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Integrated memristor for mitigating reverse-bias in perovskite solar cells
Progressive coevolution of the yeast centromere and kinetochore
Abstract During mitosis, stable but dynamic interactions between centromere DNA and the kinetochore complex enable accurate and efficient chromosome segregation. Even though many proteins of the kinetochore are highly conserved 1,2 , centromeres are among the fastest evolving regions in a genome 3,4 , showing extensive variation even on short evolutionary timescales. Here we sought to understand how organisms evolve completely new sets of centromeres that still effectively engage with the kinetochore machinery by identifying and tracking thousands of centromeres across two major fungal clades, including more than 2,500 natural strain isolates and representing over 1,000 million years of evolution. We show that new centromeres spread progressively via drift and subsequent selection and that the kinetochore, which is evolving slowly in relative terms, appears to act as a filter to determine which new centromere variants are tolerated. Together, our findings provide insight into the evolutionary constraints and trajectories shaping centromere evolution.
Integrated photonic neural network with on-chip backpropagation training
Clonal-aggregative multicellularity tuned by salinity in a choanoflagellate
Abstract Multicellularity evolved independently multiple times in eukaryotes 1–4 . Two distinct mechanisms underpin multicellularity 5 : clonality (serial cell division without sister-cell separation) and aggregation (whereby independent cells assemble into a multicellular entity). Clonal and aggregative multicellularity are traditionally considered to be mutually exclusive 1,6–8 , with rare exceptions 9 , and evolutionary hypotheses have addressed why multicellularity might diverge towards one or the other extreme 3,4 . Both animals and their sister group, the choanoflagellates, are currently known to acquire multicellularity only clonally 4,10,11 . Here we show that the choanoflagellate Choanoeca flexa 12 forms motile and contractile cell monolayers (sheets) through multiple mechanisms— C. flexa sheets can form purely clonally, purely aggregatively or through a combination of both processes. We characterize the life history of C. flexa in its natural environment—ephemeral splash pools on the island of Curaçao—and show that C. flexa undergoes reversible transitions between unicellularity and multicellularity during evaporation–refilling cycles. Different splash pools house genetically distinct strains of C. flexa and kin recognition constrains aggregation between them. We show that clonal-aggregative multicellularity is a versatile strategy for the robust establishment of multicellularity in this variable and fast-fluctuating environment. Our findings challenge former generalizations about choanoflagellates and expand the option space of choanozoan multicellularity.
Flexible paths to multicellularity
Magnetic resonance control of spin-correlated radical pair dynamics in vivo
Bacterial immune activation via supramolecular assembly with phage triggers
Abstract Bacteria use diverse mechanisms to protect themselves against phages 1–6 . Many antiphage systems form large oligomeric complexes, but how oligomerization is regulated during phage infection remains mostly unknown 7–12 . Here we demonstrate that the bacterial immunity protein ring-activated zinc-finger RNase (RAZR) assembles into an active, 24-meric ring around the circumference of large ring structures formed by two unrelated phage proteins: a putative recombinase and a portal protein. Each multi-layered, megadalton-scale complex enables RAZR to cleave RNA nonspecifically to inhibit translation and restrict phage propagation. The recognition of unrelated phage proteins that form rings with similar diameters indicates that these proteins not only bind to RAZR but also enforce a geometry crucial to activation. The lack of large ring structures in the host probably prevents auto-immunity and RAZR activation before infection. The infection-triggered oligomerization of RAZR mirrors pathogen-induced oligomerization in eukaryotic innate immune complexes 13 , underscoring a common principle of immunity across biology.
Knock knock, no one’s there. Study finds scientists’ jokes mostly fall flat
Structural and evolutionary insights into the eukaryotic RNase MRP ribonucleoprotein complex
Abstract RNase MRP is a conserved eukaryotic ribonucleoprotein essential for precursor-rRNA processing and ribosome assembly. Despite previous studies of yeast RNase MRP, the composition of RNase MRP and how it adapts to process flexible, single-stranded rRNA substrates in most eukaryotes remain enigmatic. Here, we perform an integrative structural, evolutionary, and functional dissection of human RNase MRP. Using structure-based bioinformatics and cryo-EM structural analyses, we identify NEPRO (RMP64) and C18orf21 (RMP24) as the bona fide subunits unique to RNase MRP, which are indispensable for precursor-rRNA cleavage, ribosome assembly, protein synthesis, and chondrogenesis. The structure of human RNase MRP reveals a unique ‘double-anchor’ substrate-binding mechanism that underlies evolutionary adaptations conferring broad substrate specificity. Our work on RNase MRP provides a unified evolutionary and mechanistic framework for this essential ancient ribozyme.
An integrated germline and somatic genomic model for coronary artery disease
CRISPR makes enhanced cancer-fighting immune cells inside mice
Robust antibiotic sensitization of pathogenic Pseudomonas aeruginosa via negative hysteresis in the cell envelope
Abstract Antibiotic combination in time and space is a key strategy to combat antimicrobial resistance. The success of such treatment designs requires their robust efficacy across treatment conditions and a pathogen’s genomic diversity. This study found that an initial treatment with a β-lactam antibiotic causes robust cellular sensitization towards an aminoglycoside antibiotic across the high-risk human pathogen Pseudomonas aeruginosa , including resistant strains. This phenomenon of cellular sensitization, termed negative hysteresis, is modulated by the Cpx envelope stress response system and linked to membrane stress during growth. The increase in efficacy is achieved through a β-lactam induced elevated cellular uptake of the subsequently administered aminoglycoside. Negative hysteresis and the Cpx system are linked in several cases to the expression of synergistic drug interactions, thus enhancing efficacy of antibiotic combinations. Overall, our study identifies the phenomenon of negative hysteresis as a robustly inducible phenotype and thus a unique focus for optimizing antimicrobial therapy.
Brain’s protective barrier stays leaky for years after playing contact sports
Higher education predicts global cultural similarity to WEIRD countries
Nucleolar migration regulates meiotic sex chromosome inactivation via phase separation during mammalian spermatogenesis
Dnmt1 mediates epigenetic restriction of invasive traits in clonal crayfish
Abstract Procambarus virginalis (marbled crayfish) is a parthenogenetically reproducing invasive crayfish species. Its global population is monoclonal, which raises questions about the mechanisms promoting their invasiveness. Here we show that environmental changes downregulate the highly conserved Dnmt1 DNA methyltransferase in marbled crayfish. When phenocopying this effect through a dsRNA-based in vivo knockdown, we observe enhanced invasiveness-related behavioral traits. Image cytometry and single-cell RNA sequencing reveal an expansion of mature granular immune cells and depletion of hemocyte-derived neuronal precursors, which support adult neurogenesis. Whole-genome bisulfite sequencing shows that these phenotypes coincide with a global loss of gene body DNA methylation and dysregulation of nervous and immune system genes. Additionally, we observe nucleosome destabilization to be associated with transcriptional changes after methylation loss. Taken together, our findings identify Dnmt1 as a potential canalizer of cellular and organismal phenotypes, thus providing a framework for how epigenetic mechanisms modulate invasiveness.
A dual role of EZH2 in regulating A-to-I RNA editing and mRNA stability through ADAR
Abstract Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), is a widespread modification in metazoans. Cumulative evidence has revealed the altered A-to-I editing profiles in cancers, but the underlying mechanism remains unclear. Here, we discover the well-known histone lysine methyltransferase enhancer of zeste homologue 2 (EZH2) as an unexplored ADAR interactor and editing regulator in prostate cancer (PCa). Through competing with interleukin enhancer binding factor 2 (ILF2) for ADAR1 binding, EZH2 reshapes the substrate selectivity of ADAR1 and thus exhibits a bidirectional role in editing regulation. Moreover, EZH2 depletion induces the translational repression of transportin-1 (TRN1), which further results in the accumulation of cytoplasmic ADAR1p110 isoform to protect many oncogenic transcripts from degradation. Consistently, depletion of ADAR1 dramatically enhances the sensitivity of cancer cells and tumors to EZH2 selective degraders. Collectively, our study sheds new light on a link between two layers of epigenetic regulations at histone modification and RNA editing levels, demonstrates a previously uncharacterized role of EZH2 in RNA editing and mRNA stability independently of its lysine methyltransferase activity, and reveals the significance of EZH2-ADAR1 cascade in governing RNA editing and mRNA stability, which may provide additional perspectives for the advancement of EZH2-targeting cancer therapies.
Structural basis of human γTuRC closure during CM1-activated microtubule nucleation
Toolbox of FRET-based c-di-GMP biosensors and its FRET-To-Sort application for genome-wide mapping of c-di-GMP regulation
Abstract C-di-GMP is a widespread second messenger that coordinates transitions between different lifestyles in bacteria. Levels of c-di-GMP are controlled by complex regulatory networks, and they can vary dynamically over a wide range of concentrations. To enable studies of c-di-GMP regulation under a variety of conditions, here we construct and characterize a large set of FRET-based c-di-GMP biosensors that undergo large FRET signal changes and display a stepwise coverage of diverse binding affinities, thus capable of sensitively detecting diverse cellular c-di-GMP concentrations. We subsequently apply different-affinity FRET biosensors from this toolbox to systematically investigate genome-wide network of c-di-GMP regulation in planktonic Escherichia coli cells by establishing FRET-To-Sort, which relies on FRET-based cell sorting of a barcoded transposon library. We observe prominent enrichment of mutations in two classes of flagellar genes among those affecting c-di-GMP levels, and demonstrate that inhibited flagellar rotation reduces biosynthesis of c-di-GMP due to increased proton motive force.