The pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection involves dysregulations of iron metabolism, and although the mechanism of this pathology is not yet fully ...understood, correction of iron metabolism pathways seems a promising pharmacological target. The previously observed effect of inhibiting SARS-CoV-2 infection by ferristatin II, an inducer of transferrin receptor 1 (TfR1) degradation, prompted the study of competition between Spike protein and TfR1 ligands, especially lactoferrin (Lf) and transferrin (Tf). We hypothesized molecular mimicry of Spike protein as cross-reactivity of Spike-specific antibodies with Tf and Lf. Thus, strong positive correlations (R
2
> 0.95) were found between the level of Spike-specific IgG antibodies present in serum samples of COVID-19-recovered and Sputnik V-vaccinated individuals and their Tf-binding activity assayed with peroxidase-labeled anti-Tf. In addition, we observed cross-reactivity of Lf-specific murine monoclonal antibody (mAb) towards the SARS-CoV-2 Spike protein. On the other hand, the interaction of mAbs produced to the receptor-binding domain (RBD) of the Spike protein with recombinant RBD protein was disrupted by Tf, Lf, soluble TfR1, anti-TfR1 aptamer, as well as by peptides RGD and GHAIYPRH. Furthermore, direct interaction of RBD protein with Lf, but not Tf, was observed, with affinity of binding estimated by K
D
to be 23 nM and 16 nM for apo-Lf and holo-Lf, respectively. Treatment of Vero E6 cells with apo-Lf and holo-Lf (1–4 mg/mL) significantly inhibited SARS-CoV-2 replication of both Wuhan and Delta lineages. Protective effects of Lf on different arms of SARS-CoV-2-induced pathogenesis and possible consequences of cross-reactivity of Spike-specific antibodies are discussed.
Non-pathogenic bacteria
Serratia grimesii
able to enter eukaryotic cells, but the mechanisms of their invasive activity are still unknown. We have previously shown that
S. grimesii
could
in vitro
...secrete outer membrane vesicles (OMVs) that itself penetrate eukaryotic cells and enhance the invasion of
S. grimesii
into these cells (Bozhokina et al., 2020). Therefore, the aim of this work is to study the role of
S. grimesii
OMVs in the process of interaction between bacteria and the host cell. Our results obtained that exposure to cold shock or oxidative stress caused by hydrogen peroxide increases the secretion of OMVs by
S. grimesii
, and isolated vesicles enhance bacterial invasion into CaCo-2 cells. In addition,
S. grimesii
OMVs induce immune response of CaCo-2 cells, and reveal cytotoxic activity towards these cells, determined by the level of release of lactate dehydrogenase from cell cytoplasm. In the presence of outer membrane vesicles obtained under stress conditions, bacteria could more actively adhere and penetrate into CaCo-2 cells. In addition, a participation of cell surface receptor E-cadherin in
S. grimesii
OMVs invasion into CaCo-2 cells was demonstrated for the first time. The obtained results suggest that OMVs-mediated delivery of virulence factors to eukaryotic cells may significantly contribute to the pathogenesis caused by
S. grimesii
infection.
Neurons make converging and diverging synaptic connections with distinct partner types. Whether synapses involving separate partners demonstrate similar or distinct structural motifs is not yet well ...understood. We thus used serial electron microscopy in mouse retina to map output synapses of cone bipolar cells (CBCs) and compare their structural arrangements across bipolar types and postsynaptic partners. Three presynaptic configurations emerge—single-ribbon, ribbonless, and multiribbon synapses. Each CBC type exploits these arrangements in a unique combination, a feature also found among rabbit ON CBCs. Though most synapses are dyads, monads and triads are also seen. Altogether, mouse CBCs exhibit at least six motifs, and each CBC type uses these in a stereotypic pattern. Moreover, synapses between CBCs and particular partner types appear biased toward certain motifs. Our observations reveal synaptic strategies that diversify the output within and across CBC types, potentially shaping the distinct functions of retinal microcircuits.
Display omitted
•Output synapses of cone bipolar cells (CBCs) show six structural motifs•CBC types differ in their allocation of output synapses to these motifs•Synaptic monads involving amacrine cells are commonly observed•CBC synapses with specific partners are biased toward certain motifs
Yu et al. find that mouse retinal cone bipolar cells exhibit at least six structurally distinct motifs at their output synapses. The combination of motifs of each bipolar cell type appears stereotypic. Synapses between a bipolar cell type and a postsynaptic partner type are biased toward a subset of motifs.
TDP-43 is the major disease protein associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-TDP). Here we identify the ...transcriptional elongation factor Ell-a shared component of little elongation complex (LEC) and super elongation complex (SEC)-as a strong modifier of TDP-43-mediated neurodegeneration. Our data indicate select targets of LEC and SEC become upregulated in the fly ALS/FTLD-TDP model. Among them, U12 snRNA and a stress-induced long non-coding RNA Hsrω, functionally contribute to TDP-43-mediated degeneration. We extend the findings of Hsrω, which we identify as a chromosomal target of TDP-43, to show that the human orthologue Sat III is elevated in a human cellular disease model and FTLD-TDP patient tissue. We further demonstrate an interaction between TDP-43 and human ELL2 by co-immunoprecipitation from human cells. These findings reveal important roles of Ell-complexes LEC and SEC in TDP-43-associated toxicity, providing potential therapeutic insight for TDP-43-associated neurodegeneration.
Orbital lesions compose a heterogeneous group of pathologies that often present with non-specific imaging findings on conventional magnetic resonance imaging (MRI) sequences (T1-and T2-weighted). ...Accordingly, the application of diffusion MRI offers an opportunity to further distinguish between lesions along this spectrum. Diffusion-weighted imaging (DWI) represents the simplest and most frequent clinically utilised diffusion imaging technique. Recent advances in DWI techniques have extended its application to the evaluation of a wider spectrum of neurological pathology, including orbital lesions. This review details the manifestations of select orbital pathology on DWI and underscores specific situations where diffusion imaging allows for increased diagnostic sensitivity compared to more conventional MRI techniques. These examples also describe preferred management for orbital lesions identified by DWI.
Regulation of chromatin structure is critical for brain development and function. However, the involvement of chromatin dynamics in neurodegeneration is less well understood. Here we find, launching ...from Drosophila models of amyotrophic lateral sclerosis and frontotemporal dementia, that TDP-43 impairs the induction of multiple key stress genes required to protect from disease by reducing the recruitment of the chromatin remodeler Chd1 to chromatin. Chd1 depletion robustly enhances TDP-43-mediated neurodegeneration and promotes the formation of stress granules. Conversely, upregulation of Chd1 restores nucleosomal dynamics, promotes normal induction of protective stress genes, and rescues stress sensitivity of TDP-43-expressing animals. TDP-43-mediated impairments are conserved in mammalian cells, and, importantly, the human ortholog CHD2 physically interacts with TDP-43 and is strikingly reduced in level in temporal cortex of human patient tissue. These findings indicate that TDP-43-mediated neurodegeneration causes impaired chromatin dynamics that prevents appropriate expression of protective genes through compromised function of the chromatin remodeler Chd1/CHD2. Enhancing chromatin dynamics may be a treatment approach to amyotrophic lateral scleorosis (ALS)/frontotemporal dementia (FTD).
Display omitted
•TDP-43 cripples the stress response•TDP-43 impairs nucleosomal dynamics and the induction of heat shock genes•TDP-43 physically interacts with fly Chd1 and human CHD2•Reduced levels of human CHD2 protein are observed in frontotemporal dementia
Berson et al. show that TDP-43, a protein associated with ALS and FTD, impairs the stress response by interfering with the chromatin remodeling protein Chd1 in flies and CHD2 in mammalian cells. In turn, animals expressing TDP-43 are hypersensitive to various types of stressors, indicating that this impairment may promote neurodegeneration.
The original version of this Article contained an error in the author affiliations. The affiliation of Alice Chen-Plotkin with the Department of Neurology, Perelman School of Medicine, Philadelphia, ...PA, 19104 USA was inadvertently omitted. This has now been corrected in both the PDF and HTML versions of the Article.
Extracellular ATP is implicated in numerous sensory processes ranging from the response to pain to the regulation of motility in visceral organs. The ATP receptor P2X3 is selectively expressed on ...small diameter sensory neurons, supporting this hypothesis. Here we show that mice deficient in P2X3 lose the rapidly desensitizing ATP-induced currents in dorsal root ganglion neurons. P2X3 deficiency also causes a reduction in the sustained ATP-induced currents in nodose ganglion neurons. P2X3-null mice have reduced pain-related behaviour in response to injection of ATP and formalin. Significantly, P2X3-null mice exhibit a marked urinary bladder hyporeflexia, characterized by decreased voiding frequency and increased bladder capacity, but normal bladder pressures. Immunohistochemical studies localize P2X3 to nerve fibres innervating the urinary bladder of wild-type mice, and show that loss of P2X3 does not alter sensory neuron innervation density. Thus, P2X3 is critical for peripheral pain responses and afferent pathways controlling urinary bladder volume reflexes. Antagonists to P2X3 may therefore have therapeutic potential in the treatment of disorders of urine storage and voiding such as overactive bladder.
Extracellular ATP is implicated in numerous sensory processes ranging from
the response to pain to the regulation of motility in visceral organs. The ATP receptor P2X3 is selectively expressed on ...small
diameter sensory neurons, supporting this hypothesis.
Here we show that mice deficient in P2X3 lose the rapidly desensitizing
ATP-induced currents in dorsal root ganglion neurons. P2X3 deficiency
also causes a reduction in the sustained ATP-induced currents in nodose ganglion
neurons. P2X3-null mice have reduced pain-related behaviour in
response to injection of ATP and formalin. Significantly, P2X3-null
mice exhibit a marked urinary bladder hyporeflexia, characterized by decreased
voiding frequency and increased bladder capacity, but normal bladder pressures.
Immunohistochemical studies localize P2X3 to nerve fibres innervating
the urinary bladder of wild-type mice, and show that loss of P2X3
does not alter sensory neuron innervation density. Thus, P2X3 is
critical for peripheral pain responses and afferent pathways controlling urinary
bladder volume reflexes. Antagonists to P2X3 may therefore have
therapeutic potential in the treatment of disorders of urine storage and voiding
such as overactive bladder.
PDF
