Treatment of uncontrolled asthma with dupilumab, an anti–interleukin-4 and anti–interleukin-13 receptor monoclonal antibody, in addition to usual therapy, led to a rate of severe exacerbations that ...was approximately 50% lower than the rate with placebo.
In two 16-week, placebo-controlled trials enrolling adults with moderate-to-severe atopic dermatitis, dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, was effective in ...controlling the signs and symptoms of atopic dermatitis.
Atopic dermatitis is a chronic, relapsing inflammatory skin disease that is characterized by the up-regulation of type 2 immune responses (including those involving type 2 helper T cells),
1
,
2
an impaired skin barrier, and increased
Staphylococcus aureus
colonization.
3
,
4
In patients with moderate-to-severe atopic dermatitis, skin lesions can encompass a large body-surface area and are frequently accompanied by intense, persistent pruritus, which leads to sleep deprivation, symptoms of anxiety or depression, and a poor quality of life.
5
–
7
For patients with moderate-to-severe atopic dermatitis, topical therapies have limited efficacy, and systemic treatments are associated with substantial toxic effects. Thus, there . . .
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•The Receptor-Binding Domain of the Spike protein is dependent on its disulfide bonds.•Reduction of the disulfide bonds in the RBD render it unstable.•Reduction of the disulfide bonds ...of the RBD decreases its affinity to ACE2.•The highly-reducing environment can stop SARS-CoV-2 replication in cell-based assays.
The current coronavirus pandemic is exerting a tremendously detrimental impact on global health. The Spike proteins of coronaviruses, responsible for cell receptor binding and viral internalization, possess multiple and frequently conserved disulfide bonds raising the question about their role in these proteins. Here, we present a detailed structural and functional investigation of the disulfide bonds of the SARS-CoV-2 Spike receptor-binding domain (RBD). Molecular dynamics simulations of the RBD predict increased flexibility of the surface loops when the four disulfide bonds of the domain are reduced. This flexibility is particularly prominent for the disulfide bond-containing surface loop (residues 456–490) that participates in the formation of the interaction surface with the Spike cell receptor ACE2. In vitro, disulfide bond reducing agents affect the RBD secondary structure, lower its melting temperature from 52 °C to 36–39 °C and decrease its binding affinity to ACE2 by two orders of magnitude at 37 °C. Consistent with these in vitro findings, the reducing agents tris(2-carboxyethyl)phosphine (TCEP) and dithiothreitol (DTT) were able to inhibit viral replication at low millimolar levels in cell-based assays. Our research demonstrates the mechanism by which the disulfide bonds contribute to the molecular structure of the RBD of the Spike protein, allowing the RBD to execute its viral function.
In contrast to phosphine oxides and arsine oxides, which are common and exist as stable monomeric species featuring the corresponding pnictoryl functional group (Pn=O/Pn
-O
; Pn = P, As), stibine ...oxides are generally polymeric, and the properties of the unperturbed stiboryl group (Sb=O/Sb
-O
) remain unexplored. We now report the isolation of the monomeric stibine oxide, Dipp
SbO (where Dipp = 2,6-diisopropylphenyl). Spectroscopic, crystallographic and computational studies provide insight into the nature of the Sb=O/Sb
-O
bond. Moreover, isolation of Dipp
SbO allows the chemistry of the stiboryl group to be explored. Here we show that Dipp
SbO can act as a Brønsted base, a hydrogen-bond acceptor and a transition-metal ligand, in addition engaging in 1,2-addition, O-for-F
exchange and O-atom transfer. In all cases, the reactivity of Dipp
SbO differed from that of the lighter congeners Dipp
AsO and Dipp
PO.
Sweet Tetra-Trophic Interactions Nicholls, James A.; Melika, George; Stone, Graham N.
The American naturalist,
01/2017, Letnik:
189, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Many herbivores employ reward-based mutualisms with ants to gain protection from natural enemies. We examine the evolutionary dynamics of a tetra-trophic interaction in which gall wasp herbivores ...induce their host oaks to produce nectar-secreting galls, which attract ants that provide protection from parasitoids. We show that, consistent with other gall defensive traits, nectar secretion has evolved repeatedly across the oak gall wasp tribe and also within a single genus (Disholcaspis) that includes many nectar-inducing species. Once evolved, nectar secretion is never lost in Disholcaspis, consistent with high defensive value of this trait. We also show that evolution of nectar secretion is correlated with a transition from solitary to aggregated oviposition, resulting in clustered nectar-secreting galls, which produce a resource that ants can more easily monopolize. Such clustering is commonly seen in ant guard mutualisms. We suggest that correlated evolution between maternal oviposition and larval nectar induction traits has enhanced the effectiveness of this gall defense strategy.
The reaction of copper with bis(cyclohexanone)oxaldihydrazone (cuprizone) is a challenging coordination chemistry problem that has confounded attempts at elucidation for the past 70 years. The ...product of the reaction, a blue copper complex, wherein the cuprizone ligand is hydrolyzed, has been the primary focus during its history. We have recently characterized an additional green multi-copper product which contains unhydrolyzed cuprizone, which only added to the mystery. Using density functional structure models and thermodynamic calculations we address several of the long-standing questions surrounding the copper-cuprizone reaction, as well as identify the likely reaction pathway that gives rise to the blue and green products. Cu(
ii
)-induced asymmetric hydrolysis of the cuprizone ligand is essential for formation of the blue product, followed by a series of Cu(
ii
)-induced deprotonation and coordination events, with complex formation terminating with hydrolyzed cuprizone tautomerization and intramolecular electron transfer, generating a pseudo-macrocyclic Cu(
iii
) species. Alternatively, in the presence of excess Cu(
ii
), or in non-aqueous solvents, a green multi-Cu(
ii
) complex forms comprised of alternating Cu(
ii
)-cuprizone units. Structure calculations are supported by experimental data and represent the most rigorous approach to-date toward understanding the complex solution chemistry of copper with cuprizone.
The coordination chemistry of copper-cuprizone has presented considerable challenges for over 70 years. Using computational chemistry we elucidate key events in copper-cuprizone complex formation, including the asymmetric hydrolysis of cuprizone.
While the role of microorganisms as main drivers of metal mobility and mineral formation under Earth surface conditions is now widely accepted, the formation of secondary gold (Au) is commonly ...attributed to abiotic processes. Here we report that the biomineralization of Au nanoparticles in the metallophillic bacterium Cupriavidus metallidurans CH34 is the result of Au-regulated gene expression leading to the energy-dependent reductive precipitation of toxic Au(III)-complexes. C. metallidurans, which forms biofilms on Au grains, rapidly accumulates Au(III)-complexes from solution. Bulk and microbeam synchrotron X-ray analyses revealed that cellular Au accumulation is coupled to the formation of Au(I)-S complexes. This process promotes Au toxicity and C. metallidurans reacts by inducing oxidative stress and metal resistances gene clusters (including a Au-specific operon) to promote cellular defense. As a result, Au detoxification is mediated by a combination of efflux, reduction, and possibly methylation of Au-complexes, leading to the formation of Au(I)-C-compounds and nanoparticulate Au⁰. Similar particles were observed in bacterial biofilms on Au grains, suggesting that bacteria actively contribute to the formation of Au grains in surface environments. The recognition of specific genetic responses to Au opens the way for the development of bioexploration and bioprocessing tools.
Pentaphenylantimony (SbPh5) has been previously crystallized in either a square pyramidal or trigonal bipyramidal geometry. Investigation of the solution-state structure of SbPh5 has been hampered by ...the extreme fluxionality of this compound, but previous vibrational spectroscopic studies concluded that it maintains a square pyramidal geometry in solution. This non-VSEPR-compliant geometry, which is also assumed by BiPh5 in the solid state, stands in contrast to the trigonal bipyramidal geometries of PPh5 and AsPh5. A range of phenomena have been invoked to explain this discrepancy, most notably, the increased importance of relativistic effects as group 15 is descended. We present crystallographic, spectroscopic, and computational data revealing that SbPh5 in fact assumes the VSEPR-compliant trigonal bipyramidal geometry in solution. In particular, Sb X-ray absorption spectroscopy (XAS) was used to obtain geometry-sensitive spectra that do not suffer from the slow spectroscopic time scale that has prevented NMR studies from elucidating the structure of this fluxional molecule. Sb K-edge and LIII-edge XAS spectra of crystalline solids featuring SbPh5 in either a square pyramidal (nonsolvate) or trigonal bipyramidal (cyclohexane hemisolvate or THF hemisolvate) form were compared to spectra of SbPh5 in solution. The solution-state spectra agree with those from solids containing trigonal bipyramidal SbPh5. The most diagnostic spectroscopic feature was the distribution of intensity in the Sb LIII pre-edge features. These distributions were rationalized using time-dependent density functional theory calculations that take into account spin–orbit coupling. Our use of Sb XAS not only resolves a long-standing physical inorganic question but also demonstrates more widely the utility of XAS in establishing the structures of fluxional main-group compounds. This conclusion was further supported by solid- and solution-state Raman data. Finally, we note that the present high-resolution diffraction data allow τ for nonsolvated SbPh5 to be revised to 0.216.
PBT2 (5,7-dichloro-2-(dimethylamino)methyl-8-hydroxyquinoline) is a small Cu(II)-binding drug that has been investigated in the treatment of neurodegenerative diseases, namely, Alzheimer’s disease ...(AD). PBT2 is thought to be highly effective at crossing the blood–brain barrier and has been proposed to exert anti-Alzheimer’s effects through the modulation of metal ion concentrations in the brain, specifically the sequestration of Cu(II) from amyloid plaques. However, despite promising initial results in animal models and in clinical trials where PBT2 was shown to improve cognitive function, larger-scale clinical trials did not find PBT2 to have a significant effect on the amyloid plaque burden compared with controls. We propose that the results of these clinical trials likely point to a more complex mechanism of action for PBT2 other than simple Cu(II) sequestration. To this end, herein we have investigated the solution chemistry of Cu(II) coordination by PBT2 primarily using X-ray absorption spectroscopy (XAS), high-energy-resolution fluorescence-detected XAS, and electron paramagnetic resonance. We propose that a novel bis-PBT2 Cu(II) complex with asymmetric coordination may coexist in solution with a symmetric four-coordinate Cu(II)-bis-PBT2 complex distorted from coplanarity. Additionally, PBT2 is a more flexible ligand than other 8HQs because it can act as both a bidentate and a tridentate ligand as well as coordinate Cu(II) in both 1:1 and 2:1 PBT2/Cu(II) complexes.
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