Browse Articles

Quarter- and half-filled quantum Hall states and their topological orders revealed by daughter states in bilayer graphene

In silico decrypting of the bystander effect in antibody–drug conjugates for breast cancer therapy

Abstract Antibody–Drug Conjugates (ADCs) are a promising cancer treatment that deliver toxic drugs directly to cancer cells, reducing harm to healthy tissue. A key feature of newer ADCs is the “bystander effect,” in which nearby cancer cells are also affected by passive diffusion. However, the mechanisms underlying this effect remain unclear. Using computer simulations, this study investigates how the drug’s ionization state and the linker connecting it to the antibody influence its ability to cross cell membranes. The results show that the ionization state of the drug impacts its membrane permeability, as charged molecules encounter resistance when moving through the membrane’s hydrophobic core. Moreover, the study reveals that the linker increases the drug’s overall size and hydrophobicity, thereby hindering its diffusion to adjacent cells. This finding suggests that linker design can significantly influence the efficacy of antibody–drug conjugates (ADCs) by limiting their ability to reach neighboring cancer cells. These insights enhance our understanding of ADC mechanisms and provide a valuable foundation for the optimization of next-generation ADC therapies targeting breast cancer.

Asymmetric C–H Functionalization of <i>N</i>-Boc-2,5-dihydro-1<i>H</i>-pyrrole and Its Application as a Key Step in the Synthesis of (−)-Dragocin D

Plasmodium falciparum egress disrupts endothelial junctions and activates JAK-STAT signaling in a microvascular 3D blood-brain barrier model

Abstract Cerebral malaria is a severe neurovascular complication of Plasmodium falciparum infection, with high mortality rates even after treatment with effective antimalarials. Limitations in current experimental models have hindered our knowledge of the disease. We developed a 3D blood-brain barrier (BBB) model with enhanced barrier properties using primary brain endothelial cells, astrocytes, and pericytes. Exposure to parasite egress products increases microvascular permeability, likely due to transcriptional downregulation of junctional and vascular development genes in endothelial cells. In addition, it increases the expression of ferroptosis markers, antigen presentation and type I interferon genes and upregulates the JAK-STAT pathway across all BBB cell types. Incubation with cytoadherent schizont-stage P. falciparum -infected erythrocytes induces a similar, but highly localized transcriptional shift, along with inter-endothelial gaps at sites of parasite egress, leading to enhanced permeability. Treatment with the JAK-STAT inhibitor Ruxolitinib prevents the increase in permeability induced by P. falciparum egress products. These findings provide key insights into the parasite-mediated mechanisms driving brain microvascular pathogenesis in cerebral malaria and suggest potential avenues for adjunctive therapies.

Experimental study of strength degradation in fractured surrounding rock of deep high-temperature tunnels

Iridium–Lewis Acid Bifunctional Catalyst-Enabled Regio- and Enantioselective C(sp ² )–H <i>meta</i> -Borylation of α,α-Diarylcarboxamides

Transformation of CO2 to C2+ alcohols by tailoring the oxygen bonding via Fe-based tandem catalyst

Transductive zero-shot learning via knowledge graph and graph convolutional networks

Enabling Ethanol Dehydrogenation Catalysis by Postsynthetic Anion Exchange of Triazolate-Based Metal–Organic Frameworks

Phase synchrony between prefrontal noradrenergic and cholinergic signals indexes inhibitory control

Graph representation learning via enhanced GNNs and transformers

Near-Infrared to Visible Photon Upconversion with Gold Quantum Rods and Aqueous Photo-Driven Polymerization

Antimicrobial peptide class that forms discrete β-barrel stable pores anchored by transmembrane helices

Abstract Bacteriocin peptides are weapons of inter-bacterial warfare and belong to the larger group of antimicrobial peptides (AMPs), which are frequently proposed as alternatives to antibiotics. Many AMPs kill by destroying the target’s cytoplasmic membrane using short-lived membrane perturbations. Contrastingly, protein toxins form large pores by stably assembling in the target membrane. Here we describe an AMP class termed TMcins (for transmembrane helix-containing bacteriocin), in which half of the AMP forms a transmembrane helix. This characteristic allows TMcin to assemble into stable and large oligomeric pores. The biosynthetic locus of TMcin, which was broadly active against Gram-positive bacteria, is distributed throughout two major bacterial phyla, yet bears no homology to previously reported bacteriocin biosynthetic gene clusters. Our discovery of an AMP class that achieves pore stability otherwise only found in protein toxins transforms our current understanding of AMP structure and function and underscores the continuing importance of phenotype-initiated investigations in uncovering wholly uncharacterized antimicrobials.

Warming Alaskan rivers affect first-year growth in critical northern food fishes

Ammonia Evolution in Glycine Pyrolysis via Ionic-Pair Reaction Mechanisms

SC35-mediated bZIP49 splicing regulates K⁺ channel AKT1 for salt stress adaptation in poplar

A hybrid quantitative approach for assessment of geotechnical hazards in rock tunnels using finite element and variation coefficient methods

Nickel-Catalyzed Enantioconvergent Cross-Electrophile Coupling of Benzylic Alcohols with Alkenyl Electrophiles

Structural Transition from Closed to Open for the Influenza A M2 Proton Channel as Observed by Proton-Detected Solid-State NMR

Using COVID-19 pandemic perturbation to model RSV-hMPV interactions and potential implications under RSV interventions

Abstract Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are closely related pathogens responsible for a significant burden of acute respiratory infections. Interactions between RSV and hMPV have been hypothesized, but the mechanisms of interaction are largely unknown. Here, we use a mathematical model to quantify the likelihood of interactions from population-level surveillance data and investigate whether interactions could lead to increases in hMPV burden under RSV medical interventions, including active and passive immunization. In Scotland, Korea, and three regions of Canada, annual hMPV outbreaks lag RSV outbreaks by up to 18 weeks; two Canadian regions show patterns consistent with out-of-phase biennial outbreaks. Using a two-pathogen transmission model, we show that a negative effect of RSV infection on hMPV transmissibility can explain these dynamics. We use post-pandemic RSV-hMPV rebound dynamics as an out of sample test for our model, and the model with interactions better predicts this period than a model where the pathogens are assumed to be independent. Finally, our model suggests that hMPV peak timing and magnitude may change under RSV interventions. Our analysis provides a foundation for detecting possible RSV-hMPV interactions at the population level, although such a model oversimplifies important complexities about interaction mechanisms.