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Strategies to Reinvigorate the Bedside Clinical Encounter

Microbiota-induced T cell plasticity enables immune-mediated tumour control

Abstract Therapies that harness the immune system to target and eliminate tumour cells have revolutionized cancer care. Immune checkpoint blockade (ICB), which boosts the anti-tumour immune response by inhibiting negative regulators of T cell activation 1–3 , is remarkably successful in a subset of cancer patients. Yet a significant proportion do not respond to treatment, emphasizing the need to understand factors influencing the therapeutic efficacy of ICB 4–9 . The gut microbiota, consisting of trillions of microorganisms residing in the gastrointestinal tract, has emerged as a critical determinant of immune function and response to cancer immunotherapy, with several studies demonstrating association of microbiota composition with clinical response 10–16 . However, a mechanistic understanding of how gut commensal bacteria influence the efficacy of ICB remains elusive. Here we use a gut commensal microorganism, segmented filamentous bacteria (SFB), which induces an antigen-specific T helper 17 (T H 17) cell effector program in the small intestine lamina propria (SILP) 17 , to investigate how colonization with this microbe affects the efficacy of ICB in restraining distal growth of tumours sharing antigen with SFB. We find that anti-programmed cell death protein 1 (PD-1) treatment effectively inhibits the growth of implanted SFB antigen-expressing melanoma only if mice are colonized with SFB. Through T cell receptor (TCR) clonal lineage tracing, fate mapping and peptide–major histocompatability complex (MHC) tetramer staining, we identify tumour-associated SFB-specific T helper 1 (T H 1)-like cells derived from the homeostatic T H 17 cells induced by SFB colonization in the SILP. These gut-educated ex-T H 17 cells produce high levels of the pro-inflammatory cytokines interferon (IFN)-γ and tumour necrosis factor (TNF) within the tumour microenvironment (TME), enhancing antigen presentation and promoting recruitment, expansion and effector functions of CD8 + tumour-infiltrating cytotoxic lymphocytes and thereby enabling anti-PD-1-mediated tumour control. Conditional ablation of SFB-induced IL-17A + CD4 +  T cells, precursors of tumour-associated T H 1-like cells, abolishes anti-PD-1-mediated tumour control and markedly impairs tumour-specific CD8 + T cell recruitment and effector function within the TME. Our data, as a proof of principle, define a cellular pathway by which a single, defined intestinal commensal imprints T cell plasticity that potentiates PD-1 blockade, and indicate targeted modulation of the microbiota as a strategy to broaden ICB efficacy.

Simulation of icing calculation based on VOF model for wheel spray and landing gear water accumulation

Revealing intrinsic 3D spin angular momentum of evanescent acoustic phonons on a single-crystal surface using ultrafast optoacoustics

Expiratory Central Airway Collapse

Experimental performance comparison of fixed and single-axis subfields in a large-scale outdoor photovoltaic power plant

Clusters of vascular aging manifestations predict incident cardiovascular events in the community

Updated Evidence Base for Covid-19, RSV, and Influenza Immunizations

Synthesis, characterization of Mg doped CuFe2O4 nanoparticles for potential anticancer applications

Abstract Ferrite nanoparticles (NPs) have emerged as promising candidates for cancer therapy. In this study, Mg-doped copper ferrite NPs, MgₓCu₁₋ₓFe 2 O 4 (x = 0.0, 0.5, and 1.0), were synthesized via a citrate–nitrate combustion method and evaluated for their anticancer potential. Structural and morphological characteristics were analyzed using powder X-ray diffraction, field-emission scanning electron microscopy, and energy-dispersive X-ray spectroscopy. Cytotoxicity against human cancer cell lines was assessed using MTT and flow cytometry assays, along with analyses of reactive oxygen species (ROS) generation and apoptosis. Among the compositions studied, Cu 0.5 Mg 0.5 Fe 2 O 4 demonstrated the highest cytotoxic efficacy, with IC₅₀ values of 17.2 ± 0.15 µg/mL (PC-3) and 25.04 ± 0.28 µg/mL (Caco-2). Flow cytometric analysis revealed increased total apoptosis of 42.08% and 34.95% in PC-3 and Caco-2 cells, respectively. Gene expression analysis revealed downregulation of Bcl-2 and Cyclin D and upregulation of BAX, P53, and Caspase-3, indicating ROS-mediated mitochondria-dependent apoptosis. The enhanced anticancer activity of Cu 0.5 Mg 0.5 Fe 2 O 4 is attributed to its optimized size, surface charge, and composition, which promote cellular uptake, ROS generation, DNA damage, and interactions with cellular components. These findings highlight the potential of mixed-metal ferrite nanoparticles as effective nanomaterial-based cancer therapeutics.

Linker histones consolidate heterogenous nucleosome fiber contacts by linking together multiple nucleosomes

Abstract The consensus mode for linker histone (H1) association coincides with ‘on-dyad’ binding to an individual nucleosome, making it challenging to rationalize the chromatin dynamics and compacting activities of H1 in the context of a highly heterogeneous structural scaffold. Here, we investigate the activity of the somatic H1 variants by conducting crystallographic analysis of nucleosomal assemblies and characterization of nucleosome array condensates, which recapitulate long-range nucleosome fiber interactions in chromatin. H1 is observed to associate variant-dependently with nucleosomes through a diversity of binding modes that include linking multiple nucleosomes/fibers together. Binding versatility is facilitated by the proclivity of the H1 globular domain to recognize DNA structural motifs, which are similar between an individual nucleosome and specific niches within clusters of nucleosomes. We propose that linker histones support a structurally and functionally complex repertoire for chromatin regulation by assuming a variety of context-and variant-dependent DNA binding modes.

Debt by Design — Navigating the Hazards of Medical Credit Cards

Cold-injection synthesis of highly emissive perovskite nanocrystals

Integrative taxonomic study reveals a new species of Maculolachnus (Hemiptera: Aphididae) from South Korea

Pathways to global hydrogen production within planetary boundaries

Neoadjuvant GOLP in Resectable High-Risk Intrahepatic Cholangiocarcinoma

Linking cortical morphology and neurophysiological dynamics in Parkinson’s disease

Bioinspired nanofluidic iontronic device with integrated photoreceptor and photosynaptic functions

Blood-Pressure Targets in Hypertension Management

In situ formation of nanocrystalline Ni(OH)2 in alkaline electrolyte explains superior capacitance and cycling stability of Ni3S2/NF electrodes

Abstract The free-standing Ni 3 S 2 electrode was fabricated via a simple one-step hydrothermal method at 160 °C through the sulfidization of nickel foam (NF). The as-synthesized samples exhibited X-ray diffraction (XRD) patterns and Raman spectra consistent with the formation of Ni 3 S 2 Although the XRD reflections of the Ni 3 S 2 lattice remained unchanged after short-term electrochemical activation in 3.5 M KOH electrolyte, the Raman spectrum evolved to resemble that of oxidized nickel species, indicating a surface transformation of the electrode under electrochemical conditions. Prolonged redox cycling of the electrode for more than 10,000 cycles resulted in noticeable modifications of the XRD pattern. In addition to the characteristic reflections of the Ni 3 S 2 phase, the formation of β-Ni(OH) 2 nanoparticles was observed, with an average crystallite size of approximately 2.8 nm, as estimated using the Scherrer equation. The resulting heterostructured Ni(OH) 2 /Ni 3 S 2 /NF electrode exhibited an areal capacitance of 4.1 C cm –2 at a current density of 20 mA cm –2 when evaluated in a three-electrode configuration. The electrode demonstrated progressively enhanced capacitance stability with continued cycling. Capacitance retention increased from 19% after the first 10,000 cycles to 41% after the second 10,000 cycles, 66% after the third 8,000 cycles, and ultimately 79% after the fourth 6,000 cycles. Taking into account the electrochemical activation occurring between cycling intervals, the overall capacitance retention reached 72% after more than 30,000 cycles. Although the electrode capacitance decreased during galvanostatic charge–discharge (GCD) cycling, it could be partially recovered through subsequent cyclic voltammetry (CV) activation. Concurrently, a broad XRD reflection attributable to the α-Ni(OH) 2 phase emerged, providing valuable insight into the structural evolution of the electrode and the underlying electrochemical energy-storage mechanism. The Ni(OH) 2 /Ni 3 S 2 /NF electrode aged through 10,000 GCD cycles was subsequently employed as the positive battery-type electrode in a hybrid supercapacitor, paired with an activated carbon negative electrode. The assembled device, with a Ni 3 S 2 /NF electrode area of 6 cm 2 , delivered an areal capacitance of 4.63 C cm –2 at a current density of 4 mA cm –2 and maintained 83.5% capacitance retention after more than 20,000 charge–discharge cycles.

Adaptations in Plasmodium tubulin determine distinct microtubule architectures, mechanics and drug susceptibility

Abstract Microtubules are ubiquitous yet diverse cytoskeleton filaments. However, tubulin conservation presents challenges in understanding the origins of diverse microtubule architectures. The mechanisms by which microtubule architecture varies through the life cycle of the malaria-causing parasite Plasmodium are not understood and provide a valuable framework for exploring how intrinsic properties of tubulin contribute to architectural variety. Using parasite-purified tubulin, we determine P. falciparum microtubule structures by cryo-electron microscopy. Parasite-specific sequences change the tubulin dimer structure, suggesting how drug susceptibility and polymer properties are modified. Within the P. falciparum microtubule, lateral contacts are smaller but stronger, and the lattice is stiffer than in brain microtubules. Non-canonical microtubule architectures found in parasites are highly similar to those observed in vitro, validating the physiological relevance of these properties. Our findings show how evolutionary adaptation of tubulin modulates the material properties of the microtubule cytoskeleton.