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Annulated azecines, mostly partially saturated benzo[d]azecine and dibenzo[c,g]azecine fusion isomers, constitute a unique class of alkaloids and nature-inspired azaheterocyclic compounds with interesting reactivity, physicochemical and biological properties. Due to difficulties associated with the synthesis of the benzazecine (or bioisosteric) scaffold they are not the focus of organic and medicinal chemists' consideration, whereas it is worth noting the range of their pharmacological activities and their potential application in medicinal chemistry. Herein, we reviewed the synthetic methodologies of arene-fused azecine derivatives known up to date and reported about the progress in disclosing their potential in drug discovery. Indeed, their conformational restriction or liberation drives their selectivity towards diverse biological targets, making them versatile scaffolds for developing drugs, including antipsychotic and anticancer drugs, but also small molecules with potential for anti-neurodegenerative treatments, as the recent literature shows., Competing Interests: Declaration of competing interest On behalf of all the co-authors, I declare that the authors of the manuscript entitled “Advances in synthesis of novel benzazecines and their unique pharmacological properties” have no competing interests to declare., (Copyright © 2024. Published by Elsevier Masson SAS.)

A series of structurally similar trinuclear macrocyclic copper(I) and silver(I) pyrazolate complexes bearing various short-bite diphosphine R 2 PCH(R')PR 2 ligands are reported. Upon diphosphine coordination, the planar geometry of the initial complexes undergoes bending along the line between two metal atoms coordinated to the phosphorus moieties. The complexes based on dcpm ligands (R = cyclohexyl, R' = H, Ph) do not exhibit dynamic behavior in solution at room temperature on the 31 P NMR time scale as it was previously observed for similar trinuclear copper complexes bearing the dppm (R = Ph, R' = H) scaffold. All copper(I) complexes exhibit thermally activated delayed fluorescence (TADF) behavior in the solid state. Importantly, the use of aliphatic substituents on the phosphorus atoms instead of aromatic ones leads to an almost double increase in the quantum efficiency (Φ PL ) of photoluminescence by eliminating nonradiative decay from the 3 LC Ph states of the dppm aromatic rings. The higher donating ability of the substituents in the pyrazolate ligand (CF 3 vs CH 3 ) lowers the energy of the metal-centered excited state, allowing for a significant metal impact on the T 1 state. Finally, the Ag(I) complex displays an emission efficiency of approximately 14%, being the highest among known trinuclear silver(I) pyrazolate homometallic derivatives.

An easy synthesis of novel highly functionalized 5,6-dihydroindolo[2,1- a ]isoquinolines was developed via a pseudo four-component domino reaction of 1-aroyl-3,4-dihydroisoquinolines, terminal α,β-ynones, and malononitrile. The selective formation of this biologically relevant heterocyclic core was achieved using a one-pot approach under microwave irradiation. The formation of the same skeleton through the reaction of 5,6-dihydropyrrolo[2,1- a ]isoquinolines with malonic acid dinitrile supports the proposed mechanism, involving the intermediate product of the three-component reaction. Furthermore, the disproval of an alternative reaction pathway, which involved the dimerization of malononitrile followed by three-component transformation, was demonstrated. Introducing the malononitrile dimer as a CH acid resulted in the formation of a different pyrido[3',4':4,5]pyrrolo[2,1- a ]isoquinoline core. Additionally, the synthesized 5,6-dihydroindolo[2,1- a ]isoquinolines were examined for their photophysical properties, revealing their attractive luminescent characteristics.

Cyclic trinuclear Ag(I) pyrazolate interacts with phenylacetylene forming a mix-ligand complex in which one pyrazolate ligand is changed to phenylethynide. The CC - fragment coordinates only to two silver(I) atoms via one carbon atom demonstrating unique μ 2 -η 1 σ-coordination with close Ag-C bond lengths and Ag-C-C angles. The complex exhibits blue emission under UV irradiation.

Here, An efficient approach to obtaining previously unknown furo[2',3':2,3]pyrrolo[2,1- a ]isoquinoline derivatives from readily available 1-R-1-ethynyl-2-vinylisoquinolines is described. The reaction features a simple procedure, occurs in hexaflouroisopropanol and does not require elevated temperatures. It has been found that the addition of glacial acetic acid significantly increases the yields of the target spirolactone products. Using trifluoroethanol instead of hexaflouroisopropanol results in the formation of pyrido[2,1- a ]isoquinolines.

Under microwave (MW) irradiation at 150 °C in toluene and in the presence of nucleophiles (DMAP, triphenylphosphine and tetrahydrothiophene) 1-substituted 1-ethynyl-2-vinyldi- and tetrahydroisoquinolines undergo [3,3]-sigmatropic rearrangement providing pyrrolo[2,1-b][3]benzazepines in good yields. The replacement of toluene with acetonitrile directs the rearrangement towards the formation of 7,11b-dihydro-6H-pyrido[2,1-a]isoquinolines., (© 2023 Wiley-VCH GmbH.)

Based on previous finding showing 2,3,6,11-tetrahydro-1H-azocino[4,5-b]indole as suitable scaffold of novel inhibitors of acetylcholinesterase (AChE), a main target of drugs for the treatment of Alzheimer's disease and related dementias, herein we investigated diverse newly and previously synthesized β-enamino esters (and ketones) derivatives of 1,4,7,8-tetrahydroazocines (and some azonines) fused with benzene, 1H-indole, 4H-chromen-4-one and pyrimidin-4(3H)-one. Twenty derivatives of diversely annelated eight-to-nine-membered azaheterocyclic ring, prepared through domino reaction of the respective tetrahydropyridine and azepine with activated alkynes, were assayed for the inhibitory activity against AChE and butyrylcholinesterase (BChE). As a major outcome, compound 7c, an alkylamino derivative of tetrahydropyrimido[4,5-d]azocine, was found to be a highly potent BChE-selective inhibitor, which showed a noncompetitive/mixed-type inhibition mechanism against human BChE with single digit nanomolar inhibition constant (K i  = 7.8 ± 0.2 nM). The four-order magnitude BChE-selectivity of 7c clearly reflects the effect of lipophilicity upon binding to the BChE binding cavity. The ChEs' inhibition data, interpreted by chemoinformatic tools and an in-depth in-silico study (molecular docking combined with molecular dynamics calculations), not only highlighted key structural factors enhancing inhibition potency and selectivity toward BChE, but also shed light on subtle differences distinguishing the binding sites of equine BChE from the recombinant human BChE. Compound 7c inhibited P-glycoprotein with IC 50 of 0.27 μM, which may support its ability to permeate blood-brain barrier, and proved to be no cytotoxic in human liver cancer cell line (HepG2) at the BChE bioactive concentrations. Overall, the biological profile allows us to envision 7c as a promising template to improve design and development of BChE-selective ligands of pharmaceutical interest, including inhibitors and fluorogenic probes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Cosimo D. Altomare reports equipment, drugs, or supplies was provided by University of Bari Department of Pharmacy and Pharmaceutical Sciences., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

A reaction of a cyclic trinuclear copper(I) or silver(I) pyrazolate complex ([MPz] 3 , M = Cu, Ag) with 1,1'-dimethyl-2,2'-bibenzimidazole ( L ) leads to the formation of tetranuclear adducts decorated by one or two molecules of a diimine ligand, depending on the amount of the ligand added (0.75 or 1.5 equivalents). The coordination of two L molecules stabilizes the formation of a practically idealized tetrahedral four-metal core in the case of a copper-containing complex and a distorted tetrahedron in the case of a Ag analog. In contrast, complexes containing one molecule of diimine possess two types of metals, two- and three-coordinated, forming the significantly distorted central M 4 cores. The diimine ligands are twisted in these complexes with dihedral angles of ca. 50-60°. A TD-DFT analysis demonstrated the preference of a triplet state for the twisted 1,1'-dimethyl-2,2'-bibenzimidazole and a singlet state for the planar geometry. All obtained complexes demonstrated, in a solution, the blue fluorescence of the ligand-centered (LC) nature typical for free diimine. In contrast, a temperature decrease to 77 K stabilized the structure close to that observed in the solid state and activated the triplet states, leading to green phosphorescence at ca. 500 nm. The silver-containing complex Ag 4 Pz 4 L exhibited dual emission from both the singlet and triplet states, even at room temperature., Competing Interests: The authors declare no conflict of interest.

Arterial hypertension is one of the most common life-threatening diseases, adequate control of which is largely achieved by antihypertensive drugs, including the use of telmisartan. The aim of the study was to evaluate the effect of telmisartan chronotherapy on the parameters of daily monitoring of blood pressure during the daytime and at night in elderly patients with hypertension. The study is based on a comprehensive examination of 150 patients aged 60-74 years suffering from hypertension, who are divided into 2 groups: the main (n=76) and control (n=74). Patients with hypertension in the main group received telmisartan at a dose of 80 mg/day in the evening (20.00-22.00 hours), and in the control group - in the morning at the same dose (80 mg/day). Before treatment, after 3 months and after 6 months, patients of both groups underwent daily monitoring of blood pressure with the «BPLab monitor Mn SDP-3». It was found that the evening intake of telmisartan at a dose of 80 mg/day has a more significant effect than the morning intake of the same dose of telmisartan on the indicators of daily monitoring of systolic blood pressure and diastolic blood pressure in the evening, the systolic blood pressure time index in the evening. Chronotherapy with telmisartan in elderly patients with hypertension more effectively normalizes the daily blood pressure profile with the transfer of «non-dipper» to «dipper», reduces the hypertensive load and contributes to the achievement of target blood pressure levels.

Transformations of 1-methoxymethylethynyl substituted isoquinolines triggered by terminal alkynes in alcohols were studied and new 3-benzazecine-containing compounds synthesized, such as 6-methoxymethyl-3-benzazecines incorporating an endocyclic C6-C8 allene fragment and the -ylidene derivatives 6-methoxymethylene-3-benzazecines. The reaction mechanisms were investigated and a preliminary in vitro screening of their potential inhibitory activities against human acetyl- and butyrylcholinesterases (AChE and BChE) and monoamine oxidases A and B (MAO-A and MAO-B) showed that the allene compounds were more potent than the corresponding -ylidene ones as selective AChE inhibitors. Among the allenes, 3e (R 3 = CH 2 OMe) was found to be a competitive AChE inhibitor with a low micromolar inhibition constant value ( K i = 4.9 μM), equipotent with the corresponding 6-phenyl derivative 3n (R 3 = Ph, K i = 4.5 μM), but 90-fold more water-soluble.

Various 4'-R-substituted phenyl azacyclic allenes were synthesized in good yields, and their thermal transformations were studied. For the first time, the obtained rearrangement products-new N-bridged cyclopenta[a]indenes, and the corresponding parent allenes were evaluated as potential inhibitors of acetyl- and butyrylcholinesterase. Among the tested compounds, the allene derivative 2g proved to competitively inhibit human AChE with inhibition constant value (K i ) in the low micromolar range., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature.)

Synthesis of novel C3-substituted 5,6-dihydropyrrolo[2,1-a]isoquinolines via a three-component domino reaction of 1-aroyl-3,4-dihydroisoquinolines, terminal alkynes and CH-acids under microwave irradiation in dry acetonitrile is described. The method developed enables the obtainment of highly functionalized compounds with pharmacophore groups, which are potentially biologically active., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

A series of emissive Cu(I) cationic complexes with 3-(2-pyridyl)-5-phenyl-pyrazole and various phosphines: dppbz ( 1 ), Xantphos ( 2 ), DPEPhos ( 3 ), PPh 3 ( 4 ), and BINAP ( 5 ) were designed and characterized. Complexes obtained exhibit bright yellow-green emission (ca. 520-650 nm) in the solid state with a wide range of QYs (1-78%) and lifetimes (19-119 µs) at 298 K. The photoluminescence efficiency dramatically depends on the phosphine ligand type. The theoretical calculations of buried volumes and excited states explained the emission behavior for 1 - 5 as well as their lifetimes. The bulky and rigid phosphines promote emission efficiency through the stabilization of singlet and triplet excited states.

A convenient protocol for the synthesis of 5,6-dihydropyrrolo[2,1-a]isoquinolines with various electron-withdrawing substituents at C-2 atom is described. This approach is based on the two-component domino reaction of 1-aroyl-3,4-dihydroisoquinolines with α,β-unsaturated ketones, nitroalkenes and acrylonitrile. Depending on the selected substrates, the reaction was performed in TFE under reflux or under microwave irradiation. Only for the two examples, a transition metal catalyst was used., (© 2020. Springer Nature Switzerland AG.)

Estrogen-related receptor γ (Esrrg) is a murine lupus susceptibility gene associated with T cell activation. Here, we report that Esrrg controls Tregs through mitochondria homeostasis. Esrrg deficiency impaired the maintenance and function of Tregs, leading to global T cell activation and autoimmunity in aged mice. Further, Esrrg-deficient Tregs presented an impaired differentiation into follicular Tregs that enhanced follicular helper T cells' responses. Mechanistically, Esrrg-deficient Tregs presented with dysregulated mitochondria with decreased oxygen consumption as well as ATP and NAD+ production. In addition, Esrrg-deficient Tregs exhibited decreased phosphatidylinositol and TGF-β signaling pathways and increased mTOR complex 1 activation. We found that the expression of human ESRRG, which is high in Tregs, was lower in CD4+ T cells from patients with lupus than in healthy controls. Finally, knocking down ESRRG in Jurkat T cells decreased their metabolism. Together, our results reveal a critical role of Esrrg in the maintenance and metabolism of Tregs, which may provide a genetic link between lupus pathogenesis and mitochondrial dysfunction in T cells.

This study reports intriguing features in the self-assembly of cage copper(II) silsesquioxanes in the presence of air. Despite the wide variation of solvates used, a series of prismatic hexanuclear Cu 6 cages ( 1 - 5 ) were assembled under mild conditions. In turn, syntheses at higher temperatures are accompanied by side reactions, leading to the oxidation of solvates (methanol, 1-butanol, and tetrahydrofuran). The oxidized solvent derivatives then specifically participate in the formation of copper silsesquioxane cages, allowing the isolation of several unusual Cu 8 -based ( 6 and 7 ) and Cu 6 -based ( 8 ) complexes. When 1,4-dioxane was applied as a reaction medium, deep rearrangements occurred (with a total elimination of silsesquioxane ligands), causing the formation of mononuclear copper(II) compounds bearing oxidized dioxane fragments ( 9 and 11 ) or a formate-driven 1D coordination polymer ( 10 ). Finally, a "directed" self-assembly of sil- and germsesquioxanes from copper acetate (or formate) resulted in the corresponding acetate (or formate) containing Cu 6 cages ( 12 and 13 ) that were isolated in high yields. The structures of all of the products 1 - 13 were established by single-crystal X-ray diffraction, mainly based on the use of synchrotron radiation. Moreover, the catalytic activity of compounds 12 and 13 was evaluated toward the mild homogeneous oxidation of C 5 -C 8 cycloalkanes with hydrogen peroxide to form a mixture of the corresponding cyclic alcohols and ketones.

The work is devoted to the study of the possibility of determining the critical points of phase diagrams by measuring the EMF of electrochemical cells relative to a metal that is not part of the test substance. The measurement results of the concentration dependences of the EMF for the Cu x TiS 2 system in the electrochemical cells Na|Na + |Cu x TiS 2 and Cu|Cu + |Cu x TiS 2 in the concentration range 0 < x < 0.7 are compared. It was determined that the chemical potential of the ion is independent of x in a satisfactory approximation. The EMF difference in the given cells is close to the standard electrode potentials difference for respective metals. It is concluded that the dependences E ( x ) for both types of cells are similar and correlated. Therefore, one can choose any convenient metal for measurements of this kind. Using the example of measuring EMF in electrochemical cells for the Fe x TiSe 2 system concerning sodium and lithium, we showed that the elastic contribution to free energy is constant over the entire concentration range 0 < x < 0.5.

Nature-inspired, bridged polycyclic molecules share low similarity with currently available drugs, containing preferentially planar and/or achiral moieties. This "Escape from Flatland" scenario, aimed at exploring pharmacological properties of atypical molecular scaffolds, finds interest in synthetic routes leading to tridimensional-shaped molecules. Herein we report on the synthesis of N -bridged cyclopenta[ a ]indene derivatives, achieved through microwave-assisted thermal rearrangement of allene 3-benzazecines with high diastereoselectivity. The biological evaluation disclosed selective inhibition of human acetylcholinesterase or butyrylcholinesterase, depending on the substitution around the molecular core, which was rationalized by means of docking simulations. The most potent BChE inhibitor 31 was effective in neuroprotection from glutamatergic excitotoxicity and displayed low intrinsic cytotoxicity and good brain penetration. Overall, compound 31 and its close congeners 34 and 35 acted as multitarget agents addressing different biological events involved in neurodegeneration, particularly in the progression of Alzheimer's disease.

The vertebral hemangioma (VH) and vertebrogenic pain syndromes of other etiologies are currently not a problem in terms of the choice of treatment method. However, the combination of these conditions makes the situation much more challenging. The question of the safety of physical treatment methods in these patients remains open, since there is no scientific evidence in this area., Objective: To study the long-term results of electrotherapy, magnet therapy, lazer therapy, therapeutic exercises (TE), and therapeutic massage (in different combinations) in patients with degenerative-dystrophic processes of the spine and nonaggressive VH., Material and Methods: The study included 104 patients (75 females, 29 males) with degenerative-dystrophic processes of the spine and non-aggressive VH. The time between the treatment course and follow-up examination was 12 months., Results: VHs remained unchanged in 86.5% of patients. An increase in size was noted in 13.5%. In no case did the VH become aggressive. After the TE course, the rate of VH size increase was 10.8%. The combination of TE with massage and electrotherapy (including a combination of all methods) resulted in an increase in VH size in 17.9, 20.0, 23.8% of cases, respectively. When magnet therapy was used, an increase in VH size was recorded significantly less frequently ( p =0.021). No differences in the rate of VH size increase depending on sex, age (40-70 years), localization, and size were observed. In case of multiple VHs, the rate of growth was 23.1., Conclusion: A limitation of the study was the relatively small number of patients, which could, in some cases, affect the correctness of statistical data. Nevertheless, there is a general trend of the effect of physical treatments on the course of non-aggressive VH in patients with vertebrogenic pain syndromes. Such patients may be recommended low-frequency low-intensity electro- and magnet therapy, therapeutic back massage, and TE.

Objective: This study performed an integrated analysis of the cellular and transcriptional differences in peripheral immune cells between patients with Systemic Lupus Erythematosus (SLE) and healthy controls (HC)., Methods: Peripheral blood was analyzed using standardized flow cytometry panels. Transcriptional analysis of CD4 + T cells was performed by microarrays and Nanostring assays., Results: SLE CD4 + T cells showed an increased expression of oxidative phosphorylation and immunoregulatory genes. SLE patients presented higher frequencies of activated CD38 + HLA-DR + T cells than HC. Hierarchical clustering identified a group of SLE patients among which African Americans were overrepresented, with highly activated T cells, and higher frequencies of Th1, Tfh, and plasmablast cells. T cell activation was positively correlated with metabolic gene expression in SLE patients but not in HC., Conclusions: SLE subjects presenting with activated T cells and a hyperactive metabolic signature may represent an opportunity to correct aberrant immune activation through targeted metabolic inhibitors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: Enamino 3-benzazecine compounds, incorporating the C6-C8 allene system, were synthesized and evaluated in vitro as inhibitors of P-glycoprotein (P-gp) and/or multidrug resistance-associated protein 1 (MRP1), two efflux pumps mainly connected with multidrug resistance (MDR) in cancer cells. Results & methodology: Most of the synthesized compounds were selective P-gp inhibitors in Calcein-AM uptake assay. Structure-activity relationships (SARs) pointed out that CO 2 Me derivatives are more potent than acetyl derivatives, and 10,11-dimethoxy compounds are five to tenfold more potent inhibitors than the respective unsubstituted compounds, and that the P-gp inhibition potency is mainly related to volume parameters. Conclusion: Nanomolar P-gp inhibitors, such as 23 (IC 50  = 4.2 nM), restored the antiproliferative activity of doxorubicin in multidrug-resistant cells. The observed activities showed that 3-benzazecine-based compounds may be promising MDR reversers.

In systemic lupus erythematosus, defective clearance of apoptotic debris and activation of innate cells result in a chronically activated type 1 IFN response, which can be measured in PBMCs of most patients. Metformin, a widely used prescription drug for Type 2 diabetes, has a therapeutic effect in several mouse models of lupus through mechanisms involving inhibition of oxidative phosphorylation and a decrease in CD4 + T cell activation. In this study, we report that in CD4 + T cells from human healthy controls and human systemic lupus erythematosus patients, metformin inhibits the transcription of IFN-stimulated genes (ISGs) after IFN-α treatment. Accordingly, metformin inhibited the phosphorylation of pSTAT1 (Y701) and its binding to IFN-stimulated response elements that control ISG expression. These effects were independent of AMPK activation or mTORC1 inhibition but were replicated using inhibitors of the electron transport chain respiratory complexes I, III, and IV. This indicates that mitochondrial respiration is required for ISG expression in CD4 + T cells and provides a novel mechanism by which metformin may exert a therapeutic effect in autoimmune diseases., (Copyright © 2019 by The American Association of Immunologists, Inc.)

The first example of trinuclear copper(I) and silver(I) pyrazolates adducts with a tertiary diphosphine (Ph 2 PCH 2 PPh 2 ) retaining trimeric [MPz] 3 core is reported. Despite rather strong M-P bonding, the complexes are able to undergo the dissociation of one M-P bond leading to the "merry-go-round" movement of P atoms over the M 3 triangle. The copper complex displays emission from 1 MLCT and 3 MLCT states. The triplet and singlet states are separated by a relatively small energy gap (1080 cm -1 ) that triggers the thermally activated delayed fluorescence (TADF) behavior and leads to the worthy quantum yield of 41% at 298 K. The silver complex in the solid state and frozen solution shows dual emission originating from the 1 IL and 3 MLCT states that is dictated by the much higher energy difference between the emissive singlet and triplet as well as by the essentially different nature of these states.

A set of silver(i) 3,5-bis(trifluoromethyl) pyrazolate adducts with 1,10-phenanthroline (L 2 ), 2,9-dimethyl-1,10-phenanthroline (neocuproine, L 3 ) and 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline (bathocuproine, L 4 ) was synthesized starting from trimeric silver pyrazolate Ag 3 Pz 3 . Reactions with sterically hindered L 3 and L 4 cause the destruction of the original trimeric core, yielding a dinuclear Ag 2 Pz 2 cycle with an unprecedented chair configuration for L 3 , while bathocuproine L 4 leads to the drastic rearrangement of the silver pyrazolate core into cationic Ag(L 4 ) 2 and anionic Ag 5 Pz 6 subunits. All complexes obtained exhibit phosphorescence in the solid state. Time-dependent density functional theory calculations demonstrate their different possible emission processes, explaining their emission behavior as well as their lifetimes.

The trinuclear copper(i) pyrazolate {[3,5-(CF3)2Pz]Cu}3 forms η2-copper/alkyne triple bond coordinated structures in the presence of acetylenes. There is no coordination of copper atoms to the phenyl ring of phenylacetylene and copper(i) acetylide formation during the interaction. It was observed that the complexes formed are the active catalytic species in click reactions.

1-( p -Methoxyphenyl)tetrazolyl-substituted 6,7-dimethoxy(6,7-methylenedioxy)-1,2,3,4-tetrahydroisoquinolines formed tetrazolyl-substituted azocines in high yields by using activated alkynes. Unsubstituted at 6,7,8-aromatic fragment 1-tetrazolylisoquinoline interacted in several pathways forming tetrazolyl-substituted azocines, 1-tetrazolyl-1-R-vinylisoquinolines and 3-azaspiro[5.5]undeca-1,7,9-triene.

Follicular helper T (T FH ) cells are expanded in systemic lupus erythematosus, where they are required to produce high affinity autoantibodies. Eliminating T FH cells would, however compromise the production of protective antibodies against viral and bacterial pathogens. Here we show that inhibiting glucose metabolism results in a drastic reduction of the frequency and number of T FH cells in lupus-prone mice. However, this inhibition has little effect on the production of T-cell-dependent antibodies following immunization with an exogenous antigen or on the frequency of virus-specific T FH cells induced by infection with influenza. In contrast, glutaminolysis inhibition reduces both immunization-induced and autoimmune T FH cells and humoral responses. Solute transporter gene signature suggests different glucose and amino acid fluxes between autoimmune T FH cells and exogenous antigen-specific T FH cells. Thus, blocking glucose metabolism may provide an effective therapeutic approach to treat systemic autoimmunity by eliminating autoreactive T FH cells while preserving protective immunity against pathogens.

Composite single crystals consisting of nanoscaled Fe 3 Se 4 inclusions encapsulated into the interlayer space of TiSe 2 matrix were obtained by the decay of homogeneous Fe 0.5 TiSe 2 intercalation compound. These composites have a high magnetic anisotropy due to the coherent bond between inclusions and the host lattice of TiSe 2 . The influence of selenium pressure over the composite surface on the composition of the inclusions is studied, and the possibility of controlling their content is demonstrated. The thermodynamic stability of the composite with a small excess of selenium in comparison with the stoichiometric material is established based on theoretical calculations. The estimated energy of the chemical bond between components of the composite is close to the van der Waals bond energy. A method to control the orientation and defects within the inclusions in the host lattice is proposed.

The thermal stability of the layered modification of the Cu 0.5 ZrTe 2 polycrystalline intercalation compound, synthesized at room temperature, has been studied in the temperature range 25-900 °C. A change in the occupation of the octahedral and tetrahedral coordinated sites in the interlayer space of the zirconium ditelluride was observed using in-situ time-resolved synchrotron X-ray powder diffraction experiments. The formation of the rhombohedral CuZr 2 Te 4 phase, which is stable in the temperature range 300-700 °C, has been observed. The copper intercalation at room temperature leads to the formation of a phase in which the Cu atoms occupy only octahedral sites in the interlayer space. At temperatures above the decay temperature of the rhombohedral CuZr 2 Te 4 , a layered phase with Cu atoms uniformly distributed between octahedral and tetrahedral sites in the interlayer space is stable. The changes in the crystal structure independent of temperature are in agreement with the previously proposed model, according to which the stability of the layered or the rhombohedral phase is determined by the entropy factor associated with the distribution of the intercalated atoms between the octahedral and tetrahedral sites in the interlayer space.

The title compound, C 25 H 27 NO 4 (I), the product of the unusual thermolysis of aza-cyclic allene methyl 10,11-dimeth-oxy-3,8-dimethyl-6-phenyl-3-aza-benzo[ d ]cyclo-deca-4,6,7-triene-5-carboxyl-ate, represents a bicyclic heterosystem and crystallizes in the monoclinic space group P 2 1 / c with three crystallographically independent mol-ecules in the unit cell. These independent mol-ecules adopt very similar geometries and differ only in the conformations of the two meth-oxy substituents on the benzene ring. In two of the three independent mol-ecules, both meth-oxy groups are almost coplanar with the benzene ring [the C-C-O-Me torsion angles are 10.8 (2), 12.3 (2), 9.1 (2) and 13.6 (3)°], whereas in the third mol-ecule, one of the meth-oxy groups is practically coplanar to and the other meth-oxy group is roughly perpendicular to the benzene ring, the C-C-O-Me torsion angles being 14.1 (2) and 76.5 (2)°. The mol-ecule of (I) comprises a fused tetra-cyclic system containing two five-membered rings (cyclo-pentenes) and two six-membered rings (piperidine and benzene). The five-membered rings have the usual envelope conformation, with the methyl-subsituted C atom as the flap in each molecule, and the six-membered piperidine ring has a chair conformation. The methyl substituent at the N atom occupies the sterically favourable equatorial position. The carboxyl-ate group lies almost within the basal plane of the parent cyclo-pentene ring [making dihedral angle of 11.68 (8), 18.94 (9) and 15.16 (9)° in the three independent mol-ecules], while the phenyl substituent is twisted by 48.26 (6), 42.04 (6) and 41.28 (6)° (for the three independent mol-ecules) relative to this plane. In the crystal, mol-ecules of (I) form stacks along the b -axis direction. The mol-ecules are arranged at van der Waals distances.

The title compound, C 19 H 19 NO 5 , (I), is the product of a domino reaction between cotarnine chloride and acetyl-acetylene catalysed by copper(I) iodide. The mol-ecule of (I) comprises a fused tetra-cyclic system containing two terminal five-membered rings (pyrrole and 1,3-dioxole) and two central six-membered rings (di-hydro-pyridine and benzene). The five-membered 1,3-dioxole ring has an envelope conformation and the central six-membered di-hydro-pyridine ring adopts a twist-boat conformation. The acyl substituent is almost coplanar with the pyrrole ring, whereas the meth-oxy substituent is twisted by 27.93 (16)° relative to the benzene ring. The 2-oxopropan-1-yl substituent is roughly perpendicular to the pyrrole ring. In the crystal, mol-ecules are stacked along the a -axis direction; the stacks are linked by weak C-H⋯O hydrogen bonds into puckered layers lying parallel to (001).

Purpose of Review: The complexity and heterogeneity of the clinical presentation in systemic lupus of erythematosus (SLE), combined to the inherent limitations of clinical research, have made it difficult to investigate the cause of this disease directly in patients. Various mouse models have been developed to dissect the cellular and genetic mechanisms of SLE, as well as to identify therapeutic targets and to screen treatments. The purpose of this review is to summarize the major spontaneous and induced mouse models of SLE and to provide an update on the major advances they have contributed to the field., Recent Findings: Mouse models of SLE have continued to contribute to understand the cellular, signaling and metabolic mechanisms contributing to the disease and how targeting these pathways can provide therapeutic targets. Whenever possible, we discuss the advantage of using one model over the others to test a specific hypothesis., Summary: Spontaneous and induced models of lupus models are useful tools for the study of the cause of the disease, identify therapeutic targets and screen treatments in preclinical studies. Each model shares specific subsets of attributes with the disease observed in humans, which provides investigators a tool to tailor to their specific needs.

The phase diagram of the quasi-binary Cu-TiS 2 system has been studied in situ in the temperature-concentration plane for the first time. Phase transitions between 2D (layered) and 3D (cubic) phases in Cu x TiS 2 (x = 0-0.5) intercalation compounds have been studied by the X-ray diffraction technique in the temperature range 20-1000 °C. It has been found that the stability of the layered phase is determined by the distribution of copper atoms between the octahedral and tetrahedral crystallographic sites. The occupation of octahedral sites dominates at low temperatures. Upon heating, tetrahedral site occupation is limited due to elastic lattice distortion and the layered phase becomes unstable and transforms to the spinel. Further heating allows the distribution of copper between octahedral and tetrahedral sites; the layered phase becomes stable again.

PBX1-d is novel splice isoform of pre-B-cell leukemia homeobox 1 (PBX1) that lacks its DNA-binding and Hox-binding domains, and functions as a dominant negative. We have shown that PBX1-d expression in CD4 + T cells is associated with systemic lupus erythematosus (SLE) in a mouse model as well as in human subjects. More specifically, PBX1-d expression leads to the production of autoreactive activated CD4+ T cells, a reduced frequency and function of Foxp3+ regulatory T (Treg) cells and an expansion of follicular helper T (Tfh) cells. Very little is known about the function of PBX1 in T cells, except that it directly regulates the expression of miRNAs associated with Treg and Tfh homeostasis. In the present study, we show that PBX1 directly regulated the expression of CD44, a marker of T cell activation. Two PBX1 binding sites in the promoter directly regulated CD44 expression, with PBX1-d driving a higher expression than the normal isoform PBX1-b. In addition, mutations in each of the two binding sites had different effects of PBX1-b and PBX1-d. Finally, we showed that an enhanced recruitment of co-factor MEIS by PBX1-d over PBX1-b, while there was no difference for co-factor PREP1 recruitment. Therefore, this study demonstrates that the lupus-associated PBX1-d isoform directly transactivates CD44, a marker of CD44 activation and memory, and that it has different DNA binding and co-factor recruitment relative to the normal isoform. Taken together, these results confirm that PBX1 directly regulates genes related to T cell activation and shows that the lupus-associated isoform PBX1-d has unique molecular functions., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

An experimental study of the electronic structure of V x Ti 1-x Se 2 system in a wide range of vanadium concentrations (x = 0.06-0.9) using x-ray photoelectron spectroscopy and resonant photoelectron spectroscopy has been performed. The partial charge transfer from the VSe 2 to TiSe 2 structural fragments is experimentally observed, and the most part of the charge is localized on the vanadium atoms in the VSe 2 structural fragments.

The electronic structure of the Ni x TiSe 2 intercalation compounds with disordered and ordered Ni atoms is studied using photoelectron, resonant photoelectron and X-ray absorption spectroscopy, theoretical calculations of the X-ray spectra and density of electronic states. The increase in the covalent component of the chemical bond of Ni and Ti with the nearest neighbour was found with increasing nickel concentration and its ordering. A significant charge transfer from the Ni atoms to the host lattice resulting in the transformation of Ti 4+ into Ti 3+ occurs, while the symmetry of the crystal lattice is lowered from the hexagonal to the monoclinic one.

Cellular metabolism represents a newly identified checkpoint of effector functions in the immune system. A solid body of work has characterized the metabolic requirements of normal T cells during activation and differentiation into polarized effector subsets. Similar studies have been initiated to characterize the metabolic requirements for B cells and myeloid cells. Only a few studies though have characterized the metabolism of immune cells in the context of autoimmune diseases. Here, we review what is known on the altered metabolic patterns of CD4 + T cells, B cells, and myeloid cells in lupus patients and lupus-prone mice and how they contribute to lupus pathogenesis. We also discuss how defects in immune metabolism in lupus can be targeted therapeutically.

The nondestructive reversible complexation of the macrocyclic group 11 metal pyrazolates {[3,5-(CF3)2Pz]M}3 (M = Cu(I), Ag(I)) to the halogen atom X = Cl, Br of η(3)-allyliron tricarbonyl halides (η(3)-2-R-C3H4)Fe(CO)3X is revealed by the variable-temperature spectroscopic (IR, NMR) study combined with density functional theory calculations. The composition of all complexes at room temperature is determined as 1:1. In the case of the [AgL]3 macrocycle, complexes 1:2 are observed at low temperature (<260 K). The complex's stability depends on the substituents in the allyl fragment and halide ligand as well as on the metal atom (Ag(I), Cu(I)) in the macrocycle. For bulky substituents (Me and Ph) the endo/exo equilibrium of the parent (η(3)-2-R-C3H4)Fe(CO)3X shifts upon the complex formation in favor of the exo isomer due to additional noncovalent interactions of the substituent with macrocycle.

Pbx1 controls chromatin accessibility to a large number of genes and is entirely conserved between mice and humans. The Pbx1-d dominant-negative isoform is more frequent in CD4(+) T cells from lupus patients than from healthy controls. Pbx1-d is associated with the production of autoreactive T cells in mice carrying the Sle1a1 lupus-susceptibility locus. Transgenic (Tg) expression of Pbx1-d in CD4(+) T cells reproduced the phenotypes of Sle1a1 mice, with increased inflammatory functions of CD4(+) T cells and impaired Foxp3(+) regulatory T cell (Treg) homeostasis. Pbx1-d-Tg expression also expanded the number of follicular helper T cells (TFHs) in a cell-intrinsic and Ag-specific manner, which was enhanced in recall responses and resulted in Th1-biased Abs. Moreover, Pbx1-d-Tg CD4(+) T cells upregulated the expression of miR-10a, miR-21, and miR-155, which were implicated in Treg and follicular helper T cell homeostasis. Our results suggest that Pbx1-d impacts lupus development by regulating effector T cell differentiation and promoting TFHs at the expense of Tregs. In addition, our results identify Pbx1 as a novel regulator of CD4(+) T cell effector function., (Copyright © 2016 by The American Association of Immunologists, Inc.)

An experimental study of the electronic structure of copper intercalated titanium dichalcogenides in a wide range of copper concentrations (x = 0.04-0.8) using x-ray photoelectron spectroscopy, resonant photoelectron spectroscopy, and x-ray absorption spectroscopy has been performed. Shift towards low energies of the Ti 2p and Se 3d core level spectra and a corresponding decrease in the photon energy of Ti 2p absorption spectra with the increase in copper concentration have been found. These sign-anomalous shifts may be explained by the shielding effect of the corresponding atomic shells as a result of the dynamic charge transfer during the formation of a covalent chemical bond between the copper atoms and the TiSe2 matrix.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which organ damage is mediated by pathogenic autoantibodies directed against nucleic acids and protein complexes. Studies in SLE patients and in mouse models of lupus have implicated virtually every cell type in the immune system in the induction or amplification of the autoimmune response as well as the promotion of an inflammatory environment that aggravates tissue injury. Here, we review the contribution of CD4+ T cells, B cells, and myeloid cells to lupus pathogenesis and then discuss alterations in the metabolism of these cells that may contribute to disease, given the recent advances in the field of immunometabolism.

According to spectroscopic (NMR, IR, UV/Vis) study, the interaction of pentaphosphaferrocene [Cp*Fe(η(5) -P5 )] with trimeric copper pyrazolate [(Cu{3,5-(CF3 )2 Pz})3 ] yields a new compound that is astonishingly stable in solution. Single-crystal X-ray analysis reveals unprecedented structural changes in the interacting molecules and the unique type of coordination [Cp*Fe(μ3 -η(5) :η(2) ,η(2) -P5 ){Cu(3,5-(CF3 )2 Pz)}3 ]. As a result of the 90° macrocycle folding, the copper atoms are able to behave both as a Lewis acid and as a Lewis base in the interaction with the cyclo-P5 ligand., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Monoparametric immunoassay tests for detecting botulinum toxins types A and B and multiparametric assays for simultaneous detection of botulinum toxins type A and B have been developed. It is shown that the sensitivity of assays is affected by the size of nanoparticles of colloidal gold used as a marker of antibodies, load intensity of antibodies of colloidal gold in conjugates, the type of analytical membranes, as well as the chemical composition of buffer solutions used for the storage of conjugates and immunoassay analysis. The detection limit of monoparametric immunoassay tests is 0.5 ng/ml; that of multiparametric assays, 5.0 ng/ml. The developed immunoassay can be used for rapid assay of product quality, for grade control of botulinum toxins in pharmaceuticals, and environmental monitoring.

Interaction of the copper, {[3,5-(CF(3))(2)Pz]Cu}(3), and silver, {[3,5-(CF(3))(2)Pz]Ag}(3), macrocycles [3,5-(CF(3))(2)Pz = 3,5-bis(trifluoromethyl)pyrazolate] with cyclooctatetraeneiron tricarbonyl, (cot)Fe(CO)(3), was investigated by IR and NMR spectroscopy for the first time. The formation of 1:1 complexes was observed at low temperatures in hexane. The composition of the complexes (1:1) and their thermodynamic characteristics in hexane and dichloromethane were determined. The π-electron system of (cot)Fe(CO)(3) was proven to be the sole site of coordination in solution and in the solid state. However, according to the single-crystal X-ray data, the complex has a different (2:1) composition featuring the sandwich structure. The complexes of ferrocene with copper and silver macrocycles have a columnar structure (X-ray data).

Processes accompanying the quenching of the fluorescent probe 4"-dimethylaminochalcone by hydroxyl groups of the proton-donor solvent 1-butanol have been studied. The kinetics of the deactivation of the excited state of 4"-dimethylaminochalcone has been monitored from the transition absorption spectra at a time resolution of 50 fs and fluorescence decay at a time resolution of 30 ps. The data obtained allow thinking that the next picture occurs in 1-butanol. At first stage, the 4"-dimethylaminochalcone molecule in its ground state forms a hydrogen bond with an alcohol molecule. At the second stage, the absorption of light quantum and corresponding rise of the dipole moment of 4"-dimethylaminochalcone take place, the initially existing hydrogen bond is retained. The third stage consists in the rearrangement of the 4"-dimethylaminochalcone solvation shell formed by alcohol dipole molecules due to an increase of the dipole of moment 4"-dimethylaminochalcone; this rearrangement takes an energy of about 24 kJ/mol, the arrangement time constant is close to 40 ps; the initial hydrogen bond is retained. The fourth stage involves processes that lead to fluorescence quenching; their time constant is about 200 ps. Taking into account that the quenching is a much slower process than the relaxation of the solvation shell, it was supposed that the quenching is not a direct consequence of the solvation shell relaxation or the existence of the hydrogen bond formed prior to excitation. Then the fluorescence quenching of 4"-dimethylaminochalcone can be accomplished through some other processes that are observed in other fluorescent molecules: (a) rearrangement of the initial hydrogen bond from a conformation that cannot quench the fluorescence of 4"-dimethylaminochalcone to a more "effective" conformation, (b) charge transfer between the excited of molecule 4"-dimethylaminochalcone and alcohol, or (c) solvent-induced twist of the 4"-dimethylaminochalcone amino group (its withdrawal from the molecule plane) by the action of the solvent.

We discovered a nuclear import pathway mediated by the product of the previously identified Saccharomyces cerevisiae gene PDR6 (pleiotropic drug resistance). This gene product functions as a karyopherin (Kap) for nuclear import. Consistent with previously proposed nomenclature, we have renamed this gene KAP122. Kap122p was localized both to the cytoplasm and the nucleus. As a prominent import substrate of Kap122p, we identified the complex of the large and small subunit (Toa1p and Toa2p, respectively) of the general transcription factor IIA (TFIIA). Recombinant GST-Kap122p formed a complex with recombinant His(6)-Toa1p/Toa2p. In wild-type cells, Toa1p and Toa2p were localized to the nucleus. Consistent with Kap122p being the principal Kap for import of the Toa1p-Toa2p complex, we found that deletion of KAP122 results in increased cytoplasmic localization of both Toa1p and Toa2p. Deletion of KAP122 is not lethal, although deletion of TOA1 and TOA2 is. Together these data suggest that Kap122p is the major Kap for the import of Toa1p-Toa2p into the nucleus. Like other substrate-Kap complexes, the Toa1p/Toa2p/Kap122p complex isolated from yeast cytosol or reconstituted from recombinant proteins, was dissociated by RanGTP but not RanGDP. Kap122p bound to nucleoporins, specifically, to the peptide repeat-containing fragments of Nup1p and Nup2p.

After 7-day head-down tilt at --8 degrees six healthy male test subjects were exposed to leg anesthesia achieved by peridural anesthesia (3 subjects) and electroauriculoacuanalgesia (3 subjects), with circulation parameters being monitored. The anesthetic effect was not accompanied by significant changes in hemodynamics or homeostasis.