Browse Articles

Cross-ancestry comparison of aptamer and antibody protein measures

No evidence of immediate or persistent analgesic effect from a single dose of psilocybin in three mouse models of pain

Single-cell atlas of human lung aging identifies cell type dyssynchrony and increased transcriptional entropy

Harnessing PV-oxirene for the modular synthesis of α-Oxy carbonyls

Experimental witness of quantum jump induced high-order Liouvillian exceptional points

Abstract The exceptional point has presented considerably interesting and counterintuitive phenomena associated with nonreciprocity, precision measurement, and topological dynamics. The Liouvillian exceptional point (LEP), involving the interplay of energy loss and decoherence inherently relevant to quantum jumps, has recently drawn much attention due to capability to fully capture quantum system dynamics and naturally facilitate non-Hermitian quantum investigations. It was also predicted that quantum jumps could give rise to third-order LEPs in two-level quantum systems for its high dimensional Liouvillian superoperator, which, however, has never been experimentally confirmed until now. Here we report the observation of the third-order LEPs emerging from quantum jumps in an ultracold two-level trapped-ion system. Moreover, by combining decay with dephasing processes, we present the experimental exploration of LEPs involving combinatorial effect of decay and dephasing. In particular, due to non-commutativity between the Lindblad superoperators governing LEPs for decay and dephasing, we witness the movement of LEPs driven by the competition between decay and dephasing occurring in an open quantum system. This unique feature of non-Hermitian quantum systems paves a new avenue for modifying nonreciprocity, enhancing precision measurement, and manipulating topological dynamics by tuning the LEPs.

A bacterial defense system targeting modified cytosine of phage genomic DNA

Abstract The evolutionary arms race between bacteria and phages drives the development of bacterial antiviral defense systems and phage counter-defense strategies. Restriction–modification (RM) systems protect bacteria by methylating ‘self’ DNA and cleaving unmodified phage DNA. Phages like T-even coliphages evade RM systems by substituting cytosine with 5-hydroxymethyl cytosine (5hmC) or 5-glucosylated hmC (5ghmC). Here, we characterize ‌a single-component antiviral defense system featuring a GIY-YIG endonuclease domain. Biochemical and structural analyses demonstrate that this defense system is a type IV modification-dependent restriction endonuclease that specifically degrades 5hmC- or 5ghmC-modified DNA, and we accordingly name it CMoRE ( C ytosine Mo dification ‌R ‌estriction E ndonuclease). The crystal structures reveal an N-terminal GIY-YIG nuclease domain and a C-terminal modification-sensing domain. Unique features, including a ‘GIYxY-YIG’ motif and an inhibitory negatively charged loop, distinguish CMoRE as an additional member of the GIY-YIG family. This system not only highlights the evolutionary interplay between phages and bacteria but also presents CMoRE as a potential tool for precise genomic detection of 5hmC in mammals, with implications for epigenetics research and disease diagnostics.

Identification of Chlamydia pneumoniae and NLRP3 inflammasome activation in Alzheimer’s disease retina

Abstract Chlamydia pneumoniae is an intracellular bacterium implicated in Alzheimer’s disease (AD), but its role in retinal pathology and disease progression is unclear. Here we identify Chlamydia pneumoniae inclusions in the retina, showing higher burden in AD retina and brain, increasing with APOEε4, disease stage, and cognitive deficit. Retinal and cortical proteomics reveal bacterial-infection and related NLRP3-inflammasome pathways. Retinal NLRP3 is elevated in mild cognitive impairment and activated in AD dementia, evidenced by increased caspase-1, cleaved interleukin-1β, and cleaved N-terminal gasdermin-D. Chlamydia pneumoniae associates with amyloid-β 42 , inflammation, apoptosis, pyroptosis, and AD status. In neuronal cultures and APP SWE /PS1 ΔE9 model mice, infection induces amyloid-β, inflammasome activation, neuroinflammation, and neurotoxicity, and chronic infection worsens cognition. Fewer pathogen-colocalized microglia are found in AD retinas, implying impaired clearance. Machine learning detects retinal Chlamydia pneumoniae or NLRP3, combined with amyloid-β 42 , as predictors of AD diagnosis and stage. These findings support a disease-amplifying role for Chlamydia pneumoniae and propose NLRP3-attenuation or antibiotic-based early interventions.

Can’t get motivated? This brain circuit might explain why — and it can be turned off

Additive-specific modulation of non-classical nucleation pathways

Neural crest cell-derived DKK1 and NEDD4 modulate Wnt signalling in the second heart field to orchestrate outflow tract development

Abstract Cardiac outflow tract morphogenesis requires coordinated interactions between multiple cell populations and is dependent on the contribution of cardiac progenitors from the second heart field. While neural crest cells have been proposed to impact second heart field development, how they regulate progenitor behaviour remains unclear. Here, we discover neural crest cells are a primary source of Dickkopf-1 (DKK1) which modulates Wnt signalling activity in the second heart field to influence the balance between cardiac progenitor maintenance and differentiation. We show that the ubiquitin ligase NEDD4 regulates DKK1, with disruption of Nedd4 leading to outflow tract defects. We further identify a new NEDD4 variant underlying human congenital heart disease. Our findings uncover an unexpected role for neural crest cells as a rheostat of Wnt signalling in cardiac progenitors, identifying a new molecular pathway promoting outflow tract morphogenesis, and a new causative factor of congenital heart disease.

Meta-unstable mRNAs in activated CD8+ T cells are defined by interlinked AU-rich elements and m6A mRNA methylation

Abstract CD8 + T cells can rapidly produce effector molecules following activation. This activation triggers rapid changes in gene expression that rely on the control of mRNA levels via multiple mechanisms, including RNA modifications. N 6 -methyladenosine (m 6 A) is an abundant post-transcriptional modification that promotes the decay of messenger RNAs in the cytosol. However, how recognition of m 6 A sites is integrated with other regulatory mechanisms that alter the fate of immunoregulatory mRNAs in CD8 + T cells remains unexplored. Here, we apply the m 6 A-iCLIP and GLORI methods to identify the importance of m 6 A sites flanked by AU-rich elements (AREs) within the 3’UTRs of CD8 + T cell mRNAs. Presence of such ARE-flanking m 6 A motifs predicts meta-unstable mRNAs that rapidly decay upon CD8 + T cell activation. We demonstrate interdependent effects of mutations in the identified AREs and RRACHs on TNF mRNA stability. The ARE-flanking m 6 A sites in these mRNAs show particularly high iCLIP crosslinking of YTHDF proteins, which are also identified by proteomic interactome analyses along with additional novel RNA-binding proteins. Our study reveals a crosstalk between m 6 A and ARE-dependent mechanisms in CD8 + T cells, providing new approaches for modulating mRNA decay in T cell activation.

Streamlined resource-efficient plasma amyloid-beta mass spectrometry assay has improved biomarker performance in preclinical Alzheimer’s disease

ProteoAutoNet: high-throughput co-eluted protein analysis with robotics and machine learning

Abstract Co-fractionation mass spectrometry (CF-MS) enables large-scale profiling of endogenous protein-protein interactions, yet CF-MS data generation is of low throughput and therefore predictive models are often limited by the scarcity and limited diversity of high-quality training data. To address this, we present ProteoAutoNet, a robotic experimental platform integrated with a computational workflow for high-throughput CF-MS analysis. This workflow increases the throughput of sample processing from protein complex to peptide by about two times. The integrated machine learning model incorporates targeted data augmentation to expand and diversify reliable protein interaction data, thereby improving model robustness. When applied to three thyroid cell lines, the model predicted 25,173 co-eluted proteins with an AUROC of 0.78. This analysis revealed significantly upregulated proteasome and prefoldin complexes in the lung metastatic follicular thyroid carcinoma cell line FTC238 compared with the normal thyroid cell line Nthy-ori 3-1. Notably, we identified a protein interaction between TGM2 and HK1 that was significantly upregulated in the papillary thyroid carcinoma cell line TPC-1. ProteoAutoNet provides an improved framework for investigating protein-protein interactions and uncovering interactions.

Comparative multi-omic analysis reveals conserved and derived mechanisms of fin and limb regeneration

Abstract Comparative studies of vertebrate appendages offer a powerful framework for uncovering shared components of an ancestral regeneration toolkit. Here, we employed a multi-omics comparative approach leveraging the regenerative capacity of the axolotl, zebrafish, and Polypterus senegalus , a fish capable of full fin regeneration. We identified conserved markers of proximal and distal blastema territories, shared activation of DNA damage repair, hif1a -mediated hypoxia response, and sequential activation of pro- and anti-inflammatory program. Apical epithelial ridge markers were expressed in both the wound epidermis and distal mesenchyme during limb and fin regeneration. Notably, hif4a -expressing erythrocytes were uniquely associated with proximal limb and fin amputations but not fin rays, while epidermal myoglobin expression was upregulated only in Polypterus and zebrafish fins. Genome-wide chromatin profiling identified candidate regeneration-responsive elements and a conserved enrichment for AP-1 transcription factor binding. Together, these findings identify shared and derived mechanisms of limb and fin regeneration.

Glass formation in hybrid metal halides via breaking molecular rotational order

Longitudinal plasma proteomic signatures of elite and viremic spontaneous HIV controllers

A Magnon-photon interface based on Van der Waals Magnetic semiconductor

Author Correction: Structural insights into BCDX2 complex function in homologous recombination

Uncovering the molecular logic of cortical wiring between neuronal subtypes across development through ligand–receptor inference

Ultrathin liquid cells for microsecond time-resolved cryo-EM

Abstract Microsecond time-resolved cryo-electron microscopy promises to significantly advance our understanding of protein function by rendering cryo-electron microscopy (cryo-EM) fast enough to observe proteins at work. This emerging technique involves flash melting a cryo sample with a laser beam to provide a brief time window during which dynamics are initiated. When the laser is switched off, the sample revitrifies, arresting the proteins in their transient configurations. However, observations have so far been limited to tens of microseconds only, due to the instability of the thin liquid film under laser irradiation. Here, we seal samples between two ultrathin, vapor-deposited silicon dioxide membranes to extend the observation window by an order of magnitude. These membranes not only allow for reconstructions with near-atomic spatial resolution, but can also be used to eliminate preferred particle orientation. We showcase our technology by performing a time-resolved temperature jump experiment on the 50S ribosomal subunit that provides new insights into the conformational landscape of the L1 stalk. Our experiments significantly expand the capabilities of microsecond time-resolved cryo-EM and promise to bridge the gap to the millisecond timescale, which can already be addressed with traditional approaches.