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Pressurized organic electrodes enable practical and extreme batteries
Myeloid EGFR deficiency accelerates recovery from AKI via macrophage efferocytosis and neutrophil apoptosis
Extended coverage of human serum glycosphingolipidome by 4D-RP-LC TIMS-PASEF unravels association with Parkinson’s disease
Abstract Glycosphingolipids (GSLs) are important targets in immune, infectious, lysosomal storage diseases, cancer, and neurodegenerative diseases. Circulatory GSLs profiling in clinical samples is restricted by the lack of mid- and high-throughput analytical methods and deep coverage of long-chain sialylated glycosphingolipidome. We present a 4-dimensional (4D)-glycosphingolipidomics platform for routine glycosphingolipidome profiling encompassing: extraction and fractionation of sialylated GSLs with 3 to 15 monosaccharides, neutral GSLs and sulfatides; µL-flow reversed-phase LC-TIMS-PASEF MS analysis; semi-quantification strategy adapted for fractionated glycosphingolipidome, and referential CCS, RT, and m/z values for GSLs annotation. 4D-glycosphingolipidomics of human serum reveals a high structural heterogeneity, amounting to 376 GSLs: 159 GSLs of ganglio- and neolacto-series, 145 neutral GSLs and 72 sulfatides. Here we demonstrate the platform’s utility for clinical profiling of Parkinson’s disease (PD) sera. 41 neolacto- and ganglio-species discriminate PD patients from controls and 14 GSLs differentiate sex subgroups, laying the foundation for further functional GSL studies with PD.
Alectinib in combination with bevacizumab as first-line treatment in ALK-rearranged non-small cell lung cancer (ALEK-B): a single-arm, phase 2 trial
Reply to: Reassessing gas generation from oil thermal cracking associated with the Emeishan Large Igneous Province
USP2 inhibition unleashes CD47-restrained phagocytosis and enhances anti-tumor immunity
USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination
Nucleosome dynamics render heterochromatin accessible in living human cells
Abstract The eukaryotic genome is packaged into chromatin, which is composed of a nucleosomal filament that coils up to form more compact structures. Chromatin exists in two main forms: euchromatin, which is relatively decondensed and enriched in transcriptionally active genes, and heterochromatin, which is condensed and transcriptionally repressed. It is widely accepted that chromatin architecture modulates DNA accessibility, restricting the access of sequence-specific, gene-regulatory, transcription factors to the genome. However, the evidence for this model derives primarily from experiments with isolated nuclei, in which chromatin remodeling has ceased, resulting in a static chromatin structure. Here, using a DNA methyltransferase to measure accessibility in vivo, we show that both euchromatin and heterochromatin are fully accessible in living human cells, whereas centromeric α-satellite chromatin is partly inaccessible. We conclude that all nucleosomes in euchromatin and heterochromatin are highly dynamic in living cells, except for nucleosomes in centromeric chromatin.
A ventral pallidum-locus coeruleus-lateral hypothalamus pathway modulates brain arousal in freely behaving and isoflurane-anesthetized male mice
Electrolyte droplet spraying in H2 bubbles during water electrolysis under normal and microgravity conditions
Abstract Electrolytically generated gas bubbles can significantly hamper the overall electrolysis efficiency. Therefore it is crucial to understand their dynamics in order to optimise water electrolyzer systems. Herein, we elucidate a distinct transport mechanism whereby electrolyte droplets are sprayed into H2 bubbles. These droplets arise from the fragmentation of the Worthington jet, which is engendered by the coalescence with microbubbles. The robustness of this phenomenon is corroborated under both normal and microgravity conditions. Reminiscent of bursting bubbles on a liquid-gas interface, electrolyte spraying results in a flow inside the bubble. This flow couples, in an intriguing way, with the thermocapillary convection at the bubble’s surface, clearly underlining the high interfacial mobility. In the case of electrode-attached bubbles, the sprayed droplets form electrolyte puddles affecting the dynamics near the three-phase contact line and favoring bubble detachment from the electrode. The results of this work unravel important insights into the physico-chemical aspects of electrolytic gas bubbles, integral for optimizing gas-evolving electrochemical systems.
Inhibiting peptidylarginine deiminases (PAD1-4) by targeting a Ca2+ dependent allosteric binding site
Trifluoroethanol-assisted asymmetric propargylic hydrazination to α-tertiary ethynylhydrazines enabled by sterically confined pyridinebisoxazolines
Engineering tripartite gene editing machinery for highly efficient non-viral targeted genome integration
Modular deregulation of central carbon metabolism for efficient xylose utilization in Saccharomyces cerevisiae
Abstract The tightly regulated central carbon metabolism in Saccharomyces cerevisiae, intricately linked to carbon sources utilized, poses a significant challenge to engineering efforts aimed at increasing the flux through its different pathways. Here, we present a modular deregulation strategy that enables high conversion rates of xylose through the central carbon metabolism. Specifically, employing a multifaceted approach encompassing five different engineering strategies—promoter engineering, transcription factor manipulation, biosensor construction, introduction of heterologous enzymes, and expression of mutant enzymes we engineer different modules of the central carbon metabolism at both the genetic and enzymatic levels. This leads to an enhanced conversion rate of xylose into acetyl-CoA-derived products, with 3-hydroxypropionic acid (3–HP) serving as a representative case in this study. By implementing a combination of these approaches, the developed yeast strain demonstrates a remarkable enhancement in 3–HP productivity, achieving a 4.7–fold increase when compared to our initially optimized 3–HP producing strain grown on xylose as carbon source. These results illustrate that the rational engineering of yeast central metabolism is a viable approach for boosting the metabolic flux towards acetyl–CoA–derived products on a non-glucose carbon source.
Ensemble refinement of mismodeled cryo-EM RNA structures using all-atom simulations
SARS-CoV-2 induced immune perturbations in infants vary with disease severity and differ from adults’ responses
Integrating antigen capturing nanoparticles and type 1 conventional dendritic cell therapy for in situ cancer immunization
Abstract Eliciting a robust immune response against tumors is often hampered by the inadequate presence of effective antigen presenting cells and their suboptimal ability to present antigens within the immunosuppressive tumor microenvironment. Here, we report a cascade antigen relay strategy integrating antigen capturing nanoparticles (AC-NPs) and migratory type 1 conventional dendritic cells (cDC1s), named Antigen Capturing nanoparticle Transformed Dendritic Cell therapy (ACT-DC), to facilitate in situ immunization. AC-NPs are engineered to capture antigens directly from the tumor and facilitate their delivery to adoptively transferred migratory cDC1s, enhancing antigen presentation to the lymph nodes and reshaping the tumor microenvironment. Our findings suggest that ACT-DC improves in situ antigen collection, triggers a robust systemic immune response without the need for exogenous antigens, and transforms the tumor environment into a more “immune-hot” state. In multiple tumor models including colon cancer, melanoma, and glioma, ACT-DC in combination with immune checkpoint inhibitors eliminates primary tumors in 50-100% of treated mice and effectively rejects two separate tumor rechallenges. Collectively, ACT-DC could provide a broadly effective approach for in situ cancer immunization and tumor microenvironment modulation.