While glycans are among the most abundant macromolecules on the cell with widespread functions, their role in immunity has historically been challenging to study. This is in part due to difficulties ...assimilating glycan analysis into routine approaches used to interrogate immune cell function. Despite this, recent developments have illuminated fundamental roles for glycans in host immunity. The growing field of glycoimmunology continues to leverage new tools and approaches to uncover the function of glycans and glycan-binding proteins in immunity. Here we utilize clinical vignettes to examine key roles of glycosylation in allergy, inborn errors of immunity, and autoimmunity. We will discuss the diverse functions of glycans as epitopes, as modulators of antibody function, and as regulators of immune cell function. Finally, we will highlight immune modulatory therapies that harness the critical role of glycans in the immune system.
•CD4 T-cell proliferation can occur irrespective of whether antibodies induce AMIS.•Antibodies that rapidly remove the target antigen in the absence of RBC clearance can switch an augmented antibody ...response to AMIS.
Display omitted
Antibodies against fetal red blood cell (RBC) antigens can cause hemolytic disease of the fetus and newborn (HDFN). Reductions in HDFN due to anti-RhD antibodies have been achieved through use of Rh immune globulin (RhIg), a polyclonal antibody preparation that causes antibody-mediated immunosuppression (AMIS), thereby preventing maternal immune responses against fetal RBCs. Despite the success of RhIg, it is only effective against 1 alloantigen. The lack of similar interventions that mitigate immune responses toward other RBC alloantigens reflects an incomplete understanding of AMIS mechanisms. AMIS has been previously attributed to rapid antibody-mediated RBC removal, resulting in B-cell ignorance of the RBC alloantigen. However, our data demonstrate that antibody-mediated RBC removal can enhance de novo alloimmunization. In contrast, inclusion of antibodies that possess the ability to rapidly remove the target antigen in the absence of detectable RBC clearance can convert an augmented antibody response to AMIS. These results suggest that the ability of antibodies to remove target antigens from the RBC surface can trigger AMIS in situations in which enhanced immunity may otherwise occur. In doing so, these results hold promise in identifying key antibody characteristics that can drive AMIS, thereby facilitating the design of AMIS approaches toward other RBC antigens to eliminate all forms of HDFN.
Anti-RhD immunoprophylaxis works because of antibody-mediated immunosuppression (AMIS), but the mechanisms governing AMIS are poorly understood. Using an established murine model of red blood cell (RBC) alloimmunization, Jajosky et al demonstrate that passive immunization with RBC antibodies can remove target antigens from RBCs without affecting RBC clearance or CD4+ T-cell proliferation, thereby converting an augmented RBC alloimmune response to AMIS. These data have implications for how immunoprophylaxis is approached for non-RhD hemolytic disease of the fetus and newborn.
Abstract
The histone methyltransferase Dot1 is conserved from yeast to human and methylates lysine 79 of histone H3 (H3K79) on the core of the nucleosome. H3K79 methylation by Dot1 affects gene ...expression and the response to DNA damage, and is enhanced by monoubiquitination of the C-terminus of histone H2B (H2Bub1). To gain more insight into the functions of Dot1, we generated genetic interaction maps of increased-dosage alleles of DOT1. We identified a functional relationship between increased Dot1 dosage and loss of the DUB module of the SAGA co-activator complex, which deubiquitinates H2Bub1 and thereby negatively regulates H3K79 methylation. Increased Dot1 dosage was found to promote H2Bub1 in a dose-dependent manner and this was exacerbated by the loss of SAGA-DUB activity, which also caused a negative genetic interaction. The stimulatory effect on H2B ubiquitination was mediated by the N-terminus of Dot1, independent of methyltransferase activity. Our findings show that Dot1 and H2Bub1 are subject to bi-directional crosstalk and that Dot1 possesses chromatin regulatory functions that are independent of its methyltransferase activity.
Autophagy is a critical process in the regulation of muscle mass, function and integrity. The molecular mechanisms regulating autophagy are complex and still partly understood. Here, we identify and ...characterize a novel FoxO-dependent gene, d230025d16rik which we named Mytho (Macroautophagy and YouTH Optimizer), as a regulator of autophagy and skeletal muscle integrity in vivo. Mytho is significantly up-regulated in various mouse models of skeletal muscle atrophy. Short term depletion of MYTHO in mice attenuates muscle atrophy caused by fasting, denervation, cancer cachexia and sepsis. While MYTHO overexpression is sufficient to trigger muscle atrophy, MYTHO knockdown results in a progressive increase in muscle mass associated with a sustained activation of the mTORC1 signaling pathway. Prolonged MYTHO knockdown is associated with severe myopathic features, including impaired autophagy, muscle weakness, myofiber degeneration, and extensive ultrastructural defects, such as accumulation of autophagic vacuoles and tubular aggregates. Inhibition of the mTORC1 signaling pathway in mice using rapamycin treatment attenuates the myopathic phenotype triggered by MYTHO knockdown. Skeletal muscles from human patients diagnosed with myotonic dystrophy type 1 (DM1) display reduced Mytho expression, activation of the mTORC1 signaling pathway and impaired autophagy, raising the possibility that low Mytho expression might contribute to the progression of the disease. We conclude that MYTHO is a key regulator of muscle autophagy and integrity.
The biological properties of sixteen structurally related monoanionic gold (III) bis(dithiolene/ diselenolene) complexes were evaluated. The complexes differ in the nature of the heteroatom connected ...to the gold atom (AuS for dithiolene, AuSe for diselenolene), the substituent on the nitrogen atom of the thiazoline ring (Me, Et, Pr, iPr and Bu), the nature of the exocyclic atom or group of atoms (O, S, Se, C(CN)2) and the counter-ion (Ph4P+ or Et4N+). The anticancer and antimicrobial activities of all the complexes were investigated, while the anti-HIV activity was evaluated only for selected complexes. Most complexes showed relevant anticancer activities against Cisplatin-sensitive and Cisplatin-resistant ovarian cancer cells A2780 and OVCAR8, respectively. After 48 h of incubation, the IC50 values ranged from 0.1–8 μM (A2780) and 0.8–29 μM (OVCAR8). The complexes with the Ph4P+ (P) counter-ion are in general more active than their Et4N+ (N) analogues, presenting IC50 values in the same order of magnitude or even lower than Auranofin. Studies in the zebrafish embryo model further showed that, despite their marked anticancer effect, the complexes with P counter-ion exhibited low in vivo toxicity. In general, the exocyclic exchange of sulfur by oxygen or ylidenemalononitrile (C(CN)2) enhanced the compounds toxicity. Most complexes containing the P counter ion exhibited exceptional antiplasmodial activity against the Plasmodium berghei parasite liver stages, with submicromolar IC50 values ranging from 400–700 nM. In contrast, antibacterial/fungi activities were highest for most complexes with the N counter-ion. Auranofin and two selected complexes PAuSBu(=S) and PAuSEt(=S) did not present anti-HIV activity in TZM-bl cells. Mechanistic studies for selected complexes support the idea that thioredoxin reductase, but not DNA, is a possible target for some of these complexes. The complexes P AuSBu(=S), P AuSEt(=S), P AuSEt(=Se) and P AuSeiPr(=S) displayed a strong quenching of the fluorescence intensity of human serum albumin (HSA), which indicates a strong interaction with this protein. Overall, the results highlight the promising biological activities of these complexes, warranting their further evaluation as future drug candidates with clinical applicability.
The evolution of respiratory diseases represents a considerable public health challenge, as they are among the leading causes of death worldwide. In this sense, in addition to the high prevalence of ...diseases such as asthma, chronic obstructive pulmonary disease, pneumonia, cystic fibrosis, and lung cancer, emerging respiratory diseases, particularly those caused by members of the coronavirus family, have contributed to a significant number of deaths on a global scale over the last two decades. Therefore, several studies have been conducted to optimize the efficacy of treatments against these diseases, focusing on pulmonary drug delivery using nanomedicine. Thus, the development of nanocarriers has emerged as a promising alternative to overcome the limitations of conventional therapy, by increasing drug bioavailability at the target site and reducing unwanted side effects. In this context, nanoparticles composed of chitosan (CS) show advantages over other nanocarriers because chitosan possesses intrinsic biological properties, such as anti-inflammatory, antimicrobial, and mucoadhesive capacity. Moreover, CS nanoparticles have the potential to enhance drug stability, prolong the duration of action, improve drug targeting, control drug release, optimize dissolution of poorly soluble drugs, and increase cell membrane permeability of hydrophobic drugs. These properties could optimize the performance of the drug after its pulmonary administration. Therefore, this review aims to discuss the potential of chitosan nanoparticles for pulmonary drug delivery, highlighting how their biological properties can improve the treatment of pulmonary diseases, including their synergistic action with the encapsulated drug.
New, ultrasmall nanoparticles with sizes below 5 nm have been obtained. These small rigid platforms (SRP) are composed of a polysiloxane matrix with DOTAGA (1,4,7,10‐tetraazacyclododecane‐1‐glutaric ...anhydride‐4,7,10‐triacetic acid)–Gd3+ chelates on their surface. They have been synthesised by an original top‐down process: 1) formation of a gadolinium oxide Gd2O3 core, 2) encapsulation in a polysiloxane shell grafted with DOTAGA ligands, 3) dissolution of the gadolinium oxide core due to chelation of Gd3+ by DOTAGA ligands and 4) polysiloxane fragmentation. These nanoparticles have been fully characterised using photon correlation spectroscopy (PCS), transmission electron microscopy (TEM), a superconducting quantum interference device (SQUID) and electron paramagnetic resonance (EPR) to demonstrate the dissolution of the oxide core and by inductively coupled plasma mass spectrometry (ICP‐MS), mass spectrometry, fluorescence spectroscopy, 29Si solid‐state NMR, 1H NMR and diffusion ordered spectroscopy (DOSY) to determine the nanoparticle composition. Relaxivity measurements gave a longitudinal relaxivity r1 of 11.9 s−1 mM−1 per Gd at 60 MHz. Finally, potentiometric titrations showed that Gd3+ is strongly chelated to DOTAGA (complexation constant logβ110=24.78) and cellular tests confirmed the that nanoconstructs had a very low toxicity. Moreover, SRPs are excreted from the body by renal clearance. Their efficiency as contrast agents for MRI has been proved and they are promising candidates as sensitising agents for image‐guided radiotherapy.
From the top down: Ultrasmall nanoparticles with a sub‐5 nm size have been synthesised by using a top‐down route. The nanoparticles are composed of a polysiloxane matrix holding Gd–DOTA chelates (DOTA=1,4,7,10‐ tetraazacyclododecane‐1,4,7,10‐tetraacetic acid). In rats, they have shown interesting properties as theranostic agents for radiosensitisation guided by magnetic resonance imaging.
Au(III) complexes with dithiolene ligands have been used as molecular conductors and magnetic materials
1
. These compounds feature square planar geometries, as that for cisplatin the Pt(II)-based ...compound in clinical use as chemotherapeutic drug. Based on the molecular structure, a similar mechanism of action, e.g. antitumor activity and interaction with DNA should be expected for these compounds. Reports on the biological activity of similar gold(III) compounds are relatively scarce in the literature. Only recently, a Au(III) 1,2-dithiolene cyclometalated complex had proved its potential against Gram-positive bacteria
2
. In this study we evaluated two related Au(III) complexes containing N-alkyl-1,3-thiazoline-2-thione dithiolate ligand, Au(R-thiazdt)
2
−1
(R = ethyl-1; R = hydroxyethyl-2)
3
a,b as antitumor and antimicrobial agents. The compounds were assessed in vitro towards cisplatin sensitive ovarian cancer cells (A2780), bacteria and fungus of clinical importance such as Staphylococcus aureus and Candida. Spectroscopic studies were also performed to evaluate the interaction with DNA.
The gold complexes were synthesised as previously described
3
a,b. The cytotoxic activity against the A2780 ovarian cancer cells was assessed by the IC
50
determined by the MTT assay. The antimicrobial activities of complexes 1 and 2 were assessed by the MIC values towards the Gram+ S. aureus, and the fungal strains C. glabrata and C. albicans, using reported methods
4
,
5
. The ability of compounds to bind to DNA was assessed by fluorescence spectroscopy using ethidium bromide (EB) as the fluorescence probe.
Complexes 1 and 2 presented high cytotoxic activity in the cisplatin sensitive A2780 cells even superior than cisplatin. Complex 1 was able to inhibit the growth of S. aureus and both Candida strains, while 2 was much less active. The fluorescence studies revealed a weak interaction of compounds with CT-DNA, in contrast with that found for cisplatin, although the interaction of 2 is somewhat stronger than that found for 1.
Results evidenced the importance in what way minor modifications of the Au dithiolate structure can result in loss of activity in particular the antimicrobial activity. In contrast with cisplatin, DNA is not the main target involved in their mode of action. Further studies are needed to explore other potential targets and the mechanism of action.
We show for the first time that it is possible to acquire high-resolution heteronuclear NMR correlation experiments in solid state between second-order-broadened half integer quadrupolar nuclei ...(i.e., 27Al and 17O) using the scalar J-coupling. The sensitivity of the experiment is dramatically improved at high fields (gain proportional to the fourth power of the principal field) with a combination of signal enhancement techniques. This turns a challenging experiment into a real tool. We apply this experiment to characterize a calcium aluminate glass in which we prove the presence of tricluster μ3 oxygen sites and describe the signature of their directly bonded aluminum sites. Applications involve a large range of possible pairs of quadrupolar nuclei in different materials, such as glasses, porous or mesoporous framework materials, zeolites, hybrid organic−inorganic, and bioinvolved materials.
In order to investigate at the pore scale the mechanisms involved during CO2 injection in a water saturated pore network, a series of displacement experiments is reported using high pressure ...micromodels (geological labs on chip - GLoCs) working under real geological conditions (25 < T (°C) < 75 and 4.5 < p (MPa) < 8). The experiments were focused on the influence of three experimental parameters: (i) the p, T conditions, (ii) the injection flow rates and (iii) the pore network characteristics. By using on-chip optical characterization and imaging approaches, the CO2 saturation curves as a function of either time or the number of pore volume injected were determined. Three main mechanisms were observed during CO2 injection, namely, invasion, percolation and drying, which are discussed in this paper. Interestingly, besides conventional mechanisms, two counterintuitive situations were observed during the invasion and drying processes.
PDF
