IgE Effector Mechanisms, in Concert with Mast Cells, Contribute to Acquired Host Defense against Staphylococcusaureus.

Allergies are considered to represent mal-directed type 2 immune responses against mostly innocuous exogenous compounds. Immunoglobulin E (IgE) antibodies are a characteristic feature of allergies and mediate hypersensitivity against allergens through activation of effector cells, particularly mast cells (MCs). Although the physiological functions of this dangerous branch of immunity have remained enigmatic, recent evidence shows that allergic immune reactions can help to protect against the toxicity of venoms. Because bacteria are a potent alternative source of toxins, we assessed the possible role of allergy-like type 2 immunity in antibacterial host defense. We discovered that the adaptive immune response against Staphylococcus aureus (SA) skin infection substantially improved systemic host defense against secondary SA infections in mice. Moreover, this acquired protection depended on IgE effector mechanisms and MCs. Importantly, our results reveal a previously unknown physiological function of allergic immune responses, IgE antibodies, and MCs in host defense against a pathogenic bacterium.

A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability.

While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved. Here, we investigate the metabolic enzymes and processes that are essential for the resolution of DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description of the interplay between cellular metabolism and the DNA damage response. Further analysis identified that Peroxiredoxin 1, PRDX1, contributes to the DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it reduces DNA damage-induced nuclear reactive oxygen species. Moreover, PRDX1 loss lowers aspartate availability, which is required for the DNA damage-induced upregulation of de novo nucleotide synthesis. In the absence of PRDX1, cells accumulate replication stress and DNA damage, leading to proliferation defects that are exacerbated in the presence of etoposide, thus revealing a role for PRDX1 as a DNA damage surveillance factor.

Metal-Free Directed Site-Selective Csp3 -H Borylation of Saturated Cyclic Amines.

The borylation of Csp3 -H bonds is a challenging transformation that is typically restricted to transition metal catalysis. Herein, we report the site-selective metal-free Csp3 -H borylation of saturated cyclic amines. It is possible to selectively borylate piperidine derivatives at the α or ß positions according to the reaction conditions. The mechanism was supported by NMR spectroscopy, calorimetry experiments and density functional theory (DFT) computations. It suggests that the piperidine is dehydrogenated by complexation with BBr3 to produce an enamine intermediate, which is in turn borylated at either the α or ß position according to the reaction conditions.

IgE antibodies increase honeybee venom responsiveness and detoxification efficiency of mast cells.

BACKGROUND: In contrast to their clearly defined roles in allergic diseases, the physiologic functions of Immunoglobulin E antibodies (IgEs) and mast cells (MCs) remain enigmatic. Recent research supports the toxin hypothesis, showing that MCs and IgE-related type 2 immune responses can enhance host defense against certain noxious substances, including honeybee venom (BV). However, the mechanisms by which MCs can interfere with BV toxicity are unknown. In this study, we assessed the role of IgE and certain MC products in MC-mediated BV detoxification. METHODS: We applied in vitro and in vivo fluorescence microscopyimaging, and flow cytometry, fibroblast-based toxicity assays and mass spectrometry to investigate IgE-mediated detoxification of BV cytotoxicity by mouse and human MCs in vitro. Pharmacologic strategies to interfere with MC-derived heparin and proteases helped to define the importance of specific detoxification mechanisms. RESULTS: Venom-specific IgE increased the degranulation and cytokine responses of MCs to BV in vitro. Passive serum sensitization enhanced MC degranulation in vivo. IgE-activated mouse or human MCs exhibited enhanced potential for detoxifying BV by both proteolytic degradation and heparin-related interference with toxicity. Mediators released by IgE-activated human MCs efficiently degraded multiple BV toxins. CONCLUSIONS: Our results both reveal that IgE sensitization enhances the MC's ability to detoxify BV and also assign efficient toxin-neutralizing activity to MC-derived heparin and proteases. Our study thus highlights the potential importance of IgE, MCs, and particular MC products in defense against BV.

Isodesmic C-H Borylation: Perspectives and Proof of Concept of Transfer Borylation Catalysis.

The potential advantages of using arylboronic esters as boron sources in C-H borylation are discussed. The concept is showcased using commercially available 2-mercaptopyridine as a metal-free catalyst for the transfer borylation of heteroarenes using arylboronates as borylation agents. The catalysis shows a unique functional group tolerance among C-H borylation reactions, tolerating notably terminal alkene and alkyne functional groups. The mechanistic investigation is also described.

Ambiphilic Molecules: From Organometallic Curiosity to Metal-Free Catalysts.

Ambiphilic molecules were first used as functional ligands for transition elements, which could enable intriguing organometallic transformations. In the past decade, these intramolecular Lewis pairs, first considered organometallic curiosities, have become staples in organometallic chemistry and catalysis, acting as Z ligands, activating inert molecules using the concept of frustrated Lewis pair (FLP) chemistry, and acting as metal-free catalysts. In this Account, we detail our contribution to this blossoming field of research, focusing on the use of ambiphilic molecules as metal-free catalysts for CO2 reduction and C-H borylation reactions. A major emphasis is put on the mechanistic investigations we carried out using reactivity studies and theoretical tools, which helped us steer our research from stoichiometric transformations to highly active catalytic processes. We first report the interaction of aluminum-phosphine ambiphilic molecules with carbon dioxide. Although these Lewis pairs can bind CO2, a study of the deactivation process in the presence of CO2 and hydroboranes led us to discover that simple phosphinoborane molecules could act as active precatalysts for the hydroboration of carbon dioxide into methanol precursors. In these systems, the Lewis basic sites interact with the reducing agents rather than with the electrophilic carbon of CO2, increasing the nucleophilicity of hydroboranes. Simultaneously, the weak Lewis acids stabilize the oxygen of the gas molecule in the transition state, leading to high reaction rates. Replacing the phosphine by an amine leads to a system enabling CO2 hydrogenation, albeit only in stoichiometric transformations. Investigation of the protodeborylation deactivation of aminoboranes led us to develop metal-free catalysts for the C-H borylation of heteroarenes. By protecting the Lewis acid sites of these catalysts using fluoride, we were able to synthesize practical, air-stable precatalysts allowing the convenient synthesis of heteroarylboronic esters on a multigram scale. Contrary to general perception of FLP chemistry, we also demonstrated that a significant increase in activity could be obtained by reducing the steric bulk around the active site. These smaller systems exist as stable dimers and are more energetically costly to dissociate into active FLPs, but the approach of the substrate and the C-H activation step are significantly favored compared to the bulkier analogues. An in-depth study of the stability and reactivity of these aminoborane molecules also allowed us to develop a metal-free catalytic S-H bond borylation system, and to report stoichiometric and spontaneous B-B bond formation and Csp3-H bond activation processes, highlighting the importance of H2 release as a thermodynamic driving force in these FLP transformations.

Mechanism of Trypanosoma brucei gambiense resistance to human serum.

The African parasite Trypanosoma brucei gambiense accounts for 97% of human sleeping sickness cases. T. b. gambiense resists the specific human innate immunity acting against several other tsetse-fly-transmitted trypanosome species such as T. b. brucei, the causative agent of nagana disease in cattle. Human immunity to some African trypanosomes is due to two serum complexes designated trypanolytic factors (TLF-1 and -2), which both contain haptoglobin-related protein (HPR) and apolipoprotein LI (APOL1). Whereas HPR association with haemoglobin (Hb) allows TLF-1 binding and uptake via the trypanosome receptor TbHpHbR (ref. 5), TLF-2 enters trypanosomes independently of TbHpHbR (refs 4, 5). APOL1 kills trypanosomes after insertion into endosomal/lysosomal membranes. Here we report that T. b. gambiense resists TLFs via a hydrophobic ß-sheet of the T. b. gambiense-specific glycoprotein (TgsGP), which prevents APOL1 toxicity and induces stiffening of membranes upon interaction with lipids. Two additional features contribute to resistance to TLFs: reduction of sensitivity to APOL1 requiring cysteine protease activity, and TbHpHbR inactivation due to a L210S substitution. According to such a multifactorial defence mechanism, transgenic expression of T. b. brucei TbHpHbR in T. b. gambiense did not cause parasite lysis in normal human serum. However, these transgenic parasites were killed in hypohaptoglobinaemic serum, after high TLF-1 uptake in the absence of haptoglobin (Hp) that competes for Hb and receptor binding. TbHpHbR inactivation preventing high APOL1 loading in hypohaptoglobinaemic serum may have evolved because of the overlapping endemic area of T. b. gambiense infection and malaria, the main cause of haemolysis-induced hypohaptoglobinaemia in western and central Africa.

Recent Advances in the Separation of Rare Earth Elements Using Mesoporous Hybrid Materials.

Over the past decades, the need for rare earth elements (REEs) has increased substantially, mostly because these elements are used as valuable additives in advanced technologies. However, the difference in ionic radius between neighboring REEs is small, which renders an efficient sized-based separation extremely challenging. Among different types of extraction methods, solid-phase extraction (SPE) is a promising candidate, featuring high enrichment factor, rapid adsorption kinetics, reduced solvent consumption and minimized waste generation. The great challenge remains yet to develop highly efficient and selective adsorbents for this process. In this regard, ordered mesoporous materials (OMMs) possess high specific surface area, tunable pore size, large pore volume, as well as stable and interconnected frameworks with active pore surfaces for functionalization. Such features meet the requirements for enhanced adsorbents, not only providing huge reactional interface and large surface capable of accommodating guest species, but also enabling the possibility of ion-specific binding for enrichment and separation purposes. This short personal account summarizes some of the recent advances in the use of porous hybrid materials as selective sorbents for REE separation and purification, with particular attention devoted to ordered mesoporous silica and carbon-based sorbents.

Metal-Free Borylation of Heteroarenes Using Ambiphilic Aminoboranes: On the Importance of Sterics in Frustrated Lewis Pair C-H Bond Activation.

Two novel frustrated Lewis pair (FLP) aminoboranes, (1-Pip-2-BH2-C6H4)2 (2; Pip = piperidyl) and (1-NEt2-2-BH2-C6H4)2 (3; NEt2 = diethylamino), were synthesized, and their structural features were elucidated both in solution and in the solid state. The reactivity of these species for the borylation of heteroarenes was investigated and compared to previously reported (1-TMP-2-BH2-C6H4)2 (1; TMP = tetramethylpiperidyl) and (1-NMe2-2-BH2-C6H4)2 (4; NMe2 = dimethylamino). It was shown that 2 and 3 are more active catalysts for the borylation of heteroarenes than the bulkier analogue 1. Kinetic studies and density functional theory calculations were performed with 1 and 2 to ascertain the influence of the amino group of this FLP-catalyzed transformation. The C-H activation step was found to be more facile with smaller amines at the expense of a more difficult dissociation of the dimeric species. The bench-stable fluoroborate salts of all catalysts (1F-4F) have been synthesized and tested for the borylation reaction. The new precatalysts 2F and 3F are showing higher reaction rates and yields for multigram-scale syntheses.

Frustrated Lewis Pair Mediated Csp3 -H Activation.

The cleavage of a Csp3 -H bond by an N/B frustrated Lewis pair (FLP) is reported. Upon mild heating, the ambiphilic molecule (2-NMe2 -C6 H4 )2 BH activates the C-H bond of a methyl group in α position of a nitrogen atom to generate an unprecedented N-B heterocycle. Upon further heating, the novel species rearranges through a hydride abstraction/1,2-aryl shift sequence. The mechanistic details of these transformations are investigated by quantum mechanical calculations.

Spontaneous Reduction of a Hydroborane To Generate a B-B Single Bond by the Use of a Lewis Pair.

The ansa-aminohydroborane 1-NMe2 -2-(BH2 )C6 H4 crystallizes in an unprecedented type of dimer containing a B-H bond activated by one FLP moiety. Upon mild heating and without the use of any catalyst, this molecule liberates one equivalent of hydrogen to generate a diborane molecule. The synthesis and structural characterization of these new compounds, as well as the kinetic monitoring of the reaction and the DFT investigation of its mechanism, are reported.

Synthesis of Carboxylate Cp*Zr(IV) Species: Toward the Formation of Novel Metallocavitands.

With the intent of generating metallocavitands isostructural to species [(CpZr)3(µ(3)-O)(µ(2)-OH)3(κO,O,µ(2)-O2C(R))3](+), the reaction of Cp*2ZrCl2 and Cp*ZrCl3 with phenylcarboxylic acids was carried out. Depending on the reaction conditions, five new complexes were obtained, which consisted of Cp*2ZrCl(κ(2)-OOCPh) (1), (Cp*ZrCl(κ(2)-OOCPh))2(µ-κ(2)-OOCPh)2 (2), [(Cp*Zr(κ(2)-OOCPh))2(µ-κ(2)-OOCPh)2(µ(2)-OH)2]·Et2O (3·Et2O), [[Cp*ZrCl2](µ-Cl)(µ-OH)(µ-O2CC6H5)[Cp*Zr]]2(µ-O2CC6H5)2 (4), and [Cp*ZrCl4][(Cp*Zr)3(κ2-OOC(C6H4Br)3(µ3-O)(µ2-Cl)2(µ2-OH)] [5](+)[Cp*ZrCl4](-). The structural characterization of the five complexes was carried out. Species 3·Et2O exhibits host-guest properties where the diethyl ether molecule is included in a cavity formed by two carboxylate moieties. The secondary interactions between the cavity and the diethyl ether molecule affect the structural parameters of the complex, as demonstrated be the comparison of the density functional theory models for 3 and 3·Et2O. Species 5 was shown to be isostructural to the [(CpZr)3(µ(3)-O)(µ(2)-OH)3(κO,O,µ(2)-O2C(R))3](+) metallocavitands.

Ambiphilic Frustrated Lewis Pair Exhibiting High Robustness and Reversible Water Activation: Towards the Metal-Free Hydrogenation of Carbon Dioxide.

The synthesis and structural characterization of a phenylene-bridged Frustrated Lewis Pair (FLP) having a 2,2,6,6­tetramethylpiperidine (TMP) as the Lewis base and a 9-borabicyclo[3.3.1]nonane (BBN) as the Lewis acid is reported. This FLP exhibits unique robustness towards the products of carbon dioxide hydrogenation. The compound shows reversible splitting of water, formic acid and methanol while no reaction is observed in the presence of excess formaldehyde. The molecule is incredibly robust, showing little sign of degradation after heating at 80 °C in benzene with 10 equiv. of formic acid for 24 h. The robustness of the system could be exploited in the design of metal-free catalysts for the hydrogenation of carbon dioxide.

Reducing CO2 to methanol using frustrated Lewis pairs: on the mechanism of phosphine-borane-mediated hydroboration of CO2.

The full mechanism of the hydroboration of CO2 by the highly active ambiphilic organocatalyst 1-Bcat-2-PPh2-C6H4 (Bcat = catecholboryl) was determined using computational and experimental methods. The intramolecular Lewis pair was shown to be involved in every step of the stepwise reduction. In contrast to traditional frustrated Lewis pair systems, the lack of steric hindrance around the Lewis basic fragment allows activation of the reducing agent while moderate Lewis acidity/basicity at the active centers promotes catalysis by releasing the reduction products. Simultaneous activation of both the reducing agent and carbon dioxide is the key to efficient catalysis in every reduction step.

Transition-metal-free catalytic reduction of carbon dioxide.

Metal-free systems, including frustrated Lewis pairs (FLPs) have been shown to bind CO2. By reducing the Lewis acidity and basicity of the ambiphilic system, it is possible to generate active catalysts for the deoxygenative hydroboration of carbon dioxide to methanol derivatives with conversion rates comparable to those of transition-metal-based catalysts.

Zirconium(IV) metallocavitands as blue-emitting materials.

A series of zirconium-carboxylate metallocavitands with the general formula [(CpZr)3(µ-κ2,O',O″CR)3(µ3-O)(µ2-OH)3]Cl (Cp = cyclopentadienyl; R = C5H4N (5), C6H7N (6), C18H14N (7), and C18H12N (8)) were synthesized in moderate to high yields (40-83%) by reacting the corresponding carboxylic acids 1-4 with Cp2ZrCl2 in a self-assembly procedure at room temperature. The metallocavitands were characterized using (1)H and (13)C NMR spectroscopy and by single-crystal X-ray diffraction. Complexes 7 and 8 exhibit efficient photoluminescence properties in solution. The photoluminescence peak of 7 was observed at 464 nm and that of 8 at 422 nm with respective quantum yields in solution of 87 and 65%.

Synthesis and complexation study of new ExTTF-based hosts for fullerenes.

A new series of exTTF hosts has been synthesized for supramolecular binding study of fullerenes C60 and C70. Binding constants for C60 in chlorobenzene, toluene, toluene-CH2Cl2 and CS2 have been calculated for different hosts and a direct structure-affinity relationship has been established. As predicted, receptors with two exTTF moieties (1, 3 and 4) have demonstrated higher binding abilities toward C70 than C60. Depending on the linker used to attach the exTTF unit to the core of the host, different binding modes (1 : 1 and 2 : 1) have been obtained.

A highly active phosphine-borane organocatalyst for the reduction of CO2 to methanol using hydroboranes.

In this work, we report that organocatalyst 1-Bcat-2-PPh2-C6H4 ((1); cat = catechol) acts as an ambiphilic metal-free system for the reduction of carbon dioxide in presence of hydroboranes (HBR2 = HBcat (catecholborane), HBpin (pinacolborane), 9-BBN (9-borabicyclo[3.3.1]nonane), BH3·SMe2 and BH3·THF) to generate CH3OBR2 or (CH3OBO)3, products that can be readily hydrolyzed to methanol. The yields can be as high as 99% with exclusive formation of CH3OBR2 or (CH3OBO)3 with TON (turnover numbers) and TOF (turnover frequencies) reaching >2950 and 853 h(-1), respectively. Furthermore, the catalyst exhibits "living" behavior: once the first loading is consumed, it resumes its activity on adding another loading of reagents.

On the interaction of acetone with electrophilic metallocavitands having extended cavities.

We report the synthesis and characterization of tantalum-boronate trimetallic clusters of general formula {[Cp*Ta](3)(µ(2)-RB(O)(2))(3)(µ(2)-OH)(µ(2)-O)(2)(µ(3)-OH)} (R= 4-(C(6)H(5))(C(6)H(4)) (Ta(3)-4Ph), 4-(C(6)H(5)O)(C(6)H(4)) (Ta(3)-4OPh), 4-(C(7)H(7)O)(C(6)H(4)) (Ta(3)-4OBn), 4-(C(8)H(5))(C(6)H(4)) (Ta(3)-4PhEt), and 4-(C(12)H(7))(C(6)H(4)) (Ta(3)-4Napht)). All complexes have been characterized by NMR spectroscopy and X-ray diffraction. The trimetallic species feature a large Lewis acid type cavity allowing for substrate binding in both the solid and the liquid state using a unique electrostatic interaction and a hydrogen bond. ΔH° and ΔS° values for association of acetone with the complexes vary between -2.0 and -4.1 kcal·mol(-1) and -3 and 2 cal·mol(-1)·K(-1), respectively, showing weaker binding than smaller cavitands of the same type. The barrier for acetone exchange at equilibrium is similar for all complexes, and ΔH(‡) values vary between 8.2 and 11.4 kcal·mol(-1).