Selective ortho-C-H Activation in Arenes without Functional Groups.

Aromatic C-H activation in alkylarenes is a key step for the synthesis of functionalized organic molecules from simple hydrocarbon precursors. Known examples of such C-H activations often yield mixtures of products resulting from activation of the least hindered C-H bonds. Here we report highly selective ortho-C-H activation in alkylarenes by simple iridium complexes. We demonstrate that the capacity of the alkyl substituent to override the typical preference of metal-mediated C-H activation for the least hindered aromatic C-H bonds results from transient insertion of iridium into the benzylic C-H bond. This enables fast iridium insertion into the ortho-C-H bond, followed by regeneration of the benzylic C-H bond by reductive elimination. Bulkier alkyl substituents increase the ortho selectivity. The described chemistry represents a conceptually new alternative to existing approaches for aromatic C-H bond activation.

Efficient Palladium-Catalyzed Synthesis of 2-Aryl Propionic Acids.

A flexible two-step, one-pot procedure was developed to synthesize 2-aryl propionic acids including the anti-inflammatory drugs naproxen and flurbiprofen. Optimal results were obtained in the presence of the novel ligand neoisopinocampheyldiphenylphosphine (NISPCPP) (9) which enabled the efficient sequential palladium-catalyzed Heck coupling of aryl bromides with ethylene and hydroxycarbonylation of the resulting styrenes to 2-aryl propionic acids. This cascade transformation leads with high regioselectivity to the desired products in good yields and avoids the need for additional purification steps.

Reversible Insertion of Ir into Arene Ring C-C Bonds with Improved Regioselectivity at a Higher Reaction Temperature.

Regioselective metal insertion into aromatic C-C bonds is a long-standing problem critical for development of new arene functionalizations and cleaner conversion of fossil fuel into value-added chemicals. We report reversible insertion of iridium into the aromatic C-C bonds of η4-bound methyl arenes to give eight-membered diiridium metallacycles with yields up to 99%. While at 50-100 °C the reaction yields a mixture of isomers corresponding to iridium insertion in both unsubstituted and Me-substituted ring C-C bonds, at 150 °C a single isomer dominates. Kinetic and DFT studies suggest that at 150 °C insertion of iridium is reversible, allowing equilibration of the metallacycle products via a diiridium arene sandwich complex. The selectivity of metal insertion is determined by the relative stabilities of isomeric metallacycles governed by steric repulsion between methyl groups of the hydrocarbon chain of the cleaved arene and the Cp* ligands.

Experts' opinion about the primary headache diagnostic criteria of the ICHD-3rd edition beta in children and adolescents.

BACKGROUND: The 2013 International Classification of Headache Disorders-3 (ICHD-3) was published in a beta version to allow the clinicians to confirm the validity of the criteria or to suggest improvements based on field studies. The aim of this work was to review the Primary Headache Disorders Section of ICHD-3 beta data on children and adolescents (age 0-18 years), and to suggest changes, additions, and amendments. METHODS: Several experts in childhood headache across the world applied different aspects of ICHD-3 beta in their normal clinical practice. Based on their personal experience and the literature available on pediatric headache, they made observations and proposed suggestions for the primary headache disorders section of ICHD-3 beta data on children and adolescents. RESULTS: Some headache disorders in children have specific features which are different from those seen in adults and which should be acknowledged and considered. Some features in children were found to be age-dependent: clinical characteristics, risks factors and etiologies have a strong bio psycho-social basis in children and adolescents making primary headache disorders in children distinct from those in adults. CONCLUSIONS: Several recommendations are presented in order to make ICHD-3 more appropriate for use with children.

Experts' opinion about the pediatric secondary headaches diagnostic criteria of the ICHD-3 beta.

BACKGROUND: The 2013 International Classification of Headache Disorders-3 was published in a beta version to allow clinicians to confirm the validity of the criteria or suggest improvements based on field studies. The aim of this work was to review the Secondary Headache Disorders and Cranial Neuralgias and Other Headache Disorders sections of ICHD-3 beta data on children and adolescents (age 0-18 years) and to suggest changes, additions, and amendments. METHODS: Several experts in childhood headache across the world applied different aspects of ICHD-3 beta in their normal clinical practice. Based on their personal experience and the available literature on pediatric headache, they made observations and proposed suggestions for the mentioned headache disorders on children and adolescents. RESULTS: Some headache disorders in children have specific features, which are different from adults that should be acknowledged and considered. Some features in children were found to be age-dependent: clinical characteristics, risks factors and etiologies have a strong bio psychosocial basis in children and adolescents making primary headache disorders in children distinct from those in adults. CONCLUSIONS: Several recommendations are presented in order to make ICHD-3 more appropriate for use in children.

Selective Arene Cleavage by Direct Insertion of Iridium into the Aromatic Ring.

We report an unprecedented selective cleavage of aromatic C-C bonds through the insertion of well-defined iridium complexes into the aromatic ring of simple alkylarenes. The insertion occurs at 50-100 °C without the activation of weaker C-H and C-C bonds and gives unique metallacycles in high yields. Key to the success of this approach is metal-induced deformation of the arene ring, which creates temporary ring strain and promotes direct and selective insertion of the metal into the otherwise inert arene ring C-C bonds.

Linear-selective hydroarylation of unactivated terminal and internal olefins with trifluoromethyl-substituted arenes.

We report a series of hydroarylations of unactivated olefins with trifluoromethyl-substituted arenes that occur with high selectivity for the linear product without directing groups on the arene. We also show that hydroarylations occur with internal, acyclic olefins to yield linear alkylarene products. Experimental mechanistic data provide evidence for reversible formation of an alkylnickel-aryl intermediate and rate-determining reductive elimination to form the carbon-carbon bond. Labeling studies show that formation of terminal alkylarenes from internal alkenes occurs by initial establishment of an equilibrating mixture of alkene isomers, followed by addition of the arene to the terminal alkene. Computational (DFT) studies imply that the aryl C-H bond transfers to a coordinated alkene without oxidative addition and support the conclusion from experiment that reductive elimination is rate-determining and forms the anti-Markovnikov product. The reactions are inverse order in α-olefin; thus the catalytic reaction occurs, in part, because isomerization creates a low concentration of the reactant α-olefin.

Computational biomechanics for a standing human body: Modal analysis and simulation.

We develop computational mechanical modeling and methods for the analysis and simulation of the motions of a human body. This type of work is crucial in many aspects of human life, ranging from comfort in riding, the motion of aged persons, sports performance and injuries, and many ergonomic issues. A prevailing approach for human motion studies is through lumped parameter models containing discrete masses for the parts of the human body with empirically determined spring, mass, damping coefficients. Such models have been effective to some extent; however, a much more faithful modeling method is to model the human body as it is, namely, as a continuum. We present this approach, and for comparison, we choose two digital CAD models of mannequins for a standing human body, one from the versatile software package LS-DYNA and another from open resources with some of our own adaptations. Our basic view in this paper is to regard human motion as a perturbation and vibration from an equilibrium position which is upright standing. A linear elastodynamic model is chosen for modal analysis, but a full nonlinear viscoelastoplastic extension is possible for full-body simulation. The motion and vibration of these two mannequin models is analyzed by modal analysis, where the normal vibration modes are determined. LS-DYNA is used as the supercomputing and simulation platform. Four sets of low-frequency modes are tabulated, discussed, visualized, and compared. Higher frequency modes are also selectively displayed. We have found that these modes of motion and vibration form intrinsic basic modes of biomechanical motion of the human body. This view is supported by our finding of the upright walking motion as a low-frequency mode in modal analysis. Such a "walking mode" shows the in-phase and out-of-phase movements between the legs and arms on the left and right sides of a human body, implying that this walking motion is spontaneous, likely not requiring any directives from the brain. Dynamic motions of CAD mannequins are also simulated by drop tests for comparisons and the validity of the models is discussed through Fourier frequency analysis. All computed modes of motion are collected in several sets of video animations for ease of visualization. Samples of LS-DYNA computer codes are also included for possible use by other researchers.

In Search of a Target Gene for a Desirable Phenotype in Aquaculture: Genome Editing of Cyprinidae and Salmonidae Species.

Aquaculture supplies the world food market with a significant amount of valuable protein. Highly productive aquaculture fishes can be derived by utilizing genome-editing methods, and the main problem is to choose a target gene to obtain the desirable phenotype. This paper presents a review of the studies of genome editing for genes controlling body development, growth, pigmentation and sex determination in five key aquaculture Salmonidae and Cyprinidae species, such as rainbow trout (Onchorhynchus mykiss), Atlantic salmon (Salmo salar), common carp (Cyprinus carpio), goldfish (Carassius auratus), Gibel carp (Carassius gibelio) and the model fish zebrafish (Danio rerio). Among the genes studied, the most applicable for aquaculture are mstnba, pomc, and acvr2, the knockout of which leads to enhanced muscle growth; runx2b, mutants of which do not form bones in myoseptae; lepr, whose lack of function makes fish fast-growing; fads2, Δ6abc/5Mt, and Δ6bcMt, affecting the composition of fatty acids in fish meat; dnd mettl3, and wnt4a, mutants of which are sterile; and disease-susceptibility genes prmt7, gab3, gcJAM-A, and cxcr3.2. Schemes for obtaining common carp populations consisting of only large females are promising for use in aquaculture. The immobilized and uncolored zebrafish line is of interest for laboratory use.

Effects of MTHFR gene polymorphism on the clinical and electrophysiological characteristics of migraine.

BACKGROUND: It was previously shown that the MTHFR gene polymorphism correlated with an increased risk of migraine, particularly migraine with aura. The substitution of cytosine for thymine at the position 677 of the MTHFR gene leads to formation of the thermolabile form of the protein and development of hyperhomocysteinemia, which increases the probability of migraine. The purpose of this study was to determine whether the replacement of C677T in the gene MTHFR influenced any particular symptoms of the disease. METHODS: We have analyzed clinical and electrophysiological characteristics of 83 patients with migraine (migraine with aura (MA), 19 patients, and migraine without aura (MO), 64 patients, according to the ICHD-II (2003)) taking into account their genotypes of C677T variant of MTHFR. RESULTS: We have shown that MA was significantly more prevalent among the T-allele carriers (37.2%), as compared to the СС genotype patients (0%), р < 0.0001. Patients with TT genotype were not only more likely to have accompanying symptoms (significant differences were found only for photophobia), but also more sensitive to migraine attack triggers. In RP-VEP test results we observed a trend that the T-allele carriers were presented with the decreased N75/P100 amplitudes and a positive habituation index, as compared to the СС genotype patients. CONCLUSIONS: Thus, according to our data, the MTHFR genotypes are associated with several clinical and electrophysiological characteristics of migraine.

A heterogeneous nickel catalyst for the hydrogenolysis of aryl ethers without arene hydrogenation.

A heterogeneous nickel catalyst for the selective hydrogenolysis of aryl ethers to arenes and alcohols generated without an added dative ligand is described. The catalyst is formed in situ from the well-defined soluble nickel precursor Ni(COD)(2) or Ni(CH(2)TMS)(2)(TMEDA) in the presence of a base additive, such as (t)BuONa. The catalyst selectively cleaves C(Ar)-O bonds in aryl ether models of lignin without hydrogenation of aromatic rings, and it operates at loadings down to 0.25 mol % at 1 bar of H(2) pressure. The selectivity of this catalyst for electronically varied aryl ethers differs from that of the homogeneous catalyst reported previously, implying that the two catalysts are distinct from each other.

Selective cleavage of unactivated arene ring C-C bonds by iridium: key roles of benzylic C-H activation and metal-metal cooperativity.

The cleavage of aromatic C-C bonds is central for conversion of fossil fuels into industrial chemicals and designing novel arene functionalisations through ring opening, expansion and contraction. However, the current progress is hampered by both the lack of experimental examples of selective oxidative addition of aromatic C-C bonds and limited understanding of the factors that favour insertion into the C-C rather than the C-H bonds. Here, we describe the comprehensive mechanism of the only reported chemo- and regioselective insertion of a transition metal into a range of substituted arene rings in simple iridium(i) complexes. The experimental and computational data reveal that this ring cleavage requires both reversible scission of a benzylic C-H bond and cooperativity of two Ir centres sandwiching the arene in the product-determining intermediate. The mechanism explains the chemoselectivity and scope of this unique C-C activation in industrially important methylarenes and provides a general insight into the role of metal-metal cooperativity in the cleavage of unsaturated C-C bonds.

Infrainguinal bypass under triple nerve block in patients with severely compromised left ventricular ejection fraction and chronic limb-threatening ischemia.

A severely compromised left ventricular ejection fraction (LVEF) is a major limitation for lower extremity bypass reconstruction both under general anesthesia or neuraxial anesthesia (NA). A series of eight infrainguinal bypass procedures were performed under peripheral nerve block in five patients (three males and two females; median age, 67 years) with chronic limb-threatening ischemia and a preoperative LVEF of 35% or less (median, 27%; range, 20%-35%). There were no conversions to neuraxial anesthesia/general anesthesia or early postoperative complications. This study showed that open infrainguinal reconstructions can be performed safely under peripheral nerve blockade in this vulnerable category of patients.

Selective, radical-free activation of benzylic C-H bonds in methylarenes.

We report rare examples of exclusive benzylic C-H oxidative addition in industrially important methylarenes using simple η4-arene iridium complexes. Mechanistic studies showed that coordinatively unsaturated η2-arene intermediates are responsible for the selective activation of benzylic, not aromatic C-H bonds and formation of stable benzyl complexes after trapping with a phosphine ligand.

Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin-17 inhibitors and their practical management.

INTRODUCTION: Interleukin 17A (IL-17A) is a pro-inflammatory cytokine produced by helper T cells (Th17) and other cells of the immune system and exerts pleiotropic effects on multiple cell lines. The role of IL-17 in the pathogenesis of numerous inflammatory disorders is well-documented. IL-17 activates signaling through the IL-17 receptor, which induces other proinflammatory cytokines, antimicrobial peptides, and neutrophil chemokines that are important for antifungal activity. EVIDENCE ACQUISITION: Healthy levels of IL-17 can protect the host against extracellular bacterial and fungal infections in mucous membranes and epithelia. IL-17 deficiency reduces control of certain infections, while excessive IL-17 can produce unwanted inflammatory effects. EVIDENCE SYNTHESIS: Although the efficacy of the therapeutic blockade of this cytokine has been proven in several autoimmune diseases such as psoriasis and psoriatic arthritis, this strategy could also exacerbate fungal infections in such patients. Therefore, a better understanding of IL-17-mediated immunity to Candida is necessary for the development of autoimmune therapeutics that maintain antifungal immunity. CONCLUSIONS: In this review, we include a study of the new anti-IL-17 biological agents (secukinumab, ixekizumab, and bromalizumab) used for moderate-to-severe psoriasis and psoriatic arthritis treatment in clinical practice, as well as pivotal trials with bimekizumab. We study the relationship of these biological agents and the appearance of candidiasis in its various clinical forms.

A general and efficient catalyst for palladium-catalyzed C-O coupling reactions of aryl halides with primary alcohols.

An efficient procedure for palladium-catalyzed coupling reactions of (hetero)aryl bromides and chlorides with primary aliphatic alcohols has been developed. Key to the success is the synthesis and exploitation of the novel bulky di-1-adamantyl-substituted bipyrazolylphosphine ligand L6. Reaction of aryl halides including activated, nonactivated, and (hetero)aryl bromides as well as aryl chlorides with primary alcohols gave the corresponding alkyl aryl ethers in high yield. Noteworthy, functionalizations of primary alcohols in the presence of secondary and tertiary alcohols proceed with excellent regioselectivity.

Transition-Metal-Mediated Cleavage of C-C Bonds in Aromatic Rings.

Metal-mediated cleavage of aromatic C-C bonds has a range of potential synthetic applications: from direct coal liquefaction to synthesis of natural products. However, in contrast to the activation of aromatic C-H bonds, which has already been widely studied and exploited in diverse set of functionalization reactions, cleavage of aromatic C-C bonds remains Terra incognita. This Minireview summarizes the recent progress in this field and outlines key challenges to be overcome to develop synthetic methods based on this fundamental organometallic transformation.

Palladium-catalyzed formylation of aryl bromides: elucidation of the catalytic cycle of an industrially applied coupling reaction.

The first comprehensive study of the catalytic cycle of the palladium-catalyzed formylation of aryl bromides with synthesis gas (CO/H2, 1:1) is presented. The formylation in the presence of efficient (Pd/PR2(n)Bu, R = 1-Ad, (t)Bu) and nonefficient (Pd/P(t)Bu3) catalysts was investigated. The main organometallic complexes involved in the catalytic cycle were synthesized and characterized, and their solution chemistry was studied in detail. Comparison of stoichiometric and catalytic reactions using P(1-Ad)2(n)Bu, the most efficient ligand known for the formylation of aryl halides, led to two pivotal results: (1) The corresponding carbonylpalladium(0) complex [Pd(n)(CO)(m)L(n)] and the respective hydrobromide complex [Pd(Br)(H)L2] are resting states of the active catalyst, and they are not directly involved in the catalytic cycle. These complexes maintain the concentration of most active [PdL] species at a low level throughout the reaction, making oxidative addition the rate-determining step, and provide high catalyst longevity. (2) The product-forming step proceeds via base-mediated hydrogenolysis of the corresponding acyl complex, e.g., [Pd(Br)(p-CF3C6H4CO){P(1-Ad)2(n)Bu}]2 (8), under mild conditions (25-50 degrees C, 5 bar). Stoichiometric studies using the less efficient Pd/P(t)Bu3 catalyst resulted in the isolation and characterization of the first stable three-coordinated neutral acylpalladium complex, [Pd(Br)(p-CF3C6H4CO)(P(t)Bu3)] (10). Hydrogenolysis of 10 needed significantly more drastic conditions compared to that of dimeric 8. In the presence of amine base, complex 10 gave a catalytically inactive diamino acyl complex, which explains the low activity of the Pd/P(t)Bu3 catalyst formylation of aryl bromides.

Identification of microsatellite loci in sea anemones Aulactinia stella and Cribrinopsis albopunctata (family Actiniidae).

From the DNA libraries enriched by the repeat motifs (AAAC) 6, (AATC) 6, (ACAG) 6, (ACCT) 6, (ACTC) 6, ACTG) 6, (AAAT) 8, (AACT) 8, (AAGT) 8, (AGAT) 8, for two viviparous sea anemones Aulactinia stella and Cribrinopsis albopunctata, 41 primer pairs were developed. These primer pairs resulted in the identification of 41 candidate microsatellite loci in either A. stella or C. albopunctata. Polymorphic loci were identified in both sea anemone species for 13 of the primer pairs and can be applicable for population genetics researches.