The rockefeller university

Thoeris systems use proteins with Toll/interleukin-1 receptor domains to protect prokaryotes from phage infection through the synthesis of a cyclic adenosine diphosphate ribose signalling molecule, which activates an effector that depletes the host of the essential metabolite NAD+ to limit viral propagation. How infection is recognized during Thoeris immunity is not known. Here we investigate the staphylococcal Thoeris defense system, ThsA-B1-B2, and found that, upon infection, the major capsid proteins of Siphoviridae phages from serogroup B, but not A, form a complex with ThsB1 and ThsB2 to activate Thoeris defense. Thoeris cyclases from Streptococcus also recognize major capsid proteins. Our results suggest that the accumulation of capsid mutations that enable avoidance of Thoeris recognition may be an important evolutionary force behind the structural diversity of prokaryotic viruses. More broadly, given that some mammalian immune pathways contain Toll/interleukin-1 receptor domains that recognize viral structures, our findings highlight a conserved mechanism of innate antiviral immunity.

Intravenous immunoglobulin (IVIG) administered at high doses is used to treat a wide array of autoimmune diseases. Studies in murine models have identified that the anti-inflammatory activity of IVIG is dependent on sialylation of the N-linked glycan on the CH2 domain of immunoglobulin G (IgG), the type I IgG inhibitory Fc receptor Fc gamma RIIB, and the type II Fc receptor dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). We hypothesized that DC-SIGN, a C-type lectin, may directly interact with glycans on Fc gamma RIIB, augmenting its ability to bind sialylated IgG. We found that Fc-engineering sialylated IgG1 to enhance its affinity for Fc gamma RIIB resulted in a molecule that was more potent than IVIG in reducing the inflammatory sequelae of antibody or T cell-mediated autoimmune diseases, providing the basis for a class of potent anti-inflammatory therapeutics.

Transcription in bacteria is a multi-step process. In the first step, contacts between RNA polymerase and the promoter DNA must be established for transcription initiation to begin, but then these contacts must be broken for the enzyme to transition into the elongation phase. Single-molecule and biochemical observations report that promoter escape is a highly regulated and sometimes rate-limiting step in the transcription cycle; however, the structural mechanisms of promoter escape remain obscure. Promoter escape also serves as the target for the clinically important antibiotic rifampicin, used to treat tuberculosis. Here, we present seven distinct intermediates showing the structural details of M. tuberculosis RNA polymerase initial transcribing complexes and promoter escape, using a de novo cryo-electron microscopy approach. We describe the structural rearrangements that RNA polymerase undergoes to clear the promoter, including those required to release the initiation factor, sigma, providing a structural account for decades of biochemical observations. These structures and supporting biochemistry provide a model of promoter escape, a universal step in the transcription cycle, with conformations that may be used to develop Rifampicin alternatives.

BackgroundRed mullet (Mullus barbatus) is a key species in Mediterranean fisheries, yet its stock structure and population dynamics remain poorly understood due to a lack of comprehensive genomic resources. This study provides the first high-quality reference genome for M. barbatus and a comprehensive set of SNP markers to investigate its population structure and adaptive potential across the Mediterranean.ResultsUsing the newly generated chromosome-level reference genome, we re-analyzed a Mediterranean-wide reduced-representation genomic dataset. Our analysis reveals a panmictic population structure with strong genetic connectivity across the species' range, likely driven by extensive larval dispersal and multigenerational gene flow. Despite minimal genome-wide differentiation, outlier analysis identified candidate loci under directional selection, linked to key biological processes such as ontogeny and environmental adaptation.ConclusionsThis study presents the first genomic resource for M. barbatus, providing valuable insights into its genetic structure and adaptive mechanisms. While the identification of loci under selection offers promising leads, these findings are preliminary due to the limited genomic coverage of the dataset. Nonetheless, they pave the way for future genomic studies to explore how M. barbatus adapts to environmental and anthropogenic pressures. These results hold significant implications for the sustainable management of Mediterranean fisheries, especially in the context of climate change and conservation.

Juvenile hormones (JH) regulate insect development, reproduction, and behavior. The JH analog Methoprene, widely used in pest control, disrupts these processes by inhibiting maturation rather than causing mortality. Beyond its physiological effects, Methoprene influences insect behavior, including mate choice, social organization, and foraging, by altering neuronal sensitivity and gene expression via the Methoprene-tolerant receptor. These behavioral disruptions may negatively impact insect populations, including pollinators like honeybees. While laboratory studies highlight Methoprene's behavioral consequences, field research is needed to assess its ecological effects. Understanding these broader impacts is crucial for evaluating the risks associated with JH-based pest control strategies.

CD40 agonism enhances antitumor immunity but is limited by systemic toxicity and poor efficacy. Here, we present a phase 1 study (NCT04059588) of intratumoral (i.t.) 2141-V11, an Fc-engineered anti-CD40 agonistic antibody with enhanced binding to the inhibitory receptor Fc gamma RIIB. Among 12 metastatic cancer patients, 2141-V11 was well tolerated without dose-limiting toxicities. Six patients experienced tumor reduction, including two complete responses in melanoma and breast cancer. 2141-V11 induced regression in injected and non-injected lesions, correlating with systemic CD8+T cell activation and mature tertiary lymphoid structures (TLSs) in complete responders. In CD40/Fc gamma Rs humanized mice bearing orthotopic tumors, i.t. 2141-V11 promoted de novo TLS formation, facilitating i.t. CD8+ T cell effector responses independent of lymph node priming. The resulting local immune responses by 2141-V11 mediated abscopal antitumor effects and sustained immune memory. These findings demonstrate that i.t. 2141-V11 is safe and promotes immune-privileged tumor microenvironments that promote systemic and durable antitumor immunity.

Communication is crucial to social life, and in ants, it is mediated primarily through olfaction. Ants have more odorant receptor (OR) genes than any other group of insects, generated through tandem duplications that produce large genomic arrays of related genes. The mechanism by which olfactory sensory neurons (OSNs) produce a single functional OR from these arrays remains unclear. In ant OSNs, only mRNA from one OR in an array is exported into the cytoplasm, while upstream genes are silent and transcripts from downstream genes remain nuclear. Here, we show that readthrough transcription in the downstream direction generates non-translated transcripts. We also find that OR promoters are bidirectional, producing anti-sense long non-coding RNAs. We suspect that neither readthrough nor antisense transcription produces functional RNA but that bidirectional transcription alone is critical to suppressing the expression of all other OR genes in a tandem array. Finally, we present evidence that this regulatory architecture is conserved across ants and bees, suggesting that this mechanism for functionally monogenic OR expression is widespread in insects with expanded OR repertoires.

The cellular basis of COVID-19 severity in patients with deficiencies in type I IFN immunity remains unclear. In this study, we differentiated cardiomyocytes and macrophages from IFNAR1 competent (IFNAR1comp) and deficient (IFNAR1def) induced pluripotent stem cells (iPSCs), and analyzed virus replication and cytokine production after exposure to SARS-CoV-2. Cardiomyocytes expressed the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) and showed abundant SARS-CoV-2 replication, which was higher in IFNAR1def than IFNAR1comp cells. Treatment with exogenous IFN alpha mitigated infection in IFNAR1comp, but not in IFNAR1def cardiomyocytes. In contrast, macrophages did not express ACE2 and did not support SARS-CoV-2 replication, but produced pro-inflammatory cytokines upon virus exposure, which was impaired in IFNAR1def macrophages. In conclusion, type I IFNs decrease SARS-CoV-2 replication in human iPSC-derived cardiomyocytes, while they increase cytokine responses of macrophages.