Science Advances最新文献

Neurotransmitters (NTs) mediate trans-synaptic signaling, and disturbances in their levels are linked to aging and brain disorders. Here, we ascribe an additional function for NTs in mediating intracellular protein aggregation by interaction with cytosolic protein fibrils. Cell-based seeding experiments revealed monoaminergic NTs as inhibitors of tau. Seeding is a disease-relevant mechanism involving catalysis by fibrils, leading to the aggregation of proteins in Alzheimer's disease and other neurodegenerative diseases. Chemotyping small molecules with varied backbone structures revealed determinants of aggregation inhibitors and catalysts. Among those identified were monoaminergic NTs. Dose titrations revealed bimodal effects indicative of fibril disaggregation, with aggregation catalysis occurring at low ratios of NTs and inhibited seeding ensuing at higher concentrations. Bimodal effects by NTs extend from in vitro systems to dopaminergic neurons, suggesting that pharmacotherapies that modify intracellular NT levels could shape the neuronal protein aggregation environment.

Far-from-equilibrium systems can form memories of previous deformations or driving. In systems from sheared glassy materials to buckling beams to crumpled sheets, this behavior is dominated by return-point memory, in which revisiting a past extremum of driving restores the system to a previous state. Cyclic driving with both positive and negative strains forms multiple nested memories, as in a single-dial combination lock, while asymmetric driving (only positive strain) cannot. We study this case in a general model of hysteresis that considers discrete elements called hysterons. We show how two hysterons with a frustrated interaction can violate return-point memory, realizing multiple memories of asymmetric driving. This reveals a general principle for designing systems that store sequences of cyclic driving, whether symmetric or asymmetric. In disordered systems, asymmetric driving is a sensitive tool for the direct measurement of frustration.

The Epstein-Barr virus (EBV) infects nearly 90% of adults globally and is linked to over 200,000 annual cancer cases. Immunocompromised individuals from conditions such as primary immune disorders, HIV, or posttransplant immunosuppressive therapies are particularly vulnerable because of EBV's transformative capability. EBV remodels B cell metabolism to support energy, biosynthetic precursors, and redox equivalents necessary for transformation. Most EBV-driven metabolic pathways center on mitochondria. However, how EBV regulates B cell mitochondrial function and metabolic fluxes remains unclear. Here, we show that EBV boosts cardiolipin (CL) biosynthesis, essential for mitochondrial cristae biogenesis, via EBV nuclear antigen 2/MYC-induced CL enzyme transactivation. Pharmacological and CRISPR genetic analyses underscore the essentiality of CL biosynthesis in EBV-transformed B cells. Metabolomic and isotopic tracing highlight CL's role in sustaining respiration, one-carbon metabolism, and aspartate synthesis. Disrupting CL biosynthesis destabilizes mitochondrial matrix enzymes pivotal to these pathways. We demonstrate EBV-induced CL metabolism as a therapeutic target, offering synthetic lethal strategies against EBV-associated B cell malignancies.

The hypervirulent carbapenem-resistant Klebsiella pneumoniae (hv-CRKP) poses a substantial challenge to the global health care. However, the mechanism behind its evolution and transmission remain elusive. Here, four virulence plasmid types were identified from 310 hv-CRKP isolates collected nationwide during 2017-2018, based on their aerobactin (iuc locus) lineage and IncFIB replicons. Notably, pIUC1-IncFIB(K)₃₇ and pIUC1-IncFIB(Mar), representing two epidemic virulence plasmids in Asia and Europe, respectively, accounted for >90% of the hv-CRKP episodes. Analysis of 494 K. pneumoniae isolates (376 from 2010-2013; 118 from 2017-2018) and 2578 public K. pneumoniae genomes indicated the notable role of IncFIB(Mar) plasmids in the hv-CRKP emergence and spread. Conjugation assays showed the helper IncFIB(Mar) plasmid could efficiently transfer into a hypervirulent strain and uniquely retromobilize with pIUC1-IncFIB(K)₃₇ back into CRKP. Thereafter, the IncFIB(Mar) plasmid either lost rapidly or recombined with pIUC1-IncFIB(K)₃₇, generating the hybrid pIUC1-IncFIB(Mar) plasmid. Our findings elucidated formation, evolution, and dissemination trajectories of the two major hv-CRKP strains in different regions.

Viral manipulation of posttranslational modifications (PTMs) is critical to enable control over host defenses. Evidence suggests that one such PTM, adenosine 5'-diphosphate (ADP)-ribosylation, is important for viral replication, but the host and viral components involved are poorly understood. Here, we demonstrate that several human poly(ADP-ribose) polymerase (PARP) proteins, including the zinc-finger domain containing PARP7 (TiPARP) and PARP12, directly ADP-ribosylate the alphaviral nonstructural proteins (nsPs), nsP3 and nsP4. These same human PARP proteins inhibit alphavirus replication in a manner that can be antagonized by the ADP-ribosylhydrolase activity of the virally encoded macrodomain. Last, we find that knockdown of any of the three CCCH zinc-finger domain containing PARPs, PARP7, PARP12, or the enzymatically inactive PARP13 (ZAP/ZC3HAV1), attenuates the antiviral effects of interferon-γ on alphavirus replication. Combined with evolutionary analyses, these data suggest that zinc-finger PARPs share an ancestral antiviral function that can be antagonized by the activity of viral macrodomains, indicative of an ongoing evolutionary conflict between host ADP-ribosylation and viruses.

Ice core measurements reveal dipole-like snow accumulation trends over West Antarctica throughout the 20th century, with an increase of >2000 billion metric tons over the Antarctic Peninsula and Ellsworth Land but a decrease of ~500 billion metric tons over Marie Byrd Land. Although atmospheric teleconnections were frequently revealed, linking variability between tropics and higher latitudes on interannual and decadal timescales, centennial-scale teleconnection is absent from literature. Here, using statistical analysis and numerical experiments, we reveal that changes of tropical oceans throughout the 20th century drive the long-term Antarctic snowfall trend. A pronounced warming over the tropical Atlantic and a moderate cooling over the equatorial Pacific have driven an adjustment of moisture transport and thus snowfall pattern in West Antarctica. Our study reveals a centennial tropical-polar teleconnection, producing long-term trends with opposing changes across the regions. Remote forcing from the tropics increased the mass accumulation over Antarctica, balanced rapid iceshelf thinning in recent decades, contributing to global sea-level changes.

Parasitoid wasps, one of the most diverse and species-rich animal groups on Earth, produce venoms that manipulate host development and physiology to exploit resources. However, mechanisms of actions of these venoms remain poorly understood. Here, we discovered that the endoparasitoid wasp, Asobara japonica, induces apoptosis, autophagy, and mitotic arrest in the adult tissue precursors of its host Drosophila larvae. We termed this phenomenon imaginal disc degradation (IDD). A multi-omics approach facilitated identification of two venom proteins of A. japonica necessary for IDD, which is critical for parasitism success. Our study highlights a venom-mediated hijacking strategy of the parasitoid wasp that allows the host larvae to grow, but ultimately prevents their metamorphosis.

Precise neoepitope discovery is crucial for effective cancer therapeutic vaccines. Conventional approaches struggle to build a repertoire with sufficient immunogenic epitopes. We developed a workflow leveraging full-length ribosome-nascent chain complex-bound mRNA sequencing (FL-RNC seq) and artificial intelligence-based predictive models to accurately identify the neoepitope landscape, especially large-scale transcript variants (LSTVs) missed by short-read sequencing. In the MC38 mouse model, we identified 22 LSTV-derived neoepitopes encoded by a synthesized mRNA lipid nanoparticle vaccine. As a standalone therapy and combined with anti-PD-1 immunotherapy, the vaccine curbed tumor progression, induced robust T cell-specific immunity, and modulated the tumor microenvironment. This underscores the multifaceted potentials of LSTV-derived vaccines. Our approach expands the neoepitope source repertoire, offering a method for discovering personalized cancer vaccines applicable to a broader tumor range. The results highlight the importance of comprehensive neoepitope identification and the promise of LSTV-based vaccines for cancer immunotherapy.

Linking sensory-evoked traveling waves to underlying circuit patterns is critical to understanding the neural basis of sensory perception. To form this link, we performed simultaneous electrophysiology and two-photon calcium imaging through transparent NeuroGrids and mapped touch-evoked traveling waves and underlying microcircuit dynamics. In awake mice, both passive and active whisker touch elicited traveling waves within and across barrels, with a fast early component followed by a late wave that lasted hundreds of milliseconds poststimulus. Notably, late waves were modulated by perceived value and predicted behavioral choice in a two-whisker discrimination task. We found that the late wave feature was (i) modulated by motor feedback, (ii) differentially engaged a sparse ensemble reactivation pattern across layer 2/3, which a balanced-state network model reconciled via feedback-induced inhibitory stabilization, and (iii) aligned to regenerative layer 5 apical dendritic Ca²⁺ events. Our results reveal that translaminar spacetime patterns organized by cortical feedback support sparse touch-evoked traveling waves.

Excellent indicators of technology, social organization, exchange patterns, and even beliefs, beads are a topic of research in their own right. Findings made between 2010 and 2011 at the Montelirio tholos burial, part of the Valencina Copper Age mega-site, in south-western Spain, revealed what amounts to the largest single-burial ever-documented assemblage of beads. Furthermore, the Montelirio beads were part of unparalleled beaded attires worn by some of the people buried in the grave, mostly females. A multi-analytical study undertaken over the past 5 years-including a meticulous quantification of the collection, the characterization of the raw materials, radiocarbon dating and chronometric statistical modeling, morphometric analysis, phytolith analysis, experimental work and contextual analysis-reveals several previously unidentified aspects of these remarkable creations. This includes the role of the attires as sumptuary attributes heavily loaded of symbolism, used by a selected group of women of high social significance.