern University, studies misinformation--but not the political lies that get most of the attention. She's interested in false information about cancer, and why people fall for it. "There's a lot of people online trying to sell their snake oil," she says.

Following through on his vows to shake up the U.S. government, President Donald Trump's new administration quickly issued a flurry of executive orders and other decisions, some with big implications for research and global health, sowing worry and confusion among many scientists. The White House this week proposed--and 2 days later rescinded--an unprecedented order to freeze huge chunks of federal spending, including research grants. The 27 January budget memo directed political appointees at every agency to decide whether the funds "conform with administrative priorities" as spelled out in a slew of executive orders Trump has issued since taking office. Despite withdrawing the memo, the White House said agencies must still comply with the executive orders, which ban support for programs that include promoting "Marxist equity, transgenderism, and Green New Deal social engineering policies." A federal judge had already temporarily halted implementation of the memo, which generated a public outcry.

It has become increasing clear that mutation affects phenotypic variation and disease risk across humans. However, there are many different types of mutation. Seplyarskiy et al. applied a matrix factorization method to large human genomic datasets to identify germline mutational processes in an unsupervised manner. From this survey, nine robust mutational components were identified and specific mechanisms generating seven of these processes were proposed from correlations with genomic features. These results confirm and improve upon our understanding of mutational processes and reveal likely mechanisms of mutation in the human genome. Science , aba7408, this issue p. [1030][1] Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric. [1]: /lookup/doi/10.1126/science.aba7408

Gene-regulatory networks govern the development of organs. Sarropoulos et al. analyzed mouse cerebellar development in the context of gene-regulatory networks. Single nuclear profiles analyzing chromatin accessibility in about 90,000 cells revealed diversity in progenitor cells and genetic programs guiding cellular differentiation. The footsteps of evolution were apparent in varying constraints on different cell types. Science , abg4696, this issue p. [eabg4696][1] ### INTRODUCTION The cerebellum contributes to many complex brain functions, including motor control, language, and memory. During development, distinct neural cells are generated at cerebellar germinal zones in a spatiotemporally restricted manner. Cis-regulatory elements (CREs), such as enhancers and promoters, and the transcription factors that bind to them are central to cell fate specification and differentiation. Although most CREs undergo rapid turnover during evolution, a few are conserved across vertebrates. ### RATIONALE Bulk measurements of CRE activity have provided insights into gene regulation in the cerebellum, as well as into the evolutionary dynamics of CREs during organ development. However, they lack the cellular resolution required to assess cell-type differences in regulatory constraint and unravel the regulatory programs associated with the specification and differentiation of cell types. ### RESULTS Here, we generated a single-cell atlas of gene regulation in the mouse cerebellum spanning 11 developmental stages, from the beginning of neurogenesis to adulthood. By acquiring snATAC-seq (single-nucleus assay for transposase accessible chromatin using sequencing) profiles for ~90,000 cells, we mapped all major cerebellar cell types and identified candidate CREs. Characterization of CRE activity across the cerebellum development highlights the cell- and time-specificity of gene regulation. Many of the differentially accessible CREs are specific to a single cell type and state, but we also identified a fraction of CREs with pleiotropic (shared) activity. At early developmental stages, temporal changes in CRE activity are shared between progenitor cells from different germinal zones, supporting a model of cell fate induction through common temporal cues. Pleiotropic CREs in major cerebellar neuron types (granule cells, Purkinje cells, and inhibitory interneurons) are more active at early differentiation states, and the regulatory programs gradually diverge as differentiation proceeds. Based on comparisons to vertebrate genomes, we observed a decrease in CRE sequence conservation during development for all cerebellar cell types, a pattern that is largely explained by differentiation as well as by additional temporal differences between cells from matched differentiation states. Across cell types, differences in regulatory conservation are most pronounced in the adult, where microglia—the immune cells of the brain—show the fastest evolutionary turnover. By contrast, mature astrocytes harbor the most conserved intergenic CREs, not only in the cerebellum but also across a wide range of cell types in adult mouse organs. To evaluate the conservation of CRE activity, we acquired snATAC-seq profiles for ~20,000 cerebellar cells from the gray short-tailed opossum, a marsupial separated from mouse by ~160 million years of evolution. Our comparative analysis of CRE activity in the two therian species reinforced our sequence-based conclusions regarding differences in CRE constraint across cell types and developmental stages and also revealed that despite the overall high turnover of CREs, radical repurposing of spatiotemporal CRE activity is rare, at least between cell types in the same tissue. ### CONCLUSION This study reveals extensive temporal differences in CRE activity across cerebellar cell types and a shared decrease in CRE conservation during development and differentiation. Given that the cerebellum has been successfully used as a model system to study cell fate specification, neurogenesis, and other developmental processes, we expect that our observations regarding the developmental and evolutionary dynamics of regulatory elements, and their interplay, are also applicable to mammalian organs in general. ![Figure][2] Cis-regulatory elements in cerebellar cells. snATAC-seq delineates cell- and time-specific CRE activity in the developing mouse cerebellum (left). The chromatin accessibility profiles of cerebellar neuron types gradually diverge during differentiation as the activity of pleiotropic (shared) CREs decreases (top right). The evolutionary conservation of CRE sequences in vertebrates and activity in therian mammals decreases across development and differs between cell types (bottom right). mRNA, messenger RNA; PCA, principal components analysis; TF, transcription factor. Organ development is orchestrated by cell- and time-specific gene regulatory networks. In this study, we investigated the regulatory basis of mouse cerebellum development from early neurogenesis to adulthood. By acquiring snATAC-seq (single-nucleus assay for transposase accessible chromatin using sequencing) profiles for ~90,000 cells spanning 11 stages, we mapped cerebellar cell types and identified candidate cis - regulatory elements (CREs). We detected extensive spatiotemporal heterogeneity among progenitor cells and a gradual divergence in the regulatory programs of cerebellar neurons during differentiation. Comparisons to vertebrate genomes and snATAC-seq profiles for ∼20,000 cerebellar cells from the marsupial opossum revealed a shared decrease in CRE conservation during development and differentiation as well as differences in constraint between cell types. Our work delineates the developmental and evolutionary dynamics of gene regulation in cerebellar cells and provides insights into mammalian organ development. [1]: /lookup/doi/10.1126/science.abg4696 [2]: pending:yes