Early Organic Chemistry in Kyiv: Serhii Mykolayovych Reformatskyi (1860-1934) and his Name Reaction.

Serhiy Mykolayovych Reformatskyi, [Ukrainian: Рeφopмaтcьκий, Cepгiй Mиκoлaйoвич; Russian: Sergei Nikolaevich Reformatskii, РeΦopмaтcκий, Cepгeй Hиκoлaeвич (1860-1934)] was a product of Zaitsev's laboratory in Kazan Imperial University in Russia and one of the founding fathers of organic chemistry in Ukraine. He discovered his eponymous reaction while a graduate student in Kazan under Zaitsev, studying the synthesis of homoallylic alcohols. He modified this reaction by replacing the olefinic π bond of an allyl halide with a carbonyl group. In the prototype reaction, he treated ethyl haloacetates with zinc and aldehydes or ketones. The reaction gave the corresponding ß-hydroxyesters and remains an important synthetic method. Work on the reaction over the ensuing century and a quarter has led to the discovery of analogous reactions using a wide range of metals, and even permitting the use of water as a solvent.

Early Physical Organic Chemistry: Nikolai Aleksandrovich Menshutkin (1842-1907) and Reaction Velocities.

The name of Menshutkin is most frequently associated with his eponymous reaction (the quaternization of tertiary amines with alkyl halides). However, he made encyclopedic contributions to the field of reaction kinetics, where he carried out extensive studies of the effects of reactant structure on the rates of esterification of monohydric, dihydric and trihydric alcohols with monocarboxylic acids, and monobasic and dibasic carboxylic acids and anhydrides with monohydric alcohols. In these studies, he deduced an order of reactivity of alcohols in esterification on the basis of their reactions with acetic acid, and the effects of acid structure on the rates of esterification based on the reaction of the carboxylic acid with isobutyl alcohol. When his attention later turned to the substitution chemistry of amines, he defined the parameters that affected their reactions: anilines were less reactive than alkylamines, secondary more reactive than primary amines, and the reaction was accelerated by replacing benzene as a solvent with alcohols. The wide-ranging work of Menshutkin, the physical organic chemist, is discussed.

A different kind of Nierenstein reaction. The Chemical Society's mistreatment of Maximilian Nierenstein.

Between 1920 and 1922, the University of Bristol biochemist, Maximilian Nierenstein, published four papers in a series exploring the structure of catechin in the Journal of the Chemical Society. The Society then abruptly refused to accept any more of his papers on catechin, or any other subject. It provided him with no reasons for the embargo until 1925. It then transpired that Nierenstein was boycotted because it was deemed that he had not responded adequately to criticisms of his work made by his rival in catechin research, the German natural products chemist, Karl Freudenberg. It was not until 1929 that, as a result of a petition by a group of his former Bristol pupils and friends, that Nierenstein was again permitted to publish in the Society's journal. The paper explores the Chemical Society's treatment of Nierenstein in detail, sheds new light on his career and his reaction to the Society's unprecedented boycott, examines some of the structural chemistry involved in the disputes, and discusses whether Nierenstein's research deserves the label of 'bad science'.

The Minor Impurity in Spent Ores of the "Siberian Metal": Ruthenium Turns 175.

The year 2019 commemorates the 175th anniversary of the discovery of the last of the platinum group metals, ruthenium. The discovery of this element is now attributed to the Russian chemist, Karl Karlovich Klaus (Carl Ernst Claus, 1796-1864). At that time, he was Professor of Chemistry at Kazan University, on the Volga River approximately 750 km (450 mi) east of Moscow. Klaus, whose laboratory practices violated practically every modern rule of laboratory safety, actually discovered the existence of the element in a crude extract of the spent platinum ores from the mint, by its odd taste and smell! Klaus and his discovery (including its defense against critics, who included Berzelius) are discussed here.

Static to Dynamic: Kazan Chemists and the Transformation from Chemical Structure to Reaction Regiochemistry.

During the sesquicentennial of the first publication of Markovnikov's Rule, it is appropriate to re-visit the development of A. M. Butlerov's version of the theory of chemical structure, and its extension from molecular structure (static) to reaction regiochemistry (dynamic) by Butlerov's student (disciple!), V. V. Markovnikov.

Aleksei Yevgen'evich Chichibabin (1871-1945): A Century of Pyridine Chemistry.

Tutor, journalist, patriot, and defector: Aleksei Yevgen'evich Chichibabin made seminal contributions to the chemistry of pyridines. As the Chichibabin reaction enters its second century, it is appropriate to re-examine the life of this remarkable chemist and his legacy to heterocyclic chemistry.

Recapitulating the human tumor microenvironment: Colon tumor-derived extracellular matrix promotes angiogenesis and tumor cell growth.

Extracellular matrix (ECM) is an essential and dynamic component of all tissues and directly affects cellular behavior by providing both mechanical and biochemical signaling cues. Changes in ECM can alter tissue homeostasis, potentially leading to promotion of cellular transformation and the generation of tumors. Therefore, understanding ECM compositional changes during cancer progression is vital to the development of targeted treatments. Previous efforts to reproduce the native 3D cellular microenvironment have utilized protein gels and scaffolds that incompletely recapitulate the complexity of native tissues. Here, we address this problem by extracting and comparing ECM from normal human colon and colon tumor that had metastasized to liver. We found differences in protein composition and stiffness, and observed significant differences in vascular network formation and tumor growth in each of the reconstituted matrices, both in vitro and in vivo. We studied free/bound ratios of NADH in the tumor and endothelial cells using Fluorescence Lifetime Imaging Microscopy as a surrogate for the metabolic state of the cells. We observed that cells seeded in tumor ECM had higher relative levels of free NADH, consistent with a higher glycolytic rate, than those seeded in normal ECM. These results demonstrate that the ECM plays an important role in the growth of cancer cells and their associated vasculature.

Overexpression of type VI collagen in neoplastic lung tissues.

Type VI collagen (COL6), an extracellular matrix protein, is important in maintaining the integrity of lung tissue. An increase in COL6 mRNA and protein deposition was found in the lungs of patients with pulmonary fibrosis, a chronic inflammatory condition with a strong association with lung cancer. In the present study, we demonstrated overexpression of COL6 in the lungs of non-small cell lung cancers. We hypothesized that excessive COL6 in the lung interstitium may exert stimulatory effects on the adjacent cells. In vitro stimulation of monocytes with COL6 resulted in the production of IL-23, which may promote tumor development in an environment of IL-23-mediated lung inflammation, where tissue modeling occurs concurrently with excessive COL6 production. In addition, COL6 was capable of stimulating signaling pathways that activate focal adhesion kinase and extracellular signal­regulated kinase 1/2 in lung epithelial cells, which may also facilitate the development of lung neoplasms. Taken together, our data suggest the potential role of COL6 in promoting lung neoplasia in diseased lungs where COL6 is overexpressed.

Activation of dendritic cell function by soypeptide lunasin as a novel vaccine adjuvant.

The addition of an appropriate adjuvant that activates the innate immunity is essential to subsequent development of the adaptive immunity specific to the vaccine antigens. Thus, any innovation capable of improving the immune responses may lead to a more efficacious vaccine. We recently identified a novel immune modulator using a naturally occurring seed peptide called lunasin. Lunasin was originally isolated from soybeans, and it is a small peptide containing 43 amino acids. Our studies revealed stimulatory effects of lunasin on innate immune cells by regulating expression of a number of genes that are important for immune responses. The objective was to define the effectiveness of lunasin as an adjuvant that enhances immune responses. The immune modulating functions of lunasin were characterized in dendritic cells (DCs) from human peripheral blood mononuclear cells (PBMCs). Lunasin-treated conventional DCs (cDCs) not only expressed elevated levels of co-stimulatory molecules (CD86, CD40) but also exhibited up-regulation of cytokines (IL1B, IL6) and chemokines (CCL3, CCL4). Lunasin-treated cDCs induced higher proliferation of allogeneic CD4+ T cells when comparing with medium control treatment in the mixed leukocyte reaction (MLR). Immunization of mice with ovalbumin (OVA) and lunasin inhibited the growth of OVA-expressing A20 B-lymphomas, which was correlated with OVA-specific CD8+ T cells. In addition, lunasin was an effective adjuvant for immunization with OVA, which together improved animal survival against lethal challenge with influenza virus expressing the MHC class I OVA peptide SIINFEKL (PR8-OTI). These results suggest that lunasin may function as a vaccine adjuvant by promoting DC maturation, which in turn enhances the development of protective immune responses to the vaccine antigens.

The functional effects of color perception and color imagery.

Functional imaging research and studies of brain-damaged patients suggest the mechanisms of color perception and color imagery have some degree of overlap. Previous research into color imagery has focused on compound images consisting of both color and form, e.g., whole objects. Little is known regarding the characteristics of pure color imagery-color without form structure. Binocular rivalry has proven to be a successful method for assessing mental imagery indirectly, quantitatively, and reliably. Here, we utilized this technique to access pure color imagery. Experiment 1 consisted of three conditions, in which participants were instructed to either imagine pure colors according to a letter cue, imagine pure colors in the presence of background luminance, or passively view weak perceptual color patches. Subsequently, a brief rivalry display was presented. Results indicated that perceptual dominance during rivalry was significantly biased by the participants' prior color imagery and perception. However, for imagery, the addition of background luminance attenuated this priming effect. In Experiment 2, we tested whether color imagery was location-specific in retinotopic space. Color imagery was only found to prime subsequent rivalry when the imagery and rivalry stimuli occurred at the same retinotopic location. These results demonstrate that imagery of pure colors without form structure can influence subsequent color perception and can be localized in retinotopic space. These results are consistent with previous studies examining mental imagery of compound visual stimuli and demonstrate the potential of investigations into mental imagery of individual visual features.

The heterocyclic ring of 4-substituted-1,8-naphthalimides is NOT inert to nucleophilic attack, contrary to earlier reports.

The heterocyclic ring of N-aryl-4-chloro-1,8-naphthalimides, reported to be resistant to nucleophilic attack, reacts with primary amine nucleophiles at room temperature to give 4-chloro-N-alkyl-1,8-naphthalimides. The reaction is first order in the naphthalimide. The Hammett plot is linear (R(2) 0.996) with a large positive slope (+3.0), consistent with substantial negative charge development at nitrogen in the activated complex.

The color "fruit": object memories defined by color.

Most fruits and other highly color-diagnostic objects have color as a central aspect of their identity, which can facilitate detection and visual recognition. It has been theorized that there may be a large amount of overlap between the neural representations of these objects and processing involved in color perception. In accordance with this theory we sought to determine if the recognition of highly color diagnostic fruit objects could be facilitated by the visual presentation of their known color associates. In two experiments we show that color associate priming is possible, but contingent upon multiple factors. Color priming was found to be maximally effective for the most highly color diagnostic fruits, when low spatial-frequency information was present in the image, and when determination of the object's specific identity, not merely its category, was required. These data illustrate the importance of color for determining the identity of certain objects, and support the theory that object knowledge involves sensory specific systems.

New adjuvants to enhance anticoagulant activity of warfarin.

New adjuvants of warfarin anticoagulant activity have been developed. These compounds, which are 1,4-methano-1,2,3,4-tetrahydroanthracene-9,10-diol derivatives, act synergistically with warfarin to potentiate its anticoagulant effect. None of the compounds tested is an effective oral anticoagulant in the absence of warfarin.

NMR, mass spectrometry and chemical evidence reveal a different chemical structure for methanobactin that contains oxazolone rings.

Methanobactin (mb) is a small copper-binding peptide produced by methanotrophic bacteria and is intimately involved in both their copper metabolism and their role in the global carbon cycle. The structure for methanobactin comprises seven amino acids plus two chromophoric residues that appear unique to methanobactin. In a previously published structure, both chromophoric residues contain a thiocarbonyl attached to a hydroxyimidazolate ring. In addition, one is attached to a pyrrolidine ring, while the other is attached to an isopropyl ester. A published X-ray determined structure for methanobactin shows these two chromophoric groups forming an N2S2 binding site for a single Cu(I) ion with a distorted tetrahedral geometry. In this report we show that NMR, mass spectrometry, and chemical data reveal a chemical structure that is significantly different than the previously published one. Specifically, the 1H and 13C NMR assignments are inconsistent with an N-terminal isopropyl ester and point instead to a 3-methylbutanoyl group. Our data also indicate that oxazolone rings instead of hydroxyimidazolate rings form the core of the two chromophoric residues. Because these rings are directly involved in the binding of Cu(I) and other metals by methanobactin and are likely involved in the many chemical activities displayed by methanobactin, their correct identity is central to developing an accurate and detailed understanding of methanobactin's many chemical and biological roles. For example, the oxazolone rings make methanobactin structurally more similar to other bacterially produced bactins and siderophores and suggest pathways for its biosynthesis.

Protease-activated receptor 2 mediates eosinophil infiltration and hyperreactivity in allergic inflammation of the airway.

Trypsin and mast cell tryptase can signal to epithelial cells, myocytes, and nerve fibers of the respiratory tract by cleaving proteinase-activated receptor 2 (PAR2). Since tryptase inhibitors are under development to treat asthma, a precise understanding of the contribution of PAR2 to airway inflammation is required. We examined the role of PAR2 in allergic inflammation of the airway by comparing OVA-sensitized and -challenged mice lacking or overexpressing PAR2. In wild-type mice, immunoreactive PAR2 was detected in airway epithelial cells and myocytes, and intranasal administration of a PAR2 agonist stimulated macrophage infiltration into bronchoalveolar lavage fluid. OVA challenge of immunized wild-type mice stimulated infiltration of leukocytes into bronchoalveolar lavage and induced airway hyperreactivity to inhaled methacholine. Compared with wild-type animals, eosinophil infiltration was inhibited by 73% in mice lacking PAR2 and increased by 88% in mice overexpressing PAR2. Similarly, compared with wild-type animals, airway hyperreactivity to inhaled methacholine (40 micro g/ml) was diminished 38% in mice lacking PAR2 and increased by 52% in mice overexpressing PAR2. PAR2 deletion also reduced IgE levels to OVA sensitization by 4-fold compared with those of wild-type animals. Thus, PAR2 contributes to the development of immunity and to allergic inflammation of the airway. Our results support the proposal that tryptase inhibitors and PAR2 antagonists may be useful therapies for inflammatory airway disease.

Stress, migration, and blood pressure in Kiribati.

Investigation into the relationship between essential hypertension and migration and modernization typically conclude that modernized, urban migrants have more elevated blood pressures with age and are more at risk from hypertension than are their traditional rural sedentary compatriots. These differences are often attributed to greater stresses on the migrating or modernizing segment of the population. In contrast, this study of rural sedentes and urban migrants in Kiribati (Gilbert Islands) indicates that hypertension and elevation of pressure with age have appeared in this modernizing population which was free of essential hypertension less than twenty years previously. Yet there are no significant differences in blood pressure or the incidence of hypertension of migrants and sedentes. This similarity of rural and urban islanders' health status is traced to the stress-relieving nature of migration and the urban experience in Kiribati.