Browse Articles

The carbon nanotube gatemon qubit

14-3-3 binding maintains the Parkinson’s associated kinase LRRK2 in an inactive state

Abstract Leucine-rich repeat kinase 2 (LRRK2) is an essential regulator in cellular signaling and a major contributor to Parkinson’s disease (PD) pathogenesis. 14-3-3 proteins are critical modulators of LRRK2 activity, yet the structural basis of their interaction has remained unclear. Here, we present the cryo-electron microscopy structure of the LRRK2:14-3-3 2 autoinhibitory complex, revealing how a 14-3-3 dimer stabilizes an autoinhibited LRRK2 monomer through dual-site anchoring. The dimer engages both phosphorylated S910/S935 sites and the COR-A/B subdomains within the Roc-COR GTPase region. This spatial configuration constrains LRR domain mobility, reinforces the inactive conformation, and likely impedes LRRK2 dimerization and oligomer formation. Structure-guided mutagenesis studies show that PD-associated mutations at the COR:14-3-3 2 interface and within the GTPase domain weaken 14-3-3 binding and impair its inhibitory effect on LRRK2 kinase activity. Furthermore, we demonstrate that type I LRRK2 kinase inhibitor, which stabilizes the kinase domain in its active conformation, reduces 14-3-3 binding and promotes dephosphorylation at pS910 and pS935. Together, these findings provide a structural basis for understanding how LRRK2 is maintained in an inactive state, elucidate the mechanistic role of 14-3-3 in LRRK2 regulation, inform the interpretation of PD biomarkers, and suggest therapeutic strategies aimed at enhancing LRRK2-14-3-3 interactions to treat PD and related disorders.

Functional avidity of anti-B7H3 CAR-T constructs predicts antigen density thresholds for triggering effector function

Ultradian rhythms of CRH ^PVN neuron activity, behavior, and stress hormone secretion

The stress axis is always active, even in the absence of any threat. This manifests as hourly pulses of corticosteroid stress hormone secretion over the day. Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (CRH PVN ) control both the neuroendocrine stress axis as well as stress-associated behaviors. However, it is currently unclear how the resting activity of these neurons is coordinated with both spontaneous behavior and ultradian pulses of corticosteroid secretion. To investigate this, we performed fiber photometry recordings of CRH PVN neuron activity in Crh-Ires-Cre mice and a newly generated line of Crh-Ires-Cre rats. In both mice and rats, CRH PVN neurons displayed an ultradian rhythm of activity with reoccurring upstates of activity approximately once per hour over the 24-h day. Upstates in activity were coordinated with increases in animal activity/arousal. Chemogenetic activation of CRH PVN neurons was also sufficient to induce behavioral arousal. In rats, increases in CRH neural activity preceded some pulses of corticosteroid secretion but not others. Thus, while CRH PVN neurons display an ultradian rhythm of activity over the 24-h day that is coordinated with behavioral arousal, the relationship between CRH PVN activity and pulses of corticosteroid secretion is not one-to-one.

Tiantan vaccinia virus-based vaccine with promising safety provides sustained protection against mpox in non-human primates

Absence of phonon softening across a charge density wave transition due to quantum fluctuations

Kagome metals have emerged as a frontier in condensed matter physics due to their potential to host exotic quantum states. Among these, CsV 3 Sb 5 has attracted significant attention for the unusual coexistence of charge density wave (CDW) order and unconventional superconductivity, presenting an ideal system for exploring the emergent phenomena from the interplay of phonons, electronic fluctuations, and topological effects. The nature of CDW formation in CsV 3 Sb 5 is unconventional and has sparked considerable debate. In this study, we examine the origin of the CDW state via ab initio finite-temperature simulations of the lattice dynamics. Through a comparative study of CsV 3 Sb 5 and 2H-NbSe 2 , we demonstrate that the experimental absence of phonon softening—a hallmark of conventional CDW transition—in CsV 3 Sb 5 along with the presence of a weakly first-order transition, can be attributed to quantum zero-point atomic motion. This zero-point motion smears the free energy landscape of CDW, effectively stabilizing the pristine structure even below the CDW transition temperature. We argue that this surprising behavior could cause coexistence of pristine and CDW structures across the transition and lead to a weak first-order transition. Our predicted lattice dynamical behavior is supported by coherent phonon spectroscopy in single-crystalline CsV 3 Sb 5 . Our results provide crucial insights into the formation mechanism of CDW materials that exhibit little to no phonon softening, including cuprates, and highlight the surprising role of quantum effects in emergent properties of relatively heavy-element materials like CsV 3 Sb 5 .

Demonstration of a tunable non-Hermitian nonlinear microwave dimer

Revisiting the Eoarchean Akilia quartz-pyroxene rock with potassium isotopes: Implications for early-ocean sedimentation

The Eoarchean quartz-pyroxene rock from Akilia Island in Greenland has been proposed as one of Earth’s oldest banded iron formations (BIF) and a potential host for the earliest biosignatures. However, the origin of its protolith, whether it metamorphosed from an igneous or sedimentary precursor, remains debated. Here, we revisit this longstanding Akilia controversy using potassium isotope analyses, comparing Akilia samples with BIFs and black shales spanning the Eoarchean to Mesoproterozoic. Our results demonstrate that BIFs and black shales show systematic potassium isotope variations correlated with their potassium contents. Potassium-poor BIF layers display heavier isotopic compositions close to seawater values, whereas clay-rich layers exhibit elevated potassium contents and lighter isotopic signatures. The Akilia quartz-pyroxene rock was initially characterized by low potassium concentrations and heavy potassium isotopic compositions consistent with chemical sediments deposited from ancient seawater. It was subsequently modified by metasomatic fluids derived from nearby metamorphosed igneous rocks. These findings support a sedimentary origin for the Akilia quartz-pyroxene rock. Furthermore, our study provides an isotopic framework for interpreting ancient oceanic environments and offers insights into the potassium cycling and habitability of early Earth.

FGF receptor modulates planar cell polarity in the neuroectoderm via Vangl2 tyrosine phosphorylation

Casimir self-assembly: A platform for measuring nanoscale surface interactions in liquids

Self-assembly (SA) plays a pivotal role in nanotechnology, offering cost-effective methods for bottom–up fabrication and providing versatile model systems for investigating fundamental interactions in various bioinspired systems. However, current methods for investigating and quantifying the dynamics of SA systems are limited in their applicability to planar interfaces, particularly in liquid environments. These methods typically rely on analyzing the collective behavior of particle suspensions rather than directly probing the specific interactions between individual particles. Here, we introduce Casimir self-assembly (CaSA) as a platform, integrating colloidal science, nanophotonics, and fluctuational electrodynamics to study long-range interactions and stability in planar SA systems. Using thermal fluctuations as a probe and visible-range Fabry–Pérot resonances as an optical readout, we demonstrate that CaSA enables a direct in situ study of the Casimir–Lifshitz electrostatic interaction. This approach allows us to map stability regimes of colloidal materials by varying ionic strength and identifying conditions for stable assembly and aggregation limits, and moreover is used to measure the surface charge density of an individual colloidal object down to fractions of an electron charge per square nanometer. Our platform overcomes the limitations of current methods, providing an experimental tool for exploring SA dynamics in situ and expanding the understanding of suspension stability in liquids at the single-particle level. With potential for future applications, CaSA is scalable for studying interfacial forces and is adaptable to multivalent electrolytes and biosensing.

Asymmetric synthesis of β-amino acid derivatives by stereocontrolled C(sp3)-C(sp2) cross-electrophile coupling via radical 1,2-nitrogen migration

A bacteria-based search for drugs against avian and swine flu yields a potent and resistance-resilient channel blocker

Influenza represents a significant threat with seasonal epidemics that can transition to global pandemics, and cross-species infection presenting a continuous challenge. While vaccines and several antiviral drugs are available, constant genetic changes vitiate these prevention and treatment options. Consequently, we decided to search for inhibitors against one of the virus’s validated drug targets, its M2 channel that is blocked by aminoadamantanes. Regrettably, widespread mutations in M2 abolish the antiflu activity of said blockers. Therefore, we devised bacteria-based genetic assays that can screen for drugs against aminoadamantane-sensitive and resistant M2 channels and map the resistance potential of any identifiable blocker. Subsequent in cellulo testing and structure–activity relationship studies yielded a synergistic combination of two compounds, Theobromine and Arainosine, that exhibited remarkable antiviral activity by directly inhibiting the virus’s channel. The drug duo was potent against H1N1 pandemic swine flu, H5N1 pandemic avian flu, and aminoadamantane-resistant and sensitive strains alike, exhibiting activity that surpassed oseltamivir, the leading antiflu drug on the market. When this drug duo was tested in an animal model, it once more outperformed oseltamivir, considerably reducing disease symptoms and viral RNA progeny. Importantly, harnessing the bacterial genetic selection, we could demonstrate that the drug duo’s potential for eliciting drug resistance is significantly smaller and molecularly distinct from that of aminoadamantanes. In conclusion, the outcome of this study represents a new potential treatment option for influenza alongside an approach that is sufficiently general and readily applicable to other viral targets.

Sorting polymerization in a bichannel metal-organic framework

Abstract Accomplishing multiple synthetic tasks in parallel, including substrate capture, separation, and reaction, along with controlled arrangement of product, all in one system has remained a long-standing challenge in synthetic chemistry. Here, we report a sorting polymerization strategy that harnesses the multifunctional nature of a bichannel metal-organic framework (MOF). The MOF, [Cu(5-methylisophthalate)] n , featuring two distinct one-dimensional channels arranged in a single Kagome lattice, allows selective adsorption of monomers to different sites based on their polarity and size. This enables the sorting of different vinyl monomers and their in-situ parallel homo-polymerization within the respective channels. The process produces alternating single-chain arrays of homopolymers in a single step, a configuration unattainable by conventional approaches. Additionally, the introduction of inter-chain cross-linking allows for the isolation of the binary polymer array by removing the MOF template. This work highlights the potential of MOFs as versatile reaction platforms for the synthesis of complex, well-ordered molecular architectures from chaotic mixtures of raw materials.

A minimal model of panimmunity maintenance by horizontal gene transfer in the ecological dynamics of bacteria and phages

Bacteria and phages have been in an ongoing arms race for billions of years. To resist phages bacteria have evolved numerous defense systems, which nevertheless are still overcome by counterdefense mechanisms of specific phages. These defense/counterdefense systems are a major element of microbial genetic diversity and have been demonstrated to propagate between strains by horizontal gene transfer (HGT). It has been proposed that the totality of defense systems found in microbial communities collectively form a distributed “pan-immune” system with individual elements moving between strains via ubiquitous HGT. Here, we formulate a Lotka–Volterra type model of a bacteria/phage community interacting via a combinatorial variety of defense/counterdefense systems and show that HGT enables stable maintenance of diverse defense/counterdefense genes in the microbial pan-genome even when individual microbial strains inevitably undergo extinction. This stability requires the HGT rate to be sufficiently high to ensure that some descendant of a “dying” strain survives, thanks to the immunity acquired through HGT from the community at large, thus establishing a new strain. This mechanism of persistence for the pan-immune gene pool is fundamentally similar to the “island migration” model of ecological diversity, with genes moving between genomes instead of species migrating between islands.

Microhaplotype deep sequencing assays to capture Plasmodium vivax infection lineages

Abstract Plasmodium vivax elimination is challenged by dormant liver stages (hypnozoites) that can reactivate months after initial infection resulting in relapses. Relapsing infections confound antimalarial clinical efficacy trials due to the inability to distinguish between recurrences arising from blood-stage treatment failure (recrudescence), reinfection or relapse. Genetic relatedness of paired parasite isolates, measured by identity-by-descent (IBD), can provide important information on whether individuals have had single or multiple mosquito inoculations, thus informing on recurrence origin. We developed a high-throughput amplicon sequencing assay comprising 93 multi-SNP (microhaplotype) markers to determine IBD between P. vivax clinical isolates. The assay was evaluated in 745 global infections, including 128 infection pairs from a randomized controlled trial (RCT) (ClinicalTrials.gov NCT01680406). Simulations demonstrate low error in pairwise IBD estimation at the panel (RMSE < 0.12) and IBD-based networks illustrate strong clustering by geography. IBD analysis in the RCT demonstrates a lower frequency of suspected relapses or recrudescence in patients treated with primaquine compared to those without primaquine; the impact is greater when paired with chloroquine than with artemether-lumefantrine. Our results demonstrate the potential to derive new information on P. vivax treatment and transmission using IBD generated by amplicon sequencing data that can be further improved with time-to-event models.

Orexin effect on physiological pulsations of the human brain

Sleep promotes cerebrospinal fluid (CSF) to interstitial fluid (ISF) exchange in the brain facilitated by brain pulsations. Especially brain vasomotion and arterial pulsations modulated by noradrenaline drive the intracranial fluid dynamics. Narcolepsy type 1 (NT1) entails lessened orexinergic output to wake-promoting systems including the noradrenergic locus coeruleus. As arousal state and noradrenergic signaling affect CSF-ISF clearance, we chose patients with NT1 as a human orexin-targeted model of sleep-related pathology bridging the gap between healthy awake and sleep with respect to CSF flow pulsations. We also investigated the sensitivity of magnetic resonance encephalography to detect flow with a phantom model and sought to replicate earlier pulsation findings in sleep. In this case–control study, we used fast functional MRI to map brain pulsations in groups of healthy sleeping controls (n = 13), healthy awake controls (n = 79), and awake NT1 (n = 21) patients. We measured the very low frequency (0.008 to 0.1) and cardiorespiratory frequencies and calculated in each frequency band the coefficient of variation, spectral power, and full band spectral entropy to obtain brain pulsation maps. We uncovered a brain pulsation profile from healthy waking to sleep to a sleep-related pathology NT1 prominently affected in the vascular-related vasomotor and brain arterial pulsations. Our results established how drivers of brain hydrodynamics are affected by a specific loss of key neurotransmitter governing arousal compared to healthy sleep. We also showed with a phantom model that MREG is sensitive to flow-related signal changes and solidified evidence of brain pulsations in the healthy states of sleep and wakefulness.

Origins of lithium inventory reversibility with an alloying functional layer in anode-free lithium metal batteries

Abstract Alloying coatings are widely accepted to boost the reversibility of lithium inventory in anode-free cell configurations. While diminished capacity losses are evident from electrochemical data, their impact beyond decreasing the nucleation overpotential remains elusive. Herein, in situ 7Li NMR spectroscopy is applied to differentiate capacity losses in pouch cells with representative electrochemical behavior. Next to an accelerated interphase formation, the alloying layer diminishes the formation of dead lithium deposits notably. In contrast to previous reports, the capacity lost to electronically insulated lithium deposits is not related to their tortuosity and surface area. Though alloy formation reduces the nucleation overpotential with coated copper, deconvolution of 7Li NMR spectra as well as scanning electron microscopy evidence predominantly compact lithium deposits in the initial cycles and a similar increase of high-surface area morphologies with bare and coated copper negative electrodes. Instead of improved lithium deposit morphology, the enhanced reversibility with the alloying layer is bestowed by improved interfacial transport towards the end of lithium dissolution. These insights add to the mechanistic understanding of dead lithium formation, exploiting impedance spectroscopy in the discharged state as a valuable tool to assess the ability to dissolve lithium metal from a given substrate.

SCoTCH-seq reveals that 5-hydroxymethylcytosine encodes regulatory information across DNA strands

In mammalian genomes, cytosine modifications form a layer of regulatory information alongside the genetic code. Decoding this information is crucial to our understanding of biology and disease. Established sequencing methods cannot simultaneously resolve cytosine’s three most common forms—cytosine (C), 5-methylcytosine (mC), and 5-hydroxymethylcytosine (hmC)—across both strands of the DNA double helix. Thus, how epigenetic information is distributed in DNA remains unclear. Here, we present S trand- Co upled T andem C ytosine H ydroxymethylation and methylation sequencing (SCoTCH-seq): an accurate and quantitative, base-resolution approach to sequence genomes, together with mC and hmC, in both strands of the same DNA fragment. We show that different forms of cytosine combine across the double helix at CpG sites to form discrete information states in the mouse epigenome. These CpG states have distinct genomic distributions—including at promoters, enhancers, and gene bodies—and have different relationships with transcription. We show that while all possible forms of hydroxymethylation occur, hmC is predominantly asymmetric and that different forms of asymmetric hmC are not equivalent. Our findings demonstrate that 5-hydroxymethylcytosine combines with different cytosine variants across the DNA double helix to form distinct states of regulatory information.

Inhibition mediated by group III metabotropic glutamate receptors regulates habenula activity and defensive behaviors

Abstract Inhibition plays a key role in brain functions. While typically linked to GABA, inhibition can be induced by glutamate via metabotropic glutamate receptors (mGluRs). Here, we investigated the role of mGluR-mediated inhibition in the habenula, a conserved, glutamatergic brain hub involved in adaptive and defensive behaviors. We found that zebrafish and mice habenula express group III mGluRs. We showed that group III mGluRs regulate membrane potential and calcium activity of zebrafish habenula. Perturbing group III mGluRs increased sensory-evoked excitation and reduced selectivity. We identified inhibition as the primary communication mode among habenula neurons. Blocking group III mGluRs reduces this inhibition and increases neural synchrony. Consistently, we demonstrated that multisensory integration in the habenula relies on competitive suppression, that partly depends on group III mGluRs. Genetic and pharmacological perturbation of group III mGluRs amplified neural responses and defensive behaviors. Our findings highlight an essential role for mGluR-driven inhibition in encoding information and regulating defensive behaviors.

Foraging ants as liquid brains: Movement heterogeneity shapes collective efficiency

Liquid brains conceptualize living systems that operate without central control, where collective outcomes emerge from local and dynamic interactions. This concept extends beyond ants and other social insects to include immune systems, slime molds, and microbiomes. In such systems, connectivity scales with population density, facilitating more efficient information transfer as group size increases. However, in sparse conditions, where fewer individuals interact, movement likely plays a crucial role in shaping connectivity, ensuring optimal collective efficiency. We tested this hypothesis during the foraging process of Aphaenogaster senilis , an ant species that does not primarily rely on chemical communication. We empirically measured ant movement behavior and characterized their foraging dynamics across large spatiotemporal scales, closely reflecting the species’ natural ecology. Integrating observed movement heterogeneity into a neuronal-like model, we quantitatively replicated ants foraging efficiency and spatiotemporal dynamics. Our results reveal that a simple feedback mechanism, mediated by local interactions, governs the foraging patterns of A. senilis . Such feedback is modulated by adjusting the proportion of two coexisting movement behaviors: recruits, which facilitated information transfer and food exploitation by aggregating closely to the nest and the food patches, and scouts, which could bypass this feedback and discover alternative food sources. Therefore, distinct movement patterns contributed differently to optimizing each phase of the foraging process, proving an adaptive mechanism to balance exploration and exploitation. Our findings underscore how incorporating specific biologically grounded insights into complex systems frameworks, enhances our understanding of the mechanisms underlying collective intelligence in biological systems.