Science current issue 
  • Target student mental well-being 
  • News at a glance 
  • New mutations raise specter of 'immune escape 
  • Disgraced COVID-19 studies are still routinely cited 
  • Controversial study says U.S. labs use 111 million mice, rats 
  • What causes IBS pain? Maybe immune flare-ups 
  • Global temperatures in 2020 tied record highs 
  • Separation anxiety 
  • Drivers of mosquito mating 
  • Snapshots of a light-triggered transition 
  • Thermopower and harvesting heat 
  • A host metabolite promotes Salmonella survival 
  • Racing against unwanted isomerization 
  • Sex differences in immune responses 
  • Masatoshi Koshiba (1926-2020) 
  • Rethinking immigration policies for STEM doctorates 
  • Darwin and human evolution 
  • A barrier breaker's complicated legacy 
  • Shortfin mako sharks speeding to the brink 
  • Mediterranean sharks and rays need action 
  • Tilapia farming threatens Brazil's waters 
  • Enhancer-gene interactions drive split 
  • A metabolic circuit in T cell immunity 
  • Yeast switches for glucose and galactose 
  • Two-part formation of the Solar System 
  • Opening charge transport pathways 
  • From offense to defense 
  • An innate response to ovarian cancer 
  • Resonance on the pulse 
  • Antiviral responses differ with sex 
  • From development to disease 
  • Cryo-EM uncovers polycomb interactions 
  • Cross-talk between histone modifications 
  • Cellular beauty is skin deep 
  • Watching a phase transition unfold 
  • Modeling single-atom reactivity 
  • Keeping Z-olefins intact with iridium 
  • Salmonella profits from immunometabolism 
  • Cuticular pheromone circadian regulation 
  • Deubiquitylation errors cause disease 
  • PD-1 blockade carries perils 
  • A shared Toll for innate immunity 
  • Unveiling the secret of vetiver's scent 
  • Letting the nodes know 
  • Forest-savanna fire guard 
  • Neutrophil bioenergetics are specialized 
  • Coevolution in India 
  • Oceans suppress crater formation 
  • Variations enhance sensitivity 
  • Bifurcation of planetary building blocks during Solar System formation 

    Geochemical and astronomical evidence demonstrates that planet formation occurred in two spatially and temporally separated reservoirs. The origin of this dichotomy is unknown. We use numerical models to investigate how the evolution of the solar protoplanetary disk influenced the timing of protoplanet formation and their internal evolution. Migration of the water snow line can generate two distinct bursts of planetesimal formation that sample different source regions. These reservoirs evolve in divergent geophysical modes and develop distinct volatile contents, consistent with constraints from accretion chronology, thermochemistry, and the mass divergence of inner and outer Solar System. Our simulations suggest that the compositional fractionation and isotopic dichotomy of the Solar System was initiated by the interplay between disk dynamics, heterogeneous accretion, and internal evolution of forming protoplanets.

  • Ultrafast nanoimaging of the order parameter in a structural phase transition 

    Understanding microscopic processes in materials and devices that can be switched by light requires experimental access to dynamics on nanometer length and femtosecond time scales. Here, we introduce ultrafast dark-field electron microscopy to map the order parameter across a structural phase transition. We use ultrashort laser pulses to locally excite a 1T-TaS2 (1T-polytype of tantalum disulfide) thin film and image the transient state of the specimen by ultrashort electron pulses. A tailored dark-field aperture array allows us to track the evolution of charge-density wave domains in the material with simultaneous femtosecond temporal and 5-nanometer spatial resolution, elucidating relaxation pathways and domain wall dynamics. The distinctive benefits of selective contrast enhancement will inspire future beam-shaping technology in ultrafast transmission electron microscopy.

  • Unraveling CO adsorption on model single-atom catalysts 

    Understanding how the local environment of a "single-atom" catalyst affects stability and reactivity remains a challenge. We present an in-depth study of copper1, silver1, gold1, nickel1, palladium1, platinum1, rhodium1, and iridium1 species on Fe3O4(001), a model support in which all metals occupy the same twofold-coordinated adsorption site upon deposition at room temperature. Surface science techniques revealed that CO adsorption strength at single metal sites differs from the respective metal surfaces and supported clusters. Charge transfer into the support modifies the d-states of the metal atom and the strength of the metal–CO bond. These effects could strengthen the bond (as for Ag1–CO) or weaken it (as for Ni1–CO), but CO-induced structural distortions reduce adsorption energies from those expected on the basis of electronic structure alone. The extent of the relaxations depends on the local geometry and could be predicted by analogy to coordination chemistry.

  • Iridium-catalyzed Z-retentive asymmetric allylic substitution reactions 

    Z-Olefins are challenging synthetic targets owing to their relative thermodynamic instability. Transition metal–catalyzed asymmetric allylic substitution reactions are well known for installing stereocenters adjacent to branched or E-linear olefins. However, analogous reactions for the synthesis of optically active Z-olefin products are rare. Here we report iridium-catalyzed asymmetric allylic substitution reactions that retain Z-olefin geometries while establishing an adjacent quaternary stereocenter. The formation of transient anti--allyl-iridium intermediates and their capture by external nucleophiles before isomerization to the thermodynamically more stable syn--allyl-iridium counterparts have been observed. These results provide a promising method for preparing chiral Z-olefinic compounds.

  • Convergent evolution of pain-inducing defensive venom components in spitting cobras 

    Convergent evolution provides insights into the selective drivers underlying evolutionary change. Snake venoms, with a direct genetic basis and clearly defined functional phenotype, provide a model system for exploring the repeated evolution of adaptations. While snakes use venom primarily for predation, and venom composition often reflects diet specificity, three lineages of cobras have independently evolved the ability to spit venom at adversaries. Using gene, protein, and functional analyses, we show that the three spitting lineages possess venoms characterized by an up-regulation of phospholipase A2 (PLA2) toxins, which potentiate the action of preexisting venom cytotoxins to activate mammalian sensory neurons and cause enhanced pain. These repeated independent changes provide a fascinating example of convergent evolution across multiple phenotypic levels driven by selection for defense.

  • Nanoscale localized contacts for high fill factors in polymer-passivated perovskite solar cells 

    Polymer passivation layers can improve the open-circuit voltage of perovskite solar cells when inserted at the perovskite–charge transport layer interfaces. Unfortunately, many such layers are poor conductors, leading to a trade-off between passivation quality (voltage) and series resistance (fill factor, FF). Here, we introduce a nanopatterned electron transport layer that overcomes this trade-off by modifying the spatial distribution of the passivation layer to form nanoscale localized charge transport pathways through an otherwise passivated interface, thereby providing both effective passivation and excellent charge extraction. By combining the nanopatterned electron transport layer with a dopant-free hole transport layer, we achieved a certified power conversion efficiency of 21.6% for a 1-square-centimeter cell with FF of 0.839, and demonstrate an encapsulated cell that retains ~91.7% of its initial efficiency after 1000 hours of damp heat exposure.

  • Transvection regulates the sex-biased expression of a fly X-linked gene 

    Sexual dimorphism in animals results from sex-biased gene expression patterns. These patterns are controlled by genetic sex determination hierarchies that establish the sex of an individual. Here we show that the male-biased wing expression pattern of the Drosophila biarmipes gene yellow, located on the X chromosome, is independent of the fly sex determination hierarchy. Instead, we find that a regulatory interaction between yellow alleles on homologous chromosomes (a process known as transvection) silences the activity of a yellow enhancer functioning in the wing. Therefore, this enhancer can be active in males (XY) but not in females (XX). This transvection-dependent enhancer silencing requires the yellow intron and the chromatin architecture protein Mod(mdg4). Our results suggest that transvection can contribute more generally to the sex-biased expression of X-linked genes.

  • Host succinate is an activation signal for Salmonella virulence during intracellular infection 

    Key to the success of intracellular pathogens is the ability to sense and respond to a changing host cell environment. Macrophages exposed to microbial products undergo metabolic changes that drive inflammatory responses. However, the role of macrophage metabolic reprogramming in bacterial adaptation to the intracellular environment has not been explored. Here, using metabolic profiling and dual RNA sequencing, we show that succinate accumulation in macrophages is sensed by intracellular Salmonella Typhimurium (S. Tm) to promote antimicrobial resistance and type III secretion. S. Tm lacking the succinate uptake transporter DcuB displays impaired survival in macrophages and in mice. Thus, S. Tm co-opts the metabolic reprogramming of infected macrophages as a signal that induces its own virulence and survival, providing an additional perspective on metabolic host–pathogen cross-talk.

  • Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity 

    Infection triggers expansion and effector differentiation of T cells specific for microbial antigens in association with metabolic reprograming. We found that the glycolytic enzyme lactate dehydrogenase A (LDHA) is induced in CD8+ T effector cells through phosphoinositide 3-kinase (PI3K) signaling. In turn, ablation of LDHA inhibits PI3K-dependent phosphorylation of Akt and its transcription factor target Foxo1, causing defective antimicrobial immunity. LDHA deficiency cripples cellular redox control and diminishes adenosine triphosphate (ATP) production in effector T cells, resulting in attenuated PI3K signaling. Thus, nutrient metabolism and growth factor signaling are highly integrated processes, with glycolytic ATP serving as a rheostat to gauge PI3K-Akt-Foxo1 signaling in the control of T cell immunity. Such a bioenergetic mechanism for the regulation of signaling may explain the Warburg effect.

  • Clock genes and environmental cues coordinate Anopheles pheromone synthesis, swarming, and mating 

    Anopheles mating is initiated by the swarming of males at dusk followed by females flying into the swarm. Here, we show that mosquito swarming and mating are coordinately guided by clock genes, light, and temperature. Transcriptome analysis shows up-regulation of the clock genes period (per) and timeless (tim) in the head of field-caught swarming Anopheles coluzzii males. Knockdown of per and tim expression affects Anopheles gambiae s.s. and Anopheles stephensi male mating in the laboratory, and it reduces male An. coluzzii swarming and mating under semifield conditions. Light and temperature affect mosquito mating, possibly by modulating per and/or tim expression. Moreover, the desaturase gene desat1 is up-regulated and rhythmically expressed in the heads of swarming males and regulates the production of cuticular hydrocarbons, including heptacosane, which stimulates mating activity.

  • Ancient balancing selection maintains incompatible versions of the galactose pathway in yeast 

    Metabolic pathways differ across species but are expected to be similar within a species. We discovered two functional, incompatible versions of the galactose pathway in Saccharomyces cerevisiae. We identified a three-locus genetic interaction for growth in galactose, and used precisely engineered alleles to show that it arises from variation in the galactose utilization genes GAL2, GAL1/10/7, and phosphoglucomutase (PGM1), and that the reference allele of PGM1 is incompatible with the alternative alleles of the other genes. Multiloci balancing selection has maintained the two incompatible versions of the pathway for millions of years. Strains with alternative alleles are found primarily in galactose-rich dairy environments, and they grow faster in galactose but slower in glucose, revealing a trade-off on which balancing selection may have acted.

  • AAAS 2021 Annual Meeting Program 
  • New Products 
  • A department terminated 
  • JARID2 and AEBP2 regulate PRC2 in the presence of H2AK119ub1 and other histone modifications 

    Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) cooperate to determine cell identity by epigenetic gene expression regulation. However, the mechanism of PRC2 recruitment by means of recognition of PRC1-mediated H2AK119ub1 remains poorly understood. Our PRC2 cryo–electron microscopy structure with cofactors JARID2 and AEBP2 bound to a H2AK119ub1-containing nucleosome reveals a bridge helix in EZH2 that connects the SET domain, H3 tail, and nucleosomal DNA. JARID2 and AEBP2 each interact with one ubiquitin and the H2A-H2B surface. JARID2 stimulates PRC2 through interactions with both the polycomb protein EED and the H2AK119-ubiquitin, whereas AEBP2 has an additional scaffolding role. The presence of these cofactors partially overcomes the inhibitory effect that H3K4me3 and H3K36me3 exert on core PRC2 (in the absence of cofactors). Our results support a key role for JARID2 and AEBP2 in the cross-talk between histone modifications and PRC2 activity.

  • Mapping the molecular and cellular complexity of cortical malformations 

    The cerebral cortex is an intricate structure that controls human features such as language and cognition. Cortical functions rely on specialized neurons that emerge during development from complex molecular and cellular interactions. Neurodevelopmental disorders occur when one or several of these steps is incorrectly executed. Although a number of causal genes and disease phenotypes have been identified, the sequence of events linking molecular disruption to clinical expression mostly remains obscure. Here, focusing on human malformations of cortical development, we illustrate how complex interactions at the genetic, cellular, and circuit levels together contribute to diversity and variability in disease phenotypes. Using specific examples and an online resource, we propose that a multilevel assessment of disease processes is key to identifying points of vulnerability and developing new therapeutic strategies.

  • Developmental cell programs are co-opted in inflammatory skin disease 

    The skin confers biophysical and immunological protection through a complex cellular network established early in embryonic development. We profiled the transcriptomes of more than 500,000 single cells from developing human fetal skin, healthy adult skin, and adult skin with atopic dermatitis and psoriasis. We leveraged these datasets to compare cell states across development, homeostasis, and disease. Our analysis revealed an enrichment of innate immune cells in skin during the first trimester and clonal expansion of disease-associated lymphocytes in atopic dermatitis and psoriasis. We uncovered and validated in situ a reemergence of prenatal vascular endothelial cell and macrophage cellular programs in atopic dermatitis and psoriasis lesional skin. These data illustrate the dynamism of cutaneous immunity and provide opportunities for targeting pathological developmental programs in inflammatory skin diseases.

  • Regulation of the Dot1 histone H3K79 methyltransferase by histone H4K16 acetylation 

    Dot1 (disruptor of telomeric silencing-1), the histone H3 lysine 79 (H3K79) methyltransferase, is conserved throughout evolution, and its deregulation is found in human leukemias. Here, we provide evidence that acetylation of histone H4 allosterically stimulates yeast Dot1 in a manner distinct from but coordinating with histone H2B ubiquitination (H2BUb). We further demonstrate that this stimulatory effect is specific to acetylation of lysine 16 (H4K16ac), a modification central to chromatin structure. We provide a mechanism of this histone cross-talk and show that H4K16ac and H2BUb play crucial roles in H3K79 di- and trimethylation in vitro and in vivo. These data reveal mechanisms that control H3K79 methylation and demonstrate how H4K16ac, H3K79me, and H2BUb function together to regulate gene transcription and gene silencing to ensure optimal maintenance and propagation of an epigenetic state.