The evolutionary mechanisms by which SARS-CoV-2 viruses adapt to mammalian hosts and, potentially, undergo antigenic evolution depend on the ways genetic variation is generated and selected within ...and between individual hosts. Using domestic cats as a model, we show that SARS-CoV-2 consensus sequences remain largely unchanged over time within hosts, while dynamic sub-consensus diversity reveals processes of genetic drift and weak purifying selection. We further identify a notable variant at amino acid position 655 in Spike (H655Y), which was previously shown to confer escape from human monoclonal antibodies. This variant arises rapidly and persists at intermediate frequencies in index cats. It also becomes fixed following transmission in two of three pairs. These dynamics suggest this site may be under positive selection in this system and illustrate how a variant can quickly arise and become fixed in parallel across multiple transmission pairs. Transmission of SARS-CoV-2 in cats involved a narrow bottleneck, with new infections founded by fewer than ten viruses. In RNA virus evolution, stochastic processes like narrow transmission bottlenecks and genetic drift typically act to constrain the overall pace of adaptive evolution. Our data suggest that here, positive selection in index cats followed by a narrow transmission bottleneck may have instead accelerated the fixation of S H655Y, a potentially beneficial SARS-CoV-2 variant. Overall, our study suggests species- and context-specific adaptations are likely to continue to emerge. This underscores the importance of continued genomic surveillance for new SARS-CoV-2 variants as well as heightened scrutiny for signatures of SARS-CoV-2 positive selection in humans and mammalian model systems.
Biofilms—communities of bacteria encased in a polymer-rich matrix—confer bacteria with the ability to persist in pathologic host contexts, such as the cystic fibrosis (CF) airways. How bacteria ...assemble polymers into biofilms is largely unknown. We find that the extracellular matrix produced by Pseudomonas aeruginosa self-assembles into a liquid crystal through entropic interactions between polymers and filamentous Pf bacteriophages, which are long, negatively charged filaments. This liquid crystalline structure enhances biofilm function by increasing adhesion and tolerance to desiccation and antibiotics. Pf bacteriophages are prevalent among P. aeruginosa clinical isolates and were detected in CF sputum. The addition of Pf bacteriophage to sputum polymers or serum was sufficient to drive their rapid assembly into viscous liquid crystals. Fd, a related bacteriophage of Escherichia coli, has similar biofilm-building capabilities. Targeting filamentous bacteriophage or the liquid crystalline organization of the biofilm matrix may represent antibacterial strategies.
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•Filamentous Pf bacteriophage are produced by Pseudomonas aeruginosa•Pf phage interact with host and microbial polymers to assemble higher order structures•Pf phage increase the viscosity of polymers in cystic fibrosis airway secretions•The Pf-induced liquid crystal biofilm matrix boosts tolerance to desiccation and antibiotics
Filamentous Pf bacteriophage are often highly transcribed in P. aeruginosa biofilms. Secor et al. demonstrate that filamentous Pf bacteriophage interact with host and microbial polymers to assemble higher order liquid crystal structures. The organization of the biofilm matrix into a liquid crystal enhances biofilm adhesion, desiccation survival, and antibiotic tolerance.
The manufacture of flaked stone artifacts represents a major milestone in the technology of the human lineage. Although the earliest production of primitive stone tools, predating the genus Homo and ...emphasizing percussive activities, has been reported at 3.3 million years ago (Ma) from Lomekwi, Kenya, the systematic production of sharp-edged stone tools is unknown before the 2.58–2.55 Ma Oldowan assemblages from Gona, Ethiopia. The organized production of Oldowan stone artifacts is part of a suite of characteristics that is often associated with the adaptive grade shift linked to the genus Homo. Recent discoveries from Ledi-Geraru (LG), Ethiopia, place the first occurrence of Homo ∼250 thousand years earlier than the Oldowan at Gona. Here, we describe a substantial assemblage of systematically flaked stone tools excavated in situ from a stratigraphically constrained context Bokol Dora 1, (BD 1) hereafter at LG bracketed between 2.61 and 2.58 Ma. Although perhaps more primitive in some respects, quantitative analysis suggests the BD 1 assemblage fits more closely with the variability previously described for the Oldowan than with the earlier Lomekwian or with stone tools produced by modern nonhuman primates. These differences suggest that hominin technology is distinctly different from generalized tool use that may be a shared feature of much of the primate lineage. The BD 1 assemblage, near the origin of our genus, provides a link between behavioral adaptations—in the form of flaked stone artifacts—and the biological evolution of our ancestors.
The management of advanced-stage renal cell carcinoma (RCC) has been transformed by the development of immune-checkpoint inhibitors (ICIs). Nonetheless, most patients do not derive durable clinical ...benefit from these agents. Importantly, unlike other immunotherapy-responsive solid tumours, most RCCs have only a moderate mutational burden, and paradoxically, high levels of tumour CD8
T cell infiltration are associated with a worse prognosis in patients with this disease. Building on the successes of antibodies targeting the PD-1 and CTLA4 immune checkpoints, multiple innovative immunotherapies are now in clinical development for the treatment of patients with RCC, including ICIs with novel targets, co-stimulatory pathway agonists, modified cytokines, metabolic pathway modulators, cell therapies and therapeutic vaccines. However, the successful development of such novel immune-based treatments and of immunotherapy-based combinations will require a disease-specific framework that incorporates a deep understanding of RCC immunobiology. In this Review, using the structure provided by the well-described cancer-immunity cycle, we outline the key steps required for a successful antitumour immune response in the context of RCC, and describe the development of promising new immunotherapies within the context of this framework. With this approach, we summarize and analyse the most encouraging targets of novel immune-based therapies within the RCC microenvironment, and review the landscape of emerging antigen-directed therapies for this disease.
Evidence is emerging that systemic inflammation after trauma drives structural and functional impairment of cardiomyocytes and leads to cardiac dysfunction, thus worsening the outcome of polytrauma ...patients. This study investigates the structural and molecular changes in heart tissue 4 h after multiple injuries with additional hemorrhagic shock using a clinically relevant rodent model of polytrauma. We determined mediators of systemic inflammation (keratinocyte chemoattractant, macrophage chemotactic protein 1), activated complement component C3a and cardiac troponin I in plasma and assessed histological specimen of the mouse heart via standard histomorphology and immunohistochemistry for cellular and subcellular damage and ongoing apoptosis. Further we investigated spatial and quantitative changes of connexin 43 by immunohistochemistry and western blotting. Our results show significantly increased plasma levels of both keratinocyte chemoattractant and cardiac troponin I 4 h after polytrauma and 2 h after induction of hypovolemia. Although we could not detect any morphological changes, immunohistochemical evaluation showed increased level of tissue high-mobility group box 1, which is both a damage-associated molecule and actively released as a danger response signal. Additionally, there was marked lateralization of the cardiac gap-junction protein connexin 43 following combined polytrauma and hemorrhagic shock. These results demonstrate a molecular manifestation of remote injury of cardiac muscle cells in the early phase after polytrauma and hemorrhagic shock with marked disruption of the cardiac gap junction. This disruption of an important component of the electrical conduction system of the heart may lead to arrhythmia and consequently to cardiac dysfunction.
Abstract
Since its 2015 update, MaizeGDB, the Maize Genetics and Genomics database, has expanded to support the sequenced genomes of many maize inbred lines in addition to the B73 reference genome ...assembly. Curation and development efforts have targeted high quality datasets and tools to support maize trait analysis, germplasm analysis, genetic studies, and breeding. MaizeGDB hosts a wide range of data including recent support of new data types including genome metadata, RNA-seq, proteomics, synteny, and large-scale diversity. To improve access and visualization of data types several new tools have been implemented to: access large-scale maize diversity data (SNPversity), download and compare gene expression data (qTeller), visualize pedigree data (Pedigree Viewer), link genes with phenotype images (MaizeDIG), and enable flexible user-specified queries to the MaizeGDB database (MaizeMine). MaizeGDB also continues to be the community hub for maize research, coordinating activities and providing technical support to the maize research community. Here we report the changes MaizeGDB has made within the last three years to keep pace with recent software and research advances, as well as the pan-genomic landscape that cheaper and better sequencing technologies have made possible. MaizeGDB is accessible online at https://www.maizegdb.org.
The emergence of divergent SARS-CoV-2 lineages has raised concern that novel variants eliciting immune escape or the ability to displace circulating lineages could emerge within individual hosts. ...Though growing evidence suggests that novel variants arise during prolonged infections, most infections are acute. Understanding how efficiently variants emerge and transmit among acutely-infected hosts is therefore critical for predicting the pace of long-term SARS-CoV-2 evolution. To characterize how within-host diversity is generated and propagated, we combine extensive laboratory and bioinformatic controls with metrics of within- and between-host diversity to 133 SARS-CoV-2 genomes from acutely-infected individuals. We find that within-host diversity is low and transmission bottlenecks are narrow, with very few viruses founding most infections. Within-host variants are rarely transmitted, even among individuals within the same household, and are rarely detected along phylogenetically linked infections in the broader community. These findings suggest that most variation generated within-host is lost during transmission.
Paradoxically, the pro-inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10 both activate STAT3, yet generate nearly opposing cellular responses. Here, we show that the temporal ...pattern of STAT3 activation codes for the specific cytokine response. A computational model of IL-6 and IL-10 signaling predicted that IL-6 stimulation results in transient activation of STAT3, with a rapid decline in phosphorylation and nuclear localization. In contrast, simulated IL-10 signaling resulted in sustained STAT3 activation. The predicted STAT3 patterns produced by each cytokine were confirmed experimentally in human dendritic cells. Time course microarray studies further showed that the dynamic genome-wide transcriptional responses were nearly identical at early time points following stimulation (when STAT3 is active in response to both IL-6 and IL-10) but divergent at later times (when STAT3 is active only in response to IL-10). Truncating STAT3 activation after IL-10 stimulation caused IL-10 to elicit an IL-6–like transcriptional and secretory response. That the duration of IL-10 receptor and STAT3 activation can direct distinct responses reveals a complex cellular information-coding mechanism that may be relevant to improving the prediction of the effects of drug candidates using this mechanism.
Background: Interleukin-6 and interleukin-10 both activate the same signaling mediator, STAT3, yet generate nearly opposing responses.
Results: Interleukin-6 and interleukin-10 signaling lead to different durations of STAT3 activation and consequently distinct responses.
Conclusion: The duration of receptor and STAT3 activation determines the specific cytokine response.
Significance: This work reveals a signaling coding mechanism that relieves a cellular information bottleneck.
Advances in molecular biology, microfluidics and bioinformatics have empowered the study of thousands or even millions of individual cells from malignant tumours at the single-cell level of ...resolution. This high-dimensional, multi-faceted characterization of the genomic, transcriptomic, epigenomic and proteomic features of the tumour and/or the associated immune and stromal cells enables the dissection of tumour heterogeneity, the complex interactions between tumour cells and their microenvironment, and the details of the evolutionary trajectory of each tumour. Single-cell transcriptomics, the ability to track individual T cell clones through paired sequencing of the T cell receptor genes and high-dimensional single-cell spatial analysis are all areas of particular relevance to immuno-oncology. Multidimensional biomarker signatures will increasingly be crucial to guiding clinical decision-making in each patient with cancer. High-dimensional single-cell technologies are likely to provide the resolution and richness of data required to generate such clinically relevant signatures in immuno-oncology. In this Perspective, we describe advances made using transformative single-cell analysis technologies, especially in relation to clinical response and resistance to immunotherapy, and discuss the growing utility of single-cell approaches for answering important research questions.
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