Decreasing the Bond Order between Vanadium and Oxo Ligand to Form 3d Schrock Carbynes.

Preserving vanadium in a high oxidation state during chemical transformations can be challenging due to the oxidizing nature of V(+5) species. Oxo and similar isoelectronic ligands have been utilized to stabilize V(+5) by extensive π-donation. However, decreasing the bond order between V and the oxo ligand often results in a reduction of the metal center. Herein, we report a unique transformation involving anionic V(+5) alkylidene that converts a V(+5) oxo complex to a V(+5) alkylidyne in three steps without altering the oxidation state of the metal center. This method has been used to obtain rare 3d Schrock carbynes, which provide easy and scalable access to V(+5) alkylidynes.

Dependence of rhythmic activity and oddball effects in the rat cortex on the depth of sedation during dissociative anesthesia.

The reactions to novelty manifesting in mismatch negativity in the rat brain were studied. During dissociative anesthesia, mismatch negativity-like waves were recorded from the somatosensory cortex using an epidural 32-electrode array. Experimental animals: 7 wild-type Wistar rats and 3 transgenic rats. During high-dose anesthesia, deviant 1,500 Hz tones were presented randomly among many standard 1,000 Hz tones in the oddball paradigm. "Deviant minus standard_before_deviant" difference waves were calculated using both the classical method of Naatanen and method of cross-correlation of sub-averages. Both methods gave consistent results: an early phasic component of the N40 and later N100 to 200 (mismatch negativity itself) tonic component. The gamma and delta rhythms power and the frequency of down-states (suppressed activity periods) were assessed. In all rats, the amplitude of tonic component grew with increasing sedation depth. At the same time, a decrease in gamma power with a simultaneous increase in delta power and the frequency of down-states. The earlier phasic frontocentral component is associated with deviance detection, while the later tonic one over the auditory cortex reflects the orienting reaction. Under anesthesia, this slow mismatch negativity-like wave most likely reflects the tendency of the system to respond to any influences with delta waves, K-complexes and down-states, or produce them spontaneously.

Mononuclear Four-Coordinate Bis-Fluoride Bis-NHC Complexes of Chromium(II), Iron(II), and Cobalt(II).

The reaction between silylamido complexes of Cr(II), Fe(II), and Co(II) and IMes·2HF salt in the presence of IMes (IMes = 1,3-dimesitylimidazol-2-ylidene) led to isolation of Cr(IMes)2F2 (2-Cr), Fe(IMes)2F2 (2-Fe), and Co(IMes)2F2 (2-Co). X-ray structural studies revealed that 2-Cr adopts square planar geometry, while 2-Fe and 2-Co have distorted tetrahedral geometry. Magnetic susceptibility studies of 2-Cr, 2-Fe, and 2-Co were consistent with high-spin complexes, S = 2 for 2-Cr/2-Fe and S = 3/2 for 2-Co. We demonstrated that fluoride can be successfully exchanged for cyanide and azide using trimethylsilyl cyanide and trimethylsilyl azide (3-Fe and 4-Fe). DFT studies suggest that the preference of 2-Cr to adopt square planar geometry over tetrahedral is due to its d4 metal center, where four electrons fill the lower-lying d-orbitals.

Combustion Synthesis and Reactive Spark Plasma Sintering of Non-Equiatomic CoAl-Based High Entropy Intermetallics.

The present work reports the direct production of a high-entropy (HE) intermetallic CoNi0.3Fe0.3Cr0.15Al material with a B2 structure from mechanically activated elemental powder mixtures. Fast and efficient combustion synthesis (CS), spark plasma sintering (SPS), and reactive SPS (RSPS) methods were used to synthesize the HE powders and bulks. The formation of the main B2 phase along with some amounts of secondary BCC and FCC phases are reported, and L12 intermetallic (CS scheme) and BCC based on Cr (CS + SPS and RSPS schemes at 1000 °C) were observed in all samples. The interaction between the components during heating to 1600 °C of the mechanically activated mixtures and CS powders has been studied. It has been shown that the formation of the CoNi0.3Fe0.3Cr0.15Al phase occurs at 1370 °C through the formation of intermediate intermetallic phases (Al9Me2, AlCo, AlNi3) and their solid solutions, which coincidences well with thermodynamic calculations and solubility diagrams. Compression tests at room and elevated temperatures showed that the alloy obtained by the RSPS method has enhanced mechanical properties (σp = 2.79 GPa, σ0.2 = 1.82 GPa, ε = 11.5% at 400 °C) that surpass many known alloys in this system. High mechanical properties at elevated temperatures are provided by the B2 ordered phase due to the presence of impurity atoms and defects in the lattice.

Different sensitivity to anesthesia according to ECoG data in dopamine transporter knockout and heterozygous rats.

Dopamine in the brain is involved in many important functions, including the regulation of wakefulness. There is also some evidence suggesting that the dopamine function is crucial in anesthetic function. The state of anesthesia is characterized by a change in the level of consciousness and a change in brain electrical activity. Due to impaired mechanisms of dopamine transportation back to the synaptic terminal, dopamine transporter (DAT) knockout and heterozygous rats have increased levels of the extracellular dopamine. In our work, we registered ECoG disturbances in knockout and heterozygous rats, as well as disturbances in tone and activity in acute experiments under the anesthesia Zoletil (tiletamine and zolazepam) from the somatosensory cortex using a NeuroNexus flat multielectrode array to study gamma activity. We also used four low-resistance electrodes to control the slow rhythm. Both low-resistance and high-resistance electrodes showed differences in the ECoG spectrum of heterozygotes and total knockouts from the wild type and from each other. Heterozygous rats for the DAT gene (HET) showed increased rapid beta and gamma activity and decreased slow delta activity, while complete knockouts (KO), on the contrary, showed increased delta activity and decreased beta and gamma activity. Thus, the ECoG spectrum of HET is shifted to the right, while that of KO is shifted to the left. Full knockouts also showed decreased spatial synchronization in the 30-100 Hz gamma range compared to the wild type (WT). It is assumed that sedation of HET and KO is shifted towards opposite directions compared to WT under the same anesthesia conditions.

Detecting Examinees With Item Preknowledge on Real Data.

Recently, Belov & Wollack (2021) developed a method for detecting groups of colluding examinees as cliques in a graph. The objective of this article is to study how the performance of their method on real data with item preknowledge (IP) depends on the mechanism of edge formation governed by a response similarity index (RSI). This study resulted in the development of three new RSIs and demonstrated a remarkable advantage of combining responses and response times for detecting examinees with IP. Possible extensions of this study and recommendations for practitioners were formulated.

Photoelectromagnetic Effect Induced by Terahertz Laser Radiation in Topological Crystalline Insulators Pb1-xSnxTe.

Topological crystalline insulators form a class of semiconductors for which surface electron states with the Dirac dispersion relation are formed on surfaces with a certain crystallographic orientation. Pb1-xSnxTe alloys belong to the topological crystalline phase when the SnTe content x exceeds 0.35, while they are in the trivial phase at x < 0.35. For the surface crystallographic orientation (111), the appearance of topologically nontrivial surface states is expected. We studied the photoelectromagnetic (PEM) effect induced by laser terahertz radiation in Pb1-xSnxTe films in the composition range x = (0.11-0.44), with the (111) surface crystallographic orientation. It was found that in the trivial phase, the amplitude of the PEM effect is determined by the power of the incident radiation, while in the topological phase, the amplitude is proportional to the flux of laser radiation quanta. A possible mechanism responsible for the effect observed presumes damping of the thermalization rate of photoexcited electrons in the topological phase and, consequently, prevailing of electron diffusion, compared with energy relaxation.

Design of gp120 HIV-1 entry inhibitors by scaffold hopping via isosteric replacements.

We present the development of alternative scaffolds and validation of their synthetic pathways as a tool for the exploration of new HIV gp120 inhibitors based on the recently discovered inhibitor of this class, NBD-14136. The new synthetic routes were based on isosteric replacements of the amine and acid precursors required for the synthesis of NBD-14136, guided by molecular modeling and chemical feasibility analysis. To ensure that these synthetic tools and new scaffolds had the potential for further exploration, we eventually tested few representative compounds from each newly designed scaffold against the gp120 inhibition assay and cell viability assays.

Graph Theory Approach to Detect Examinees Involved in Test Collusion.

Test collusion (TC) is sharing of test materials or answers to test questions before or during the test (important special case of TC is item preknowledge). Because of potentially large advantages for examinees involved, TC poses a serious threat to the validity of score interpretations. The proposed approach applies graph theory methodology to response similarity analyses for identifying groups of examinees involved in TC without using any knowledge about parts of test that were affected by TC. The approach supports different response similarity indices (specific to a particular type of TC) and different types of groups (connected components, cliques, or near-cliques). A comparison with an up-to-date method using real and simulated data is presented. Possible extensions and practical recommendations are given.

Olefin Metathesis by First-Row Transition Metals.

Catalytic olefin metathesis based on the second- and third-row transition metals has become one of the most powerful transformations in modern organic chemistry. The shift to first-row metals to produce fine and commodity chemicals would be an important achievement to complement existing methods with inexpensive and greener alternatives. In addition, those systems can offer unusual reactivity based on the unique electronic structure of the base metals. In this Minireview, we summarize the progress of the development of alkylidenes and metallacycles of first-row transition metals from scandium to nickel capable of performing cycloaddition and cycloreversion steps, crucial reactions in olefin metathesis. In addition, we will discuss systems capable of performing olefin metathesis; however, the nature of active species is not yet known.

Design, synthesis, and antiviral activity of a series of CD4-mimetic small-molecule HIV-1 entry inhibitors.

We presented our continuing stride to optimize the second-generation NBD entry antagonist targeted to the Phe43 cavity of HIV-1 gp120. We have synthesized thirty-eight new and novel analogs of NBD-14136, earlier designed based on a CH2OH "positional switch" hypothesis, and derived a comprehensive SAR. The antiviral data confirmed that the linear alcohol towards the "N" (C4) of the thiazole ring yielded more active inhibitors than those towards the "S" (C5) of the thiazole ring. The best inhibitor, NBD-14273 (compound 13), showed both improved antiviral activity and selectivity index (SI) against HIV-1HXB2 compared to NBD-14136. We also tested NBD-14273 against a large panel of 50 HIV-1 Env-pseudotyped viruses representing clinical isolates of diverse subtypes. The overall mean data indicate that antiviral potency against these isolates improved by ~3-fold, and SI also improved ~3-fold compared to NBD-14136. This new and novel inhibitor is expected to pave the way for further optimization to a more potent and clinically relevant inhibitor against HIV-1.

Ring-Closing Olefin Metathesis Catalyzed by Well-Defined Vanadium Alkylidene Complexes.

Vanadium-based catalysts have shown activity and selectivity in ring-opening metathesis polymerization of strained cyclic olefins comparable to those of Ru, Mo, and W catalysts. However, the application of V alkylidenes in routine organic synthesis is limited. Here, we present the first example of ring-closing olefin metathesis catalyzed by well-defined V chloride alkylidene phosphine complexes. The developed catalysts exhibit tolerance to various functional groups, such as an ether, an ester, a tertiary amide, a tertiary amine, and a sulfonamide. The size and electron-donating properties of the imido group and the phosphine play a crucial role in the stability of active intermediates. Reactions with ethylene and olefins suggest that both ß-hydride elimination of the metallacyclobutene and bimolecular decomposition are responsible for catalyst degradation.

Stereospecific Ring-Opening Metathesis Polymerization of Norbornene Catalyzed by Iron Complexes.

Developing well-defined iron-based catalysts for olefin metathesis would be a breakthrough achievement in the field not only to replace existing catalysts by inexpensive metals but also to attain a new reactivity taking advantage of the unique electronic structure of the base metals. Here, we present a two-coordinate homoleptic iron complex, Fe(HMTO)2 [HMTO=O-2,6-(2,4,6-Me3 C6 H2 )2 C6 H3 ], that is capable of performing ring-opening metathesis polymerization of norbornene to produce highly stereoregular polynorbornene (99 % cis, syndiotactic). The use of heteroleptic Fe(HMTO)(RO) [RO=(CH3 )2 CF3 CO, CH3 (CF3 )2 CO, or Ph(CF3 )2 CO] prepared in situ significantly increases the polymerization rate while preserving selectivity. The resulting polymers were characterized by 1 H and 13 C NMR spectroscopy and gel-permeation chromatography.

Risk score for predicting abdominal complications after coronary artery bypass grafting.

BACKGROUND: Although early abdominal complications after coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) are rare, the associated mortality remains high. AIM: To develop a risk score for the prediction of early abdominal complications after CABG with CPB. METHODS: This retrospective study was performed in the Federal State Budgetary Establishment "Federal Center of Cardiovascular Surgery" of the Ministry of Health of Russia (the city of Chelyabinsk) and included data of 6586 patients who underwent CABG with CPB during 2011-2017. The risk factors taken for evaluation were compared between patients with early abdominal complications (n = 73) and without them (n = 6513). We identified the most important risk factors and their influence on the development of early abdominal complications after CABG with CPB. RESULTS: Gender and the presence of postinfarction cardiosclerosis, chronic kidney disease, or diabetes in the anamnesis did not affect the occurrence of abdominal complications. The leading risk factors of the early abdominal complications after CABG with CPB were multifocal atherosclerosis, extracorporeal membrane oxygenation, intra-aortic balloon pump, atrial fibrillation, perioperative myocardial infarction, and the need for resternotomy in the postoperative period. The average value of the predicted probability was 0.087 ± 0.015 in patients with early abdominal complications after CABG with CPB and 0.0094 ± 0.0003 in patients without these complications. The percentage of correct classification turned out to be 98.9%. After calculating a score for each of the leading risk factors, we counted a total score for each particular patient. The highest risk was noted in patients with a total score of 7 or more. CONCLUSION: The developed score predicts the risk of early abdominal complications after CABG with CPB and makes it possible to stratify patients by risk groups.

Left atrial appendage aneurysm: A case report.

BACKGROUND: An aneurysm of the left atrial appendage is one of the rare but potentially hazardous heart defects. The risk of lethal complications grows with its size. To date, about 150 cases of this defect have been described in the literature. We present a case of left atrial appendage aneurysm with the deformation of the mitral valve and the left main coronary and circumflex artery, which required mitral valve annuloplasty and bifurcation stenting. CASE SUMMARY: A 58-year-old man presented to our hospital complaining of shortness of breath, general weakness, dizziness during physical exertion, and fatigue. Based on the results of echocardiography, an aneurysm of the left atrium was suspected. A free-breathing real-time cine magnetic resonance imaging with electrocardiograph synchronization confirmed the diagnosis of left atrial appendage aneurysm. The patient underwent an aneurysmectomy via a median sternotomy with cardiopulmonary bypass. Intraoperative transesophageal echocardiography revealed relative mitral insufficiency that was corrected with an annuloplasty ring. Intraoperative coronary angiogram showed impaired blood flow in the left main coronary and circumflex artery and 60% stenosis. For this reason, bifurcation stenting was performed. The patient had an uneventful postoperative clinical course and was discharged from the hospital on the 10th day in a satisfactory condition. CONCLUSION: Left atrial appendage aneurysm is a rare and dangerous heart pathology that requires surgery to prevent related complications.

Chemotherapeutic Agents Sensitize Resistant Cancer Cells to the DR5-Specific Variant DR5-B more Efficiently than to TRAIL by Modulating the Surface Expression of Death and Decoy Receptors.

TRAIL is considered a promising antitumor agent because it causes apoptosis of transformed cells without affecting normal cells. However, many types of tumors are cytokine resistant, and combination therapy with various chemotherapeutic drugs is being developed to overcome the resistance. We have demonstrated that the combination of TRAIL with doxorubicin, bortezomib, and panobinostat dramatically reduced the viability of TRAIL-resistant A549 and HT-29 cells. Chemotherapy even more efficiently sensitized cells to the DR5-specific mutant variant of TRAIL DR5-B, which does not have an affinity for decoy receptors. Bortezomib and doxorubicin greatly enhanced the surface expression of the death receptors DR5 and DR4, while panobinostat increased expression of DR5 and suppressed expression of DR4 in both cell lines. All drugs increased surface expression of the decoy receptors DcR1 and DcR2. Unlike the combined treatment, if the cells were pretreated with chemotherapy for 24 h, the cytotoxic activity of TRAIL was less pronounced, while sequential treatment of cells enhanced the effectiveness of DR5-B. The same results were obtained with agonistic anti-DR5 antibodies. Thus, the effectiveness of TRAIL was rather limited due to changes in the ratio of death and decoy receptors and DR5-specific agonists may be preferred in combination antitumor therapy regimens.

Preclinical Optimization of gp120 Entry Antagonists as anti-HIV-1 Agents with Improved Cytotoxicity and ADME Properties through Rational Design, Synthesis, and Antiviral Evaluation.

We previously reported a milestone in the optimization of NBD-11021, an HIV-1 gp120 antagonist, by developing a new and novel analogue, NBD-14189 (Ref1), which showed antiviral activity against HIV-1HXB2, with a half maximal inhibitory concentration of 89 nM. However, cytotoxicity remained high, and the absorption, distribution, metabolism, and excretion (ADME) data showed relatively poor aqueous solubility. To optimize these properties, we replaced the phenyl ring in the compound with a pyridine ring and synthesized a set of 48 novel compounds. One of the new analogues, NBD-14270 (8), showed a marked improvement in cytotoxicity, with 3-fold and 58-fold improvements in selectivity index value compared with that of Ref1 and NBD-11021, respectively. Furthermore, the in vitro ADME data clearly showed improvements in aqueous solubility and other properties compared with those for Ref1. The data for 8 indicated that the pyridine scaffold is a good bioisostere for phenyl, allowing the further optimization of this molecule.

Synthesis, Antiviral Activity, and Structure-Activity Relationship of 1,3-Benzodioxolyl Pyrrole-Based Entry Inhibitors Targeting the Phe43 Cavity in HIV-1 gp120.

The pathway by which HIV-1 enters host cells is a prime target for novel drug discovery because of its critical role in the life cycle of HIV-1. The HIV-1 envelope glycoprotein gp120 plays an important role in initiating virus entry by targeting the primary cell receptor CD4. We explored the substitution of bulky molecular groups in region I in the NBD class of entry inhibitors. Previous attempts at bulky substituents in that region abolished antiviral activity, even though the binding site is hydrophobic. We synthesized a series of entry inhibitors containing the 1,3-benzodioxolyl moiety or its bioisostere, 2,1,3-benzothiadiazole. The introduction of the bulkier groups was well tolerated, and despite only minor improvements in antiviral activity, the selectivity index of these compounds improved significantly.

Structure-based lead optimization to improve antiviral potency and ADMET properties of phenyl-1H-pyrrole-carboxamide entry inhibitors targeted to HIV-1 gp120.

We are continuing our concerted effort to optimize our first lead entry antagonist, NBD-11021, which targets the Phe43 cavity of the HIV-1 envelope glycoprotein gp120, to improve antiviral potency and ADMET properties. In this report, we present a structure-based approach that helped us to generate working hypotheses to modify further a recently reported advanced lead entry antagonist, NBD-14107, which showed significant improvement in antiviral potency when tested in a single-cycle assay against a large panel of Env-pseudotyped viruses. We report here the synthesis of twenty-nine new compounds and evaluation of their antiviral activity in a single-cycle and multi-cycle assay to derive a comprehensive structure-activity relationship (SAR). We have selected three inhibitors with the high selectivity index for testing against a large panel of 55 Env-pseudotyped viruses representing a diverse set of clinical isolates of different subtypes. The antiviral activity of one of these potent inhibitors, 55 (NBD-14189), against some clinical isolates was as low as 63 nM. We determined the sensitivity of CD4-binding site mutated-pseudoviruses to these inhibitors to confirm that they target HIV-1 gp120. Furthermore, we assessed their ADMET properties and compared them to the clinical candidate attachment inhibitor, BMS-626529. The ADMET data indicate that some of these new inhibitors have comparable ADMET properties to BMS-626529 and can be optimized further to potential clinical candidates.

A Small-Molecule Inhibitor of Prion Replication and Mutant Prion Protein Toxicity.

Into the fold: Prion diseases are neurodegenerative disorders characterized by the accumulation in the brain of a self-replicating, misfolded isoform (PrPSc ) of the cellular prion protein (PrPC ). No therapies are available for these pathologies. We capitalized on previously described cell-based assays to screen a library of small molecules, and identified 55, a compound capable of counteracting both prion replication and toxicity. Compound 55 may represent the starting point for the development of a completely new class of therapeutics for prion diseases.