Dendritic Cell-Mediated Cross-Priming by a Bispecific Neutralizing Antibody Boosts Cytotoxic T Cell Responses and Protects Mice against SARS-CoV-2.

Administration of neutralizing antibodies (nAbs) has proved to be effective by providing immediate protection against SARS-CoV-2. However, dual strategies combining virus neutralization and immune response stimulation to enhance specific cytotoxic T cell responses, such as dendritic cell (DC) cross-priming, represent a promising field but have not yet been explored. Here, a broadly nAb, TN , are first generated by grafting an anti-RBD biparatopic tandem nanobody onto a trimerbody scaffold.

Membrane binding and pore formation is Ca -dependent for the binary toxin.

The binary toxin (CDT) enters host cells via endosomal delivery like many other 'AB'-type binary toxins. In this study, the cell-binding component of CDT, termed CDTb, was found to bind and form pores in lipid bilayers upon depleting free Ca ion concentrations, and not by lowering pH, as found for other binary toxins (i.e.

The Importance of Therapeutically Targeting the Binary Toxin from .

Novel therapeutics are needed to treat pathologies associated with the binary toxin (CDT), particularly when infection (CDI) occurs in the elderly or in hospitalized patients having illnesses, in addition to CDI, such as cancer. While therapies are available to block toxicities associated with the large clostridial toxins (TcdA and TcdB) in this nosocomial disease, nothing is available yet to treat toxicities arising from strains of CDI having the binary toxin. Like other binary toxins, the active CDTa catalytic subunit of CDT is delivered into host cells together with an oligomeric assembly of CDTb subunits via host cell receptor-mediated endocytosis.

Mapping of Photochemically-Derived Dityrosine across Fe-Bound N-Acetylated α-Synuclein.

Parkinson's disease (PD) is the second most common neurological disease and belongs to a group of neurodegenerative disorders called synucleinopathies in which pathological aggregates of N-terminally acetylated α-synuclein (α-Syn) accumulate in various regions of the brain. In PD, these α-Syn aggregates have been found to contain covalent dityrosine crosslinks, which can occur either intermolecularly or intramolecularly. Cerebral metal imbalance is also a hallmark of PD, warranting investigations into the effects of brain biometals on α-Syn.

Biometals as conformational modulators of α-synuclein photochemical crosslinking.

Metal dyshomeostasis has long been linked to Parkinson's disease (PD), and the amyloidogenic protein α-synuclein (αS) is universally recognized as a key player in PD pathology. Structural consequences upon coordination of copper and iron to αS have gained attention due to significant dyshomeostasis of both metals in the PD brain. Protein-metal association can navigate protein folding in distinctive pathways based on the identity of the bio-metal in question.

Iron Redox Chemistry and Implications in the Parkinson's Disease Brain.

The etiology of Parkinson's disease (PD) is linked with cellular inclusions in the region of the brain that are enriched in the misfolded presynaptic protein -synuclein (S) and death of the dopaminergic neurons. Brain iron homeostasis governs both neurotransmission and neurodegeneration; hence, the role of iron in PD progression and neuronal health is apparent. Elevated iron deposits become prevalent in the cerebral region upon aging and even more so in the PD brain.

Copper Induced Radical Dimerization of α-Synuclein Requires Histidine.

Aggregation of the neuronal protein α-synuclein (αS) is a critical factor in the pathogenesis of Parkinson's disease. Analytical methods to detect post-translational modifications of αS are under development, yet the mechanistic underpinnings of biomarkers like dityrosine formation within αS have yet to be established. In our work, we demonstrate that Cu-bound N-terminally acetylated αS (αS) activates O resulting in both intermolecular dityrosine cross-linking within the fibrillar core as well as intramolecular cross-linking within the C-terminal region.

C-Terminal Cu Coordination to α-Synuclein Enhances Aggregation.

The structurally dynamic amyloidogenic protein α-synuclein (αS) is universally recognized as a key player in Parkinson's disease (PD). Copper, which acts as a neuronal signaling agent, is also an effector of αS structure, aggregation, and localization in vivo. In humans, αS is known to carry an acetyl group on the starting methionine residue, capping the N-terminal free amine which was a known high-affinity Cu binding site.

Iron Redox Chemistry Promotes Antiparallel Oligomerization of α-Synuclein.

Brain metal dyshomeostasis and altered structural dynamics of the presynaptic protein α-synuclein (αS) are both implicated in the pathology of Parkinson's disease (PD), yet a mechanistic understanding of disease progression in the context of αS structure and metal interactions remains elusive. In this Communication, we detail the influence of iron, a prevalent redox-active brain biometal, on the aggregation propensity and secondary structure of N-terminally acetylated αS (αS), the physiologically relevant form in humans. We demonstrate that under aerobic conditions, Fe(II) commits αS to a PD-relevant oligomeric assembly, verified by the oligomer-selective A11 antibody, that does not have any parallel β-sheet character but contains a substantial right-twisted antiparallel β-sheet component based on CD analyses and descriptive deconvolution of the secondary structure.