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New lipid nanoparticle design improves precision of mRNA vaccine delivery

Penn Engineers have redesigned a key component of lipid nanoparticles (LNPs), the delivery vehicles behind mRNA vaccines, to steer the particles toward lymph nodes while reducing off-target delivery to the liver. The advance could make mRNA vaccines more efficient, potentially achieving strong immune protection at lower doses.

“The more particles that reach the lymph nodes, the fewer particles each dose needs,” says Michael J. Mitchell, Associate Professor in Bioengineering (BE) and senior author of a new study in Journal of the American Chemical Society that describes how the researchers modified the ionizable lipid, a key LNP ingredient that helps mRNA enter cells.

In animal models, the new “aroLNPs,” whose name refers to the addition of a chemical structure called an “aromatic ring” to the ionizable lipid, delivered at least 10-fold less mRNA to the liver compared to the LNP formulation in the Moderna COVID-19 vaccine, while maintaining similar levels of lymph-node delivery.

A spinel crystal structure exhibits unusual, pressure-induced superconductivity

Superconductors are materials that conduct electricity with an electrical resistance of zero. Superconductivity is generally observed when materials are cooled down to extremely low temperatures. In some cases, however, like in so-called high-temperature superconductors, this property emerges at higher temperatures.

Researchers at the Center for High Pressure Science & Technology Advanced Research, Chinese Academy of Sciences and other institutes recently observed pressure-induced superconductivity in CuIr2S4, a spinel that typically becomes an insulator when cooled below about 230 K, meaning that electricity can no longer flow through it.

Their paper, published in Physical Review Letters, shows that progressively tuning this material’s crystal structure using pressure prompts the emergence of two distinct superconducting phases, dubbed SC-I and SC-II, with a maximum transition temperature of 18.2 K.

Nonsense-mediated mRNA decay orchestrates neuronal migration and cortical lamination while modulating Reelin and ciliary gene regulatory networks

Lin et al. show that nonsense-mediated mRNA decay (NMD) is essential for neuronal migration and cortical lamination. UPF2 regulates expression of Reelin signaling and microtubule genes via Ino80 and represses ciliary gene Foxj1 to assure normal migration, revealing a key regulated RNA decay mechanism in brain development.

RCC1 depletion drives protein transport defects and rupture in micronuclei

Spotlight: Hiba Baaziz and Daniela Cimini (Virginia Tech) discuss recent work from Zych et al. (https://hubs.la/Q0485YJy0), showing that low RCC1 levels impair protein export in micronuclei, causing overgrowth and rupture. https://hubs.la/Q0485R1g0

Micronuclei (MN), a hallmark of chromosome instability, frequently rupture, leading to protumorigenic consequences. MN rupture requires nuclear lamina defects, yet their underlying causes remain unclear. Here, we demonstrate that MN lamina gaps are linked to excessive MN growth resulting from impaired protein export. This export defect arises from reduced levels of the transport protein RCC1 in MN. Overexpressing RCC1 increases protein export and protects MN from rupture. Differences in RCC1 levels linked to chromatin state also explain why high euchromatin content increases the stability of small MN. Additional RCC1 loss in euchromatic MN results in impaired protein import. For these MN, increasing RCC1, directly or through increasing histone methylation, accelerates rupture. Our findings define a new model of MN rupture, where defects in protein export drives continuous MN growth causing nuclear lamina gaps that predispose MN to membrane rupture and where chromatin-specific features can alter rupture of small MN by further impairing nuclear transport.

Cortically-mediated muscle responses to balance perturbations increase with perturbation magnitude in older adults with and without Parkinson’s disease

New in eNeuro from Boebinger et al: Compared to young adults, older people with and without Parkinson’s disease have larger brain responses and muscle signals that hinder their balance recovery ability.

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We lack a mechanistic understanding of how cortical contributions to balance control change in aging and Parkinson’s disease (PD). Balance is governed by brainstem circuits, with higher-order centers like the cortex or basal ganglia becoming engaged as challenge increases or balance health declines. We previously showed that parallel sensorimotor feedback loops engaging brainstem and cortical circuitry contribute to muscle activity for balance control in young adults (YAs). Here, we analyze data from male and female older adults (OAs) with and without PD, decomposing perturbation-evoked tibialis anterior and medial gastrocnemius muscle activity into hierarchical components based on latencies of feedback control loops. We found that balance-correcting muscle activity followed a stereotypical waveform of long-latency responses (LLRs): LLR1 began ∼120ms and LLR2 occurred ∼210ms, respectively, consistent with subcortical and cortical feedback latencies. Both LLRs increased with balance challenge and could be explained by center of mass kinematics. Perturbation-evoked antagonist muscle activity consisted of destabilizing and stabilizing components categorized based on whether they resist the kinematic errors that drive their activation. The destabilizing component occurred at ∼180ms and was negatively correlated with clinical measures of balance ability in the OA but not PD group. Exploratory comparisons showed OA and PD groups had larger LLR2s at lower challenge levels than YAs, consistent with greater cortical engagement during balance with aging. These findings demonstrate that a neuromechanical model can decompose perturbation-evoked muscle activity into hierarchical components related to clinical balance ability and identify mechanistic changes in the neural control of balance without direct brain measurements.

Significance Statement We show that reactive balance recovery in older adults with and without Parkinson’s disease can be decomposed into distinct components that reflect hierarchical brainstem, cortical, and basal ganglia feedback loops. Using a neuromechanical model of delayed task-level feedback control, we link these components to perturbation difficulty and clinical balance ability in older adults. This framework connects specific features of agonist and antagonist muscle activity to underlying neural control processes without requiring direct brain recordings. Our findings provide a mechanistic basis for age-and disease-related changes in balance control that can inform individualized assessment and future rehabilitation strategies.

Novel Octameric Resistosome and Immune Mechanism in Wheat

After activation, these NLRs form multi-protein complexes—called resistosomes—that carry out the immune response. Studies have shown that certain resistosomes are pentameric (e.g., ZAR1 and Sr35), whereas others are hexameric (e.g., NRC2 and NRC4). These complexes initiate immune responses by triggering calcium (Ca2+) influx into the cytoplasm. However, the G10 type of CC-NLR (CCG10-NLR) immune receptors constitutes a unique clade among CC-NLRs and its activation mechanism has remained poorly understood.

Now, in a study published in Cell, a research team has revealed a novel octameric resistosome formed by an activated wheat CCG10-NLR immune receptor, which induces Ca2+ influx and immune responses through a unique channel architecture.

The researchers identified the Wheat Autoimmunity 3 (WAI3) gene, which encodes a CCG10-NLR protein. Subsequent analysis revealed that a gain-of-function (GOF) single amino acid mutation in the leucine-rich repeat (LRR) domain leads to autoactivation, providing an opportunity to study the activation mechanism of CCG10-NLR.

After expressing the WAI3 proteins in Nicotiana benthamiana, the researchers used cryo-electron microscopy to resolve the octameric structure of the activated WAI3 resistosome—marking the first time an octameric resistosome has been identified in plants.

The CCG10-NLR WAI3 resistosome differs from known resistosomes both in the number of monomers and in its conformation, representing a novel assembly mechanism for plant NLR resistosomes.

Using Nicotiana benthamiana and animal cell expression systems, the researchers also demonstrated that the WAI3 resistosome induces Ca2+ influx in plants but is not effective in animal cells. ScienceMission sciencenewshighlights.

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