Science Advances最新文献

Glaciers serve as natural archives for reconstructing past changes of atmospheric aerosol concentration and composition. While most ice-core studies have focused on inorganic species, organic compounds, which can constitute up to 90% of the submicrometer aerosol mass, have been largely overlooked. To our knowledge, this study presents the first nontarget screening record of secondary organic aerosol species preserved in a Belukha ice core (Siberia, Russian Federation), ranging from the pre-industrial to the industrial period (1800-1980 CE). We identified a total of 398 molecules, primarily polar and low-volatile compounds. Since the 1950s, the atmospheric aerosol composition has changed, with the appearance of organic molecules, including nitrogen-containing compounds, deriving from enhanced atmospheric reactions with anthropogenic NO_x, or direct emissions. In addition, there was a significant increase in the oxygen-to-carbon ratio (+3%) and the average carbon oxidation state (+18%) of the detected molecules compared to the pre-industrial period, suggesting an increased oxidative capacity of the atmosphere.

Self-healing hydrogels can autonomously repair damage, enhancing their performance stability and broadening their applications as soft devices. Although the incorporation of dynamic interactions enhances self-healing capabilities, it simultaneously weakens the hydrogels' strength. External stimuli such as heating, while accelerating the healing process, may also lead to dehydration. Developing a stable repair strategy that combines rapid healing and high mechanical strength is challenging. Here, we introduce "salt-welding" for high-strength hydrogels with rapid room temperature self-healing. This is achieved through dynamic borate ester bonds in a salt-responsive poly(methacrylamide) hydrogel. The process involves "salt-fusion" to convert fractures into a viscous liquid for swift healing, followed by "salt-concretion" to toughen the hydrogel. The hydrogels achieve a posthealing strength of 23 megapascals in 95 minutes at room temperature, with near 100% healing efficiency. Leveraging their tunable mechanical strength and rapid healing rate, the hydrogel can be tailored for applications as a reparable wear-resistant material and damping device.

Multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) family transporters are essential in glycan synthesis, flipping lipid-linked precursors across cell membranes. Yet, how they select their substrates remains enigmatic. Here, we investigate the substrate specificity of the MOP transporters in the capsular polysaccharide (CPS) synthesis pathway in Streptococcus pneumoniae. These capsule flippases collectively transport more than 100 types of capsule precursors. To determine whether they can substitute for one another, we developed a high-throughput approach to systematically examine nearly 6000 combinations of flippases and substrates. CPS flippases fall into three groups: relaxed, type-specific, and strictly specific. Cargo size and CPS acetylation affect transport, and we isolated additional gain-of-function flippase variants that can substitute for the peptidoglycan flippase YtgP (MurJ). We also showed that combining flippase variants in a single cassette allows various CPS precursors to be flipped, which may aid glycoengineering. This study reveals that MOP flippases exhibit broad specificity, shaping the evolution of glycan synthesis.

Designing binders to target undruggable proteins presents a formidable challenge in drug discovery. In this work, we provide an algorithmic framework to design short, target-binding linear peptides, requiring only the amino acid sequence of the target protein. To do this, we propose a process to generate naturalistic peptide candidates through Gaussian perturbation of the peptidic latent space of the ESM-2 protein language model and subsequently screen these novel sequences for target-selective interaction activity via a contrastive language-image pretraining (CLIP)-based contrastive learning architecture. By integrating these generative and discriminative steps, we create a Peptide Prioritization via CLIP (PepPrCLIP) pipeline and validate highly ranked, target-specific peptides experimentally, both as inhibitory peptides and as fusions to E3 ubiquitin ligase domains. PepPrCLIP-derived constructs demonstrate functionally potent binding and degradation of conformationally diverse, disease-driving targets in vitro. In total, PepPrCLIP empowers the modulation of previously inaccessible proteins without reliance on stable and ordered tertiary structures.

S-Palmitoylation is a reversible post-translational modification involving saturated fatty acid palmitate-to-cysteine linkage in the protein, which guides many aspects of macrophage physiology in health and disease. However, the precise role and underlying mechanisms of palmitoylation in Mycobacterium tuberculosis infection of macrophages remain elusive. Here, we found that M. tuberculosis infection induced the expression of zinc-finger DHHC domain-type palmitoyl-transferases (ZDHHCs), particularly ZDHHC2, in mouse macrophages. Furthermore, ZDHHC2 deficiency in mouse macrophages impaired the immunity against M. tuberculosis and reduced the production of various proinflammatory cytokines. Mechanistic studies revealed the involvement of ZDHHC2 in mediating the palmitoylation of B-RAF and C-RAF, affecting their autophagic degradation and stabilizing protein levels. The increased abundance of B-RAF and C-RAF subsequently increases the activity of the extracellular signal-regulated kinase (ERK) signaling pathway, affecting the survival of M. tuberculosis within macrophages. These findings suggest that ZDHHC2 is a potential target for treating tuberculosis.

Bacterial type IV secretion systems (T4SSs) are widespread nanomachines specialized in the transport across the cell envelope of various types of molecules including mobile genetic elements during conjugation. Despite their prevalence in Gram-positive bacteria, including relevant pathogens, their assembly and functioning remain unknown. This study addresses these gaps by investigating VirB8 proteins, known to be central components of conjugative T4SSs in Gram-positive bacteria. However, the functional packing and precise role of VirB8 in T4SSs biology remain undefined. Our findings elucidate the nature of VirB8 proteins as cell wall components, where they multimerize and exhibit a conserved assembly pattern, distinct from VirB8 in Gram-negative bacteria. We also demonstrate that VirB8 proteins interact with other T4SS subunits and DNA, indicating their pivotal role in the building of the DNA translocation channel across the cell wall. We lastly propose a distinct architecture for conjugative T4SSs in Gram-positive bacteria compared to their Gram-negative counterparts, possibly attributed to the differences in the cell wall structure.

Distinct tau amyloid assemblies underlie diverse tauopathies but defy rapid classification. Cell and animal experiments indicate tau functions as a prion, as different strains propagated in cells cause unique, transmissible neuropathology after inoculation. Strain amplification requires compatibility of the monomer and amyloid template. We used cryo-electron microscopy to study one cell-based yellow fluorescent protein (YFP)-tagged strain, resolving its amyloid nature. We then used sequential alanine (Ala) substitution (scan) within tau repeat domain (RD) to measure incorporation to preexisting tau RD-YFP aggregates. This robustly discriminated strains, defining sequences critical for monomer incorporation. We then created 3R/4R or 4R wild-type RD (amino acids 246 to 408) biosensors. Ala scan of recombinant tau seeds with the Alzheimer's disease (AD) fold matched that of AD homogenate. We scanned 22 brain lysates comprising four tauopathies. This clustered cases by neuropathological syndrome, revealed the role of amino acids in protofilament folds, and allowed strain discrimination based on amino acid requirements for prion replication.

Protein homeostasis is crucial for maintaining cardiomyocyte (CM) function. Disruption of proteostasis results in accumulation of protein aggregates causing cardiac pathologies such as hypertrophy, dilated cardiomyopathy (DCM), and heart failure. Here, we identify ubiquitin-specific peptidase 5 (USP5) as a critical determinant of protein quality control (PQC) in CM. CM-specific loss of mUsp5 leads to the accumulation of polyubiquitin chains and protein aggregates, cardiac remodeling, and eventually DCM. USP5 interacts with key components of the proteostasis machinery, including PSMD14, and the absence of USP5 increases activity of the ubiquitin-proteasome system and autophagic flux in CMs. Cardiac-specific hUSP5 overexpression reduces pathological remodeling in pressure-overloaded mouse hearts and attenuates protein aggregate formation in titinopathy and desminopathy models. Since CMs from humans with end-stage DCM show lower USP5 levels and display accumulation of ubiquitinated protein aggregates, we hypothesize that therapeutically increased USP5 activity may reduce protein aggregates during DCM. Our findings demonstrate that USP5 is essential for ubiquitin turnover and proteostasis in mature CMs.

The origins of natural hydrogen in natural gas systems of sedimentary basins and the capacity of these systems to store hydrogen remain inadequately understood, posing crucial questions for the large-scale exploration of natural hydrogen. This study reports on the natural gas composition, stable carbon and hydrogen isotopic values, and helium isotopic values of gas samples collected from the Qingshen gas deposit within volcanic rocks of the Songliao Basin. Natural hydrogen primarily originates from water radiolysis, water-rock interactions (WRI), and mantle. The Qingshen gas deposit contains 95.23 × 10⁹ cubic meters of abiotic CH₄, of which 15.24 × 10⁹ cubic meters was generated through hydrogen conversion via Fischer-Tropsch synthesis, with the maximum original hydrogen reserves calculated to be approximately 61.9 × 10⁹ cubic meters. We estimated that the study area has generated a maximum total of 572 × 10⁹ cubic meters of radiolytic hydrogen, 248 × 10⁹ cubic meters of WRI hydrogen, and 127 × 10⁹ cubic meters of mantle-derived hydrogen.

Prosocial behaviors are advantageous to social species, but the neural mechanism(s) through which others receive benefit remain unknown. Here, we found that bystander mice display rescue-like behavior (tongue dragging) toward anesthetized cagemates and found that this tongue dragging promotes arousal from anesthesia through a direct tongue-brain circuit. We found that a direct circuit from the tongue → glutamatergic neurons in the mesencephalic trigeminal nucleus (MTN^Glu) → noradrenergic neurons in the locus coeruleus (LC^NE) drives rapid arousal in the anesthetized mice that receive the rescue-like behavior from bystanders. Artificial inhibition of this circuit abolishes the rapid arousal effect induced by the rescue-like behavior. Further, we revealed that glutamatergic neurons in the paraventricular nucleus of the thalamus (PVT^Glu) that project to the nucleus accumbens shell (NAcSh) mediate the rescue-like behavior. These findings reveal a tongue-brain connection underlying the rapid arousal effects induced by rescue-like behavior and the circuit basis governing this specific form of prosocial behavior.