Ongoing evolution of SARS-CoV-2 drives escape from mRNA vaccine-induced humoral immunity.

With the onset of the COVID-19 pandemic 4 years ago, viral sequencing continues to document numerous individual mutations in the viral spike protein across many variants. To determine the ability of vaccine-mediated humoral immunity to combat continued SARS-CoV-2 evolution, we construct a comprehensive panel of pseudoviruses harboring each individual mutation spanning 4 years of the pandemic to understand the fitness cost and resistance benefits of each. These efforts identify numerous mutations that escape from vaccine-induced humoral immunity.

Discovery of 6-Fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}--methylpyridine-2-carboxamide (AZD9574): A CNS-Penetrant, PARP1-Selective Inhibitor.

PARP inhibitors have attracted considerable interest in drug discovery due to the clinical success of first-generation agents such as olaparib, niraparib, rucaparib, and talazoparib. Their success lies in their ability to trap PARP to DNA; however, first-generation PARP inhibitors were not strictly optimized for trapping nor for selectivity among the PARP enzyme family. Previously we described the discovery of the second-generation PARP inhibitor AZD5305, a selective PARP1-DNA trapper.

Fluid mediated communication among flexible micro-posts in chemically reactive solutions.

Communication in biological systems typically involves enzymatic reactions that occur within fluids confined between the soft, elastic walls of bio-channels and chambers. Through the inherent transformation of chemical to mechanical energy, the fluids can be driven to flow within the confined domains. Through fluid-structure interactions, the confining walls in turn are deformed by and affect this fluid flow.

QuickFit: A High-Throughput RT-qPCR-Based Assay to Quantify Viral Growth and Fitness In Vitro.

Quantifying viral growth rates is key to understanding evolutionary dynamics and the potential for mutants to escape antiviral drugs. Defining evolutionary escape paths and their impact on viral fitness allows for the development of drugs that are resistant to escape. In the case of HIV, combination antiretroviral therapy can successfully prevent or treat infection, but it relies on strict adherence to prevent escape.

Programming Fluid Motion Using Multi-Enzyme Micropump Systems.

In the presence of appropriate substrates, surface-anchored enzymes can act as pumps and propel fluid through microchambers. Understanding the dynamic interplay between catalytic reactions and fluid flow is vital to enhancing the accuracy and utility of flow technology. Through a combination of experimental observations and numerical modeling, we show that coupled enzyme pumps can exhibit flow enhancement, flow suppression, and changes in the directionality (reversal) of the fluid motion.

The influence of temperament and perinatal factors on language development: a longitudinal study.

Early language development is characterized by large individual variation. Several factors were proposed to contribute to individual pathways of language acquisition in infancy and childhood. One of the biologically based explaining factors is temperament, however, the exact contributions and the timing of the effects merits further research.

HIV broadly neutralizing antibody escapability drives the therapeutic efficacy of vectored immunotherapy.

Broadly neutralizing antibodies (bNAbs) have shown great promise for prevention and treatment of HIV infection. Breadth of bNAb neutralization, measured across panels of diverse viral isolates, is often used as a predictor of clinical potential. However, recent prevention studies demonstrate that the clinical efficacy of a broad and potent bNAb (VRC01) is undermined by neutralization resistance of circulating strains.

Uplift of the Tibetan Plateau driven by mantle delamination from the overriding plate.

The geodynamic evolution of the Tibetan Plateau remains highly debated. Any model of its evolution must explain the plateau's growth as constrained by palaeo-altitude studies, the spatio-temporal distribution of magmatic activity, and the lithospheric mantle removal inferred from seismic velocity anomalies in the underlying mantle. Several conflicting models have been proposed, but none of these explains the first-order topographic, magmatic and seismic features self-consistently.

Durability of immunity and clinical protection in nursing home residents following bivalent SARS-CoV-2 vaccination.

Background: Bivalent SARS-CoV-2 vaccines were developed to counter increasing susceptibility to emerging SARS-CoV-2 variants. We evaluated the durability of immunity and protection following first bivalent vaccination among nursing home residents.

Methods: We evaluated anti-spike and neutralization titers from blood in 653 community nursing home residents before and after each monovalent booster, and a bivalent vaccine.

Reactive spinal glia convert 2-AG to prostaglandins to drive aberrant astroglial calcium signaling.

The endogenous cannabinoid 2-arachidonoylglycerol (2-AG) influences neurotransmission in the central nervous system mainly by activating type 1 cannabinoid receptor (CB1). Following its release, 2-AG is broken down by hydrolases to yield arachidonic acid, which may subsequently be metabolized by cyclooxygenase-2 (COX-2). COX-2 converts arachidonic acid and also 2-AG into prostanoids, well-known inflammatory and pro-nociceptive mediators.

Broad immunogenicity to prior SARS-CoV-2 strains and JN.1 variant elicited by XBB.1.5 vaccination in nursing home residents.

Background: SARS-CoV-2 vaccination has reduced hospitalization and mortality for nursing home residents (NHRs). However, emerging variants coupled with waning immunity, immunosenescence, and variability of vaccine efficacy undermine vaccine effectiveness. We therefore need to update our understanding of the immunogenicity of the most recent XBB.

Achieving controllable and reversible snap-through in pre-strained strips of liquid crystalline elastomers.

Deformable, elastic materials that buckle in response to external stimuli can display "snap-through", which involves a transition between different, stable buckled states. Snap-through produces a quick release of stored potential energy, and thus can provide fast actuation for soft robots and other flexible devices. Liquid crystalline elastomers (LCEs) exposed to light undergo a phase transition and a concomitant mechanical deformation, allowing control of snap-through for rapid, large amplitude actuation.

Ongoing evolution of SARS-CoV-2 drives escape from mRNA vaccine-induced humoral immunity.

Since the COVID-19 pandemic began in 2020, viral sequencing has documented 131 individual mutations in the viral spike protein across 48 named variants. To determine the ability of vaccine-mediated humoral immunity to keep pace with continued SARS-CoV-2 evolution, we assessed the neutralization potency of sera from 76 vaccine recipients collected after 2 to 6 immunizations against a comprehensive panel of mutations observed during the pandemic. Remarkably, while many individual mutations that emerged between 2020 and 2022 exhibit escape from sera following primary vaccination, few escape boosted sera.

Immune Signatures of SARS-CoV-2 Infection Resolution in Human Lung Tissues.

While human autopsy samples have provided insights into pulmonary immune mechanisms associated with severe viral respiratory diseases, the mechanisms that contribute to a clinically favorable resolution of viral respiratory infections remain unclear due to the lack of proper experimental systems. Using mice co-engrafted with a genetically matched human immune system and fetal lung xenograft (fLX), we mapped the immunological events defining successful resolution of SARS-CoV-2 infection in human lung tissues. Viral infection is rapidly cleared from fLX following a peak of viral replication, histopathological manifestations of lung disease and loss of AT2 program, as reported in human COVID-19 patients.

mRNA-based monkeypox virus vaccine prevents disease in non-human primates.

The mpox outbreak in 2022 launched a vaccination campaign employing an existing vaccine with moderate protection, highlighting the lack of scalable Orthopoxvirus vaccines with optimal protection. In this issue of Cell, Zuiani et al. report pre-clinical findings of an mRNA-based mpox vaccine, paving the way for Phase I/II clinical trials.

Integrating chemistry, fluid flow, and mechanics to drive spontaneous formation of three-dimensional (3D) patterns in anchored microstructures.

Enzymatic reactions in solution drive the convection of confined fluids throughout the enclosing chambers and thereby couple the processes of reaction and convection. In these systems, the energy released from the chemical reactions generates a force, which propels the fluids' spontaneous motion. Here, we use theoretical and computational modeling to determine how reaction-convection can be harnessed to tailor and control the dynamic behavior of soft matter immersed in solution.

Enhancing antibody responses by multivalent antigen display on thymus-independent DNA origami scaffolds.

Protein-based virus-like particles (P-VLPs) are commonly used to spatially organize antigens and enhance humoral immunity through multivalent antigen display. However, P-VLPs are thymus-dependent antigens that are themselves immunogenic and can induce B cell responses that may neutralize the platform. Here, we investigate thymus-independent DNA origami as an alternative material for multivalent antigen display using the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, the primary target of neutralizing antibody responses.

Heterologous Sarbecovirus Receptor Binding Domains as Scaffolds for SARS-CoV-2 Receptor Binding Motif Presentation.

Structure-guided rational immunogen design can generate optimized immunogens that elicit a desired humoral response. Design strategies often center on targeting conserved sites on viral glycoproteins that will ultimately confer potent neutralization. For SARS-CoV-2 (SARS-2), the surface-exposed spike glycoprotein includes a broadly conserved portion, the receptor binding motif (RBM), that is required to engage the host cellular receptor, ACE2.

Self-Propelling Macroscale Sheets Powered by Enzyme Pumps.

Nanoscale enzymes anchored to surfaces act as chemical pumps by converting chemical energy released from enzymatic reactions into spontaneous fluid flow that propels entrained nano- and microparticles. Enzymatic pumps are biocompatible, highly selective, and display unique substrate specificity. Utilizing these pumps to trigger self-propelled motion on the macroscale has, however, constituted a significant challenge and thus prevented their adaptation in macroscopic fluidic devices and soft robotics.

Interlinking spatial dimensions and kinetic processes in dissipative materials to create synthetic systems with lifelike functionality.

Biological systems spontaneously convert energy input into the actions necessary to survive. Motivated by the efficacy of these processes, researchers aim to forge materials systems that exhibit the self-sustained and autonomous functionality found in nature. Success in this effort will require synthetic analogues of the following: a metabolism to generate energy, a vasculature to transport energy and materials, a nervous system to transmit 'commands', a musculoskeletal system to translate commands into physical action, regulatory networks to monitor the entire enterprise, and a mechanism to convert 'nutrients' into growing materials.

Biomimetic growth in polymer gels.

By modeling gels growing in confined environments, we uncover a biomimetic feedback mechanism between the evolving gel and confining walls that enables significant control over the properties of the grown gel. Our new model describes the monomer adsorption, polymerization and cross-linking involved in forming new networks and the resultant morphology and mechanical behavior of the grown gel. Confined between two hard walls, a thin, flat "parent" gel undergoes buckling; removal of the walls returns the gel to the flat structure.