Browse Articles

Soluble CD95L triggers Caspase-10-driven reactive oxygen species production in neutrophils and aggravates anti-neutrophil cytoplasmic antibody-vasculitis

Abstract Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a severe autoimmune disease that lacks effective targeted therapies. T cell and neutrophil activation are associated with tissue lesions in ANCA-associated vasculitis responsible for the necrotizing vasculitis of small blood vessels. Although the aberrant release of reactive oxygen species (ROS) by neutrophils contribute to the disruption of the endothelial barrier, the underlying molecular mechanisms of this oxidative burst remain unclear. Here, we observe that blood vessels in the inflamed organs of patients with AAV express CD95L, which is cleaved by metalloproteases to release soluble CD95L (sCD95L). sCD95L stimulates ROS production in AAV neutrophils via a caspase-driven mechanism. Proteomic analysis reveals that the deubiquitinase OTULIN is a caspase substrate in sCD95L-exposed neutrophils. Caspase-10 cleaves OTULIN after its aspartates at positions 31 and 54 to unleash the activity of E3 ligase complex LUBAC and trigger mitochondrion-dependent ROS production in AAV neutrophils. Inhibition of the CD95-mediated non-apoptotic signaling abrogates ROS production in AAV neutrophils and alleviates clinical symptoms in AAV and crescentic glomerulonephritis mouse models, indicating that CD95 and CD95L represent attractive molecular targets for patients with AAV.

N-Bordered Rylene Arches via Programmable Curved π-Extension

Single-molecule imaging reveals RNA polymerase II dynamics and TAF1-dependent promoter-proximal pause release

A modular chromosomal passenger complex rewires chromosome segregation in Plasmodium berghei

Abstract Faithful chromosome segregation relies on precise kinetochore-microtubule interactions and checkpoint surveillance, yet the molecular basis of these processes varies widely across eukaryotes and is only beginning to be defined in apicomplexan parasites. In the malaria parasite Plasmodium berghei , chromosome segregation is especially critical during transmission from host to mosquito: rapid mitoses generate male gametes, and meiosis in the zygote seeds the next round of infection. Here, we identify Aurora-related kinase 1 (ARK1) as a central regulator of chromosome segregation in both mitotic and meiotic contexts. ARK1 localises to spindle poles, spindles, and kinetochores, and its depletion results in short and multipolar spindles, kinetochore misalignment, and failed chromosome partitioning. ARK1 forms a minimal Chromosomal Passenger Complex (CPC) with INCENP-A during male gametogenesis, but associates with additional components, including INCENP-B, kinetochores, centromeric histones, and spindle assembly checkpoint proteins, during meiosis. This stage-specific modularity supports efficient male gamete formation while safeguarding faithful chromosome inheritance during zygote development, thereby ensuring parasite transmission to the mosquito. Together, our findings indicate that P. berghei deploys distinct CPC states across sexual development, revealing developmental plasticity in chromosome-segregation control and a potential vulnerability for blocking transmission.

ATF4 coordinates amino acid and nucleotide synthesis with selective protein translation to ensure proper DNA replication timing in leukemia cells

Abstract Proper timing of DNA replication relies on sufficient nucleotide pools and replication machinery. The upstream regulatory programs that support the biomass production needed for DNA replication, particularly in the accelerated growth setting of cancer, remain incompletely defined. Here we show that the transcription factor ATF4 coordinates amino acid and nucleotide metabolism with selective protein synthesis to ensure proper DNA replication initiation and timing in acute leukemia. Specifically, ATF4 promotes the expression of enzymes that biosynthesize amino acids required for nucleotide production and drive the transcription of tRNA charging enzymes that sustain translation of a subset of proteins involved in replication origin firing. Consequently, ATF4 inhibition limits nucleotide biosynthesis and replication machinery, thereby disrupting DNA replication timing and leading to leukemia cell differentiation and death. Our findings indicate that ATF4 coordinates metabolic and translational programs to maintain DNA replication fidelity and the differentiation blockade in leukemia cells.

Dynamic heterogeneity in the self-induced spin glass state of elemental neodymium

Abstract Spin glasses are magnetic materials exhibiting numerous magnetization patterns, that randomly vary both in real space and in time. To date, it is still not well understood what the nature of these spatiotemporal dynamics is, namely if they are completely random or if there are relevant and correlated length and time scales. Here, we demonstrate dynamic heterogeneity in the aging dynamics of elemental neodymium. We used spin-polarized scanning tunneling microscopy in combination with atomistic spin dynamics simulations to image the locally ordered magnetic patterns in the self-induced spin glass state and tracked the induced spatiotemporal dynamics in response to external perturbations. We observed that the real-space magnetization exhibited a coexistence of slow and fast dynamics coinciding with particular length scales. We adapted a wavelet paradigm to identify and correlate local spatial order with its dynamical evolution. These results provide a platform to study dynamics in spin glasses beyond the mean-field limit, linking to a generalized picture of glasses.

Structural basis of nonmuscle myosin-2 autoinhibition mechanisms

Abstract Nonmuscle myosin-2 (NM2) is a fundamental actin-based mechanochemical ATPase that regulates cellular architecture, migration, adhesion, and force generation across diverse biological contexts. NM2 function is tightly regulated by a structural transition between an autoinhibited monomeric (10S) conformation in which ATPase activity, actin binding, and filament assembly are coordinately suppressed and an enzymatically active, filamentous conformation. The autoinhibited conformation is critical for the spatial and temporal control of contractility in nonmuscle cells, yet structural insights into the 10S conformation remain largely elusive. Here, we report a ~53-nm elongated full-length structure of NM2B in the 10S conformation and four distinct cryo-EM structures representing the conformational landscape within the human NM2B 10S state. These structures reveal a tri-segmented tail fold that sequesters interfaces essential for actin binding and filament assembly. The asymmetric arrangement of myosin heavy and light chains provides a mechanistic foundation for understanding how regulatory post-translational modifications and disease-associated mutations shift NM2 conformational equilibria and may enable the development of structure-based interventions for cytoskeletal diseases including hearing loss, neurodegeneration, and cancer.

Tetravalent organic cation-enabled dual interfacial regulation for durable aqueous zinc–iodine batteries

Cobaloxime-catalysed regiodivergent hydrogen atom transfer for alkenyl and allylic carbamoylation with branched alkenes

Direction-resolved nanoscale optical imaging with near-nanometer resolution by emerging infrared torsional force microscopy

Biomimetic ferroelectric-semiconductor transistor enables neuronal multisensory integration

PGS Browser: a public platform for personalized polygenic score analysis and interpretation

Ambient pressure recovery of the structurally unconventional hydride Y3Fe4H20

Water-modulated conformational heterogeneity underlies multiple timescales of primary charge separation in photosystem II

Abstract The kinetics of charge separation in Photosystem II, initiated within the reaction center, remain debated due to spectral congestion and overlapping timescales with energy transfer. Here, by means of atomistic molecular dynamics and quantum dynamics simulations, we present a kinetic model that attributes the observed multi-exponential behavior of the primary charge separation step to water-modulated conformational heterogeneity rather than to parallel pathways involving chemically distinct intermediate radical pairs. We propose that charge separation proceeds predominantly via the $${\,{{{\rm{Chl}}}}}_{{{{\rm{D1}}}}}^{+}{\,{{{\rm{Pheo}}}}}_{{{{\rm{D1}}}}}^{-}$$ Chl D1 + Pheo D1 − intermediate radical pair, with structural fluctuations of protein and solvent, specifically dynamic water channels near the oxygen-evolving complex, governing the multi-exponential kinetics. Analytical resolution of a kinetic scheme, which also incorporates pre-equilibration within the excited-state manifold of the reaction center, yields apparent lifetimes ( < 250 fs, 386 fs, 2.7 ps) comparable with experimental data. This model reconciles previous conflicting assignments and emphasizes the role of protein-solvent dynamics in shaping ultrafast charge separation.

NK cell dysregulation may potentiate cardiovascular disease in adolescents with perinatally acquired HIV on antiretroviral therapy

Overcoming chromium poisoning in solid oxide cells through multiscale perovskite engineering

Hydroxyl chemistry regulation of cellulose biopolymers for aqueous zinc battery binders

A role for the poly-asparagine repeat in the Plasmodium histone acetyltransferase, PfGCN5

Abstract Plasmodium falciparum possesses one of the most AT-rich genomes in nature (80.6%). A consequence is an asparagine-rich proteome. A quarter of P. falciparum proteins possess poly-asparagine repeats that can extend more than 100 residues. The role of these repeats has remained a mystery in the biology of this parasite. Here, we report that the poly-asparagine repeat-containing Nterminus of the histone acetyltransferase PfGCN5 associates with the C-terminal catalytic domain after cleavage in the nucleus. Deletion of the repeat destabilizes the N-terminal polypeptide, leading to impaired parasite development and growth, particularly under stress conditions. Using high-resolution mass spectrometry and western blotting analysis, we uncovered a profound effect of the poly-asparagine repeat on acetylation of histones H3, H3.3, and H4. These findings suggest that the poly-asparagine repeat contributes to PfGCN5 acetyltransferase activity, a role previously attributed solely to its C-terminal domain. This report of a function for a poly-asparagine repeat in P. falciparum expands our understanding of a pervasive characteristic of its proteome.

Aridity-related differences in soil elemental ratios reshape microbial functional traits across global biomes

A synaptoid connectome differentiates tanycytic subpopulations and underlies neuroglial communication and neuroendocrine regulation

Abstract Tanycytes are radial-glia-like cells that play important roles in regulating the neuroendocrine system and metabolism. Synapse-like (synaptoid) connections have previously been described between neurons and tanycytes, but their structure and function are unclear. Here, we report that neuron-tanycyte synaptoids are abundant and resemble typical neuronal synapses in shape and composition. Tanycytic subtypes receive specific inputs from a variety of hypothalamic as well as extrahypothalamic neuronal populations and respond to several neurotransmitters and neuromodulators. As proof-of-principle of their functional relevance, we demonstrate in mice, that two distinct populations of kisspeptin neurons, which stimulate the gonadotropic axis, innervate different tanycytic subsets of the mediobasal hypothalamus to control basal levels of the gonadotropin luteinizing hormone (LH) and its pulsatile release pattern, in a sex‑ and region‑specific manner. Neuron-tanycyte synaptoid connections are thus widespread, diverse and functionally specific elements of hypothalamic neural circuits that play a key role in finetuning hormonal axes.