MicroRNAs (miRNAs) base-pair to messenger RNA targets and guide Argonaute proteins to mediate their silencing. This target regulation is considered crucial for animal physiology and development. However, this notion is based exclusively on studies in bilaterians, which comprise almost all lab model animals.  https://www.selleckchem.com/products/repsox.html  To fill this phylogenetic gap, we characterize the functions of two Argonaute paralogs in the sea anemone Nematostella vectensis of the phylum Cnidaria, which is separated from bilaterians by ~600 million years. Using genetic manipulations, Argonaute-immunoprecipitations and high-throughput sequencing, we provide experimental evidence for the developmental importance of miRNAs in a non-bilaterian animal. Additionally, we uncover unexpected differential distribution of distinct miRNAs between the two Argonautes and the ability of one of them to load additional types of small RNAs. This enables us to postulate a novel model for evolution of miRNA precursors in sea anemones and their relatives, revealing alternative trajectories for metazoan miRNA evolution.Fungal polyketides display remarkable structural diversity and bioactivity, and therefore the biosynthesis and engineering of this large class of molecules is therapeutically significant. Here, we successfully recode, construct and characterize the biosynthetic pathway of bikaverin, a tetracyclic polyketide with antibiotic, antifungal and anticancer properties, in S. cerevisiae. We use a green fluorescent protein (GFP) mapping strategy to identify the low expression of Bik1 (polyketide synthase) as a major bottleneck step in the pathway, and a promoter exchange strategy is used to increase expression of Bik1 and bikaverin titer. Then, we use an enzyme-fusion strategy to directly couple the monooxygenase (Bik2) and methyltransferase (Bik3) to efficiently channel intermediates between modifying enzymes, leading to an improved titer of bikaverin at 202.75 mg/L with flask fermentation (273-fold higher than the initial titer). This study demonstrates that the biosynthesis of complex fungal polyketides can be established and efficiently engineered in S. cerevisiae, highlighting the potential for natural product synthesis and large-scale fermentation in yeast.Resting membrane potential determines the excitability of the cell and is essential for the cellular electrical activities. The NALCN channel mediates sodium leak currents, which positively adjust resting membrane potential towards depolarization. The NALCN channel is involved in several neurological processes and has been implicated in a spectrum of neurodevelopmental diseases. Here, we report the cryo-EM structure of rat NALCN and mouse FAM155A complex to 2.7 Å resolution. The structure reveals detailed interactions between NALCN and the extracellular cysteine-rich domain of FAM155A. We find that the non-canonical architecture of NALCN selectivity filter dictates its sodium selectivity and calcium block, and that the asymmetric arrangement of two functional voltage sensors confers the modulation by membrane potential. Moreover, mutations associated with human diseases map to the domain-domain interfaces or the pore domain of NALCN, intuitively suggesting their pathological mechanisms.Prior research has identified associations between social media activity and psychiatric diagnoses; however, diagnoses are rarely clinically confirmed. Toward the goal of applying novel approaches to improve outcomes, research using real patient data is necessary. We collected 3,404,959 Facebook messages and 142,390 images across 223 participants (mean age = 23.7; 41.7% male) with schizophrenia spectrum disorders (SSD), mood disorders (MD), and healthy volunteers (HV). We analyzed features uploaded up to 18 months before the first hospitalization using machine learning and built classifiers that distinguished SSD and MD from HV, and SSD from MD. Classification achieved AUC of 0.77 (HV vs. MD), 0.76 (HV vs. SSD), and 0.72 (SSD vs. MD). SSD used more (P  less then  0.01) perception words (hear, see, feel) than MD or HV. SSD and MD used more (P  less then  0.01) swear words compared to HV. SSD were more likely to express negative emotions compared to HV (P  less then  0.01). MD used more words related to biological processes (blood/pain) compared to HV (P  less then  0.01). The height and width of photos posted by SSD and MD were smaller (P  less then  0.01) than HV. MD photos contained more blues and less yellows (P  less then  0.01). Closer to hospitalization, use of punctuation increased (SSD vs HV), use of negative emotion words increased (MD vs. HV), and use of swear words increased (P  less then  0.01) for SSD and MD compared to HV. Machine-learning algorithms are capable of differentiating SSD and MD using Facebook activity alone over a year in advance of hospitalization. Integrating Facebook data with clinical information could one day serve to inform clinical decision-making.A Correction to this paper has been published https//doi.org/10.1038/s41467-020-20261-6.Environmental drought and high salinity impose osmotic stress, which inhibits plant growth and yield. Thus, understanding how plants respond to osmotic stress is critical to improve crop productivity. Plants have multiple signalling pathways in response to osmotic stress in which the phytohormone abscisic acid (ABA) plays important roles. However, since little is known concerning key early components, the global osmotic stress-signalling network remains to be elucidated. Here, we review recent advances in the identification of osmotic-stress activated Raf-like protein kinases as regulators of ABA-dependent and -independent signalling pathways and discuss the plant stress-responsive kinase network from an evolutionary perspective.Upon sensing cytosolic DNA, the enzyme cGAS induces innate immune responses that underpin anti-microbial defenses and certain autoimmune diseases. Missense mutations of PRKDC encoding the DNA-dependent protein kinase (DNA-PK) catalytic subunit (DNA-PKcs) are associated with autoimmune diseases, yet how DNA-PK deficiency leads to increased immune responses remains poorly understood. In this study, we report that DNA-PK phosphorylates cGAS and suppresses its enzymatic activity. DNA-PK deficiency reduces cGAS phosphorylation and promotes antiviral innate immune responses, thereby potently restricting viral replication. Moreover, cells isolated from DNA-PKcs-deficient mice or patients carrying PRKDC missense mutations exhibit an inflammatory gene expression signature. This study provides a rational explanation for the autoimmunity of patients with missense mutations of PRKDC, and suggests that cGAS-mediated immune signaling is a potential target for therapeutic interventions.