Mild and General Protocol for Selective Deacetylation of Acetyl/Benzoyl-Protected Carbohydrates.

Herein, we report a mild and general protocol for chemoselective deacetylation of mixed acetyl- and benzoyl-protected carbohydrates under mild acidic conditions. The protocol allows quick access to partially protected carbohydrates, which serve as versatile synthetic intermediates during the total synthesis of various mono- and oligosaccharide targets. The applicability of the developed protocol was successfully demonstrated on a range of carbohydrate substrates of various configurations and substitution patterns featuring functionalized aliphatic and aromatic aglycones. The protocol has shown excellent compatibility with the widely used O-anomeric protecting groups, prespacer aglycones, and thioglycoside glycosyl donors.

Asymmetric synthesis of unnatural α-amino acids through photoredox-mediated C-O bond activation of aliphatic alcohols.

Unnatural α-amino acids constitute a fundamental class of biologically relevant compounds. However, despite the interest in these motifs, synthetic strategies have traditionally employed polar retrosynthetic disconnections. These methods typically entail the use of stoichiometric amounts of toxic and highly sensitive reagents, thereby limiting the substrate scope and practicality for scale up. In this work, an efficient protocol for the asymmetric synthesis of unnatural α-amino acids is realized through photoredox-mediated C-O bond activation in oxalate esters of aliphatic alcohols as radical precursors. The developed system uses a chiral glyoxylate-derived N-sulfinyl imine as the radical acceptor and allows facile access to a range of functionalized unnatural α-amino acids through an atom-economical redox-neutral process with CO2 as the only stoichiometric byproduct.

General Approach to Amides through Decarboxylative Radical Cross-Coupling of Carboxylic Acids and Isocyanides.

Herein, we report a silver-catalyzed protocol for decarboxylative cross-coupling between carboxylic acids and isocyanides, leading to linear amide products through a free-radical mechanism. The disclosed approach provides a general entry to a variety of decorated amides, accommodating a diverse array of radical precursors, including aryl, heteroaryl, alkynyl, alkenyl, and alkyl carboxylic acids. Notably, the protocol proved to be efficient for decarboxylative late-stage functionalization of several elaborate pharmaceuticals, demonstrating its potential applications.

First Report of Lysozyme Amyloidosis with p.F21L/T88N Amino Acid Substitutions in a Russian Family.

Lysozyme amyloidosis is caused by an amino acid substitution in the sequence of this protein. In our study, we described a clinical case of lysozyme amyloidosis in a Russian family. In our work, we described in detail the histological changes in tissues that appeared as a result of massive deposition of amyloid aggregates that affected almost all organ systems, with the exception of the central nervous system. We determined the type of amyloidosis and mutations using mass spectrometry. Using mass spectrometry, the protein composition of tissue samples of patient 1 (autopsy material) and patient 2 (biopsy material) with histologically confirmed amyloid deposits were analyzed. Amino acid substitutions p.F21L/T88N in the lysozyme sequence were identified in both sets of samples and confirmed by sequencing of the lysozyme gene of members of this family. We have shown the inheritance of these mutations in the lysozyme gene in members of the described family. For the first time, we discovered a mutation in the first exon p.F21L of the lysozyme gene, which, together with p.T88N amino acid substitution, led to amyloidosis in members of the studied family.

Construction of Phenanthridinone Skeletons through Palladium-Catalyzed Annulation.

Herein, a straightforward synthetic approach for the construction of phenanthridin-6(5H)-one skeletons is disclosed. The developed protocol relies on palladium catalysis, providing controlled access to a range of functionalized phenanthridin-6(5H)-ones in 59-88% yields. Furthermore, plausible reaction pathways are proposed based on mechanistic experiments.

Sweetened Alkylated Verdazyls Effectively Kill Cancer Cells under Light Irradiation.

The development of novel photo-dynamic therapy (PDT) agents enabling to treat the oxygen-deficient tumors is the emerging tasks for the modern medicinal chemistry. Herein, we describe the design and preparation of water-soluble agents for PDT which generate active radical species upon light irradiation. Two conjugates of carbohydrates with 1,2,4,6-substituted-1,4-dihydro-1,2,4,5-tetrazin-3(2H)-ones (AlkVZs) demonstrated high oxygen-independent cytotoxicity on PC-3 and Jurkat cancer cells under light irradiation combining with low toxicity in the dark. The efficacy of prepared compounds was estimated using MTT and Alamar Blue tests as well as microscopic dead/live colored images and flow cytometry. The analysis of obtained results reveals the influence of sugar moiety on the activity of AlkVZs. We believe that obtained compounds have high potency as platform for design of new agents for photo-dynamic therapy.

Task measuring implicit attractiveness as a function of skin tone and facial features: a failed replication.

In two studies, participants completed an implicit attractiveness task with faces as primes varying on (a) facial features from Afrocentric to Eurocentric and (b) skin tone from dark to light, and target pictures of environmental scenes varying in attractiveness. On each trial, participants were briefly primed with a face. Next, they categorized a target picture as either attractive or unattractive as quickly as possible. In addition, in Study 2, participants rated the same faces on an attractiveness scale. While results of Study 1 showed that when faces were medium in skin tone, participants were more accurate when primed with a Eurocentric face responding to attractive targets, but also more accurate when primed with an Afrocentric face responding to unattractive targets, a more powerful Study 2 failed to replicate this effect. There was no relationship between participants' explicit ratings of attractiveness and accuracy rates in the implicit attractiveness task.

Scalable total synthesis of natural vanillin-derived glucoside ω-esters.

The first total synthesis of vanilloloside, calleryanin, and a series of naturally occurring ω-esters of vanilloloside was realized through direct glycosylation of vanillin-based aglycones or late-stage derivatization of vanilloloside. All aglycones and their fragments were synthesized from vanillin as the sole aromatic precursor. Subsequently, these intermediates were used to construct various vanillin-derived glucoside ω-esters using a mild acidic deacetylation as the key synthetic step, providing the final products in the total yields of 10-50% and general purity of >95%. Additionally, the first operationally simple and sustainable synthesis of litseafoloside B was realized on large scale, avoiding the use of toxic solvents and reagents, providing an attractive alternative to isolation of this and other similar compounds from plant sources.

"Everything good against everything bad": traditional values in the search for new Russian national idea.

The purpose of the article is to explore origins, development and meaning of the Russian Orthodox Church's concept of traditional values in comparison with its interpreting and utilizing by the Russian political powers through the analysis of the main statements of the ROC's hierarchs, as well as of leading political figures in the period 2000s until nowadays. The following research questions are formulated: What are traditional values in the ROC's and state understanding, and what is the purpose of their promotion? What is the impact of traditional values discourse over people? The conclusion is made that traditional values are seen as one of substantial elements of the present-day Russian political and ideological conservatism and the core element of the identity construction. The ROC as the prominent and influential religious body is seen by political powers, as well as by general public, to be most notably linked to morality; and she seems to take for granted the status of moral authority. At the same time, there is a lack of reliable data, which make possible to estimate the real impact of traditional values over Russian people and the amount of those who share them.

Combining of synthetic VHH and immune scFv libraries for pregnancy-associated glycoproteins ELISA development.

Nanobodies (VHH) from camelid antibody libraries hold great promise as therapeutic agents and components of immunoassay systems. Synthetic antibody libraries that could be designed and generated once and for various applications could yield binders to virtually any targets, even for non-immunogenic or toxic ones, in a short term. One of the most difficult tasks is to obtain antibodies with a high affinity and specificity to polyglycosylated proteins. It requires antibody libraries with extremely high functional diversity and the use of sophisticated selection techniques. Here we report a development of a novel sandwich immunoassay involving a combination of the synthetic library-derived VHH-Fc fusion protein as a capture antibody and the immune single-chain fragment variable (scFv) as a tracer for the detection of pregnancy-associated glycoprotein (PAG) of cattle (Bos taurus). We succeeded in the generation of a number of specific scFv antibodies against PAG from the mouse immune library. Subsequent selection using the immobilized scFv-Fc capture antibody allowed to isolate 1.9 nM VHH binder from the diverse synthetic library without any overlapping with the capture antibody binding site. The prototype sandwich ELISA based on the synthetic VHH and the immune scFv was established. This is the first successful example of the combination of synthetic and immune antibody libraries in a single sandwich immunoassay. Thus, our approach could be used for the express isolation of antibody pairs and the development of sandwich immunoassays for challenging antigens. KEY POINTS: • Heavily glycosylated PAG Bos Taurus were used for immune library construction and specific scFv isolation by phage display. • Nanomolar affinity VHH for PAG was selected from the original synthetic nanobodies library. • A novel VHH/scFv-based immunoassay for Bos Taurus pregnancy determination was developed.

Multi-Omics Approach Points to the Importance of Oxylipins Metabolism in Early-Stage Breast Cancer.

The involvement of oxylipins, metabolites of polyunsaturated fatty acids, in cancer pathogenesis was known long ago, but only the development of the high-throughput methods get the opportunity to study oxylipins on a system level. The study aimed to elucidate alterations in oxylipin metabolism as characteristics of breast cancer patients. We compared the ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) oxylipin profile signatures in the blood plasma of 152 healthy volunteers (HC) and 169 patients with different stages of breast cancer (BC). To integrate lipidomics, transcriptomics, and genomics data, we analyzed a transcriptome of 10 open database datasets obtained from tissues and blood cells of BC patients and SNP data for 33 genes related to oxylipin metabolism. We identified 18 oxylipins, metabolites of omega-3 or omega-6 polyunsaturated fatty acids, that were differentially expressed between BCvsHC patients, including anandamide, prostaglandins and hydroxydocosahexaenoic acids. DEGs analysis of tissue and blood samples from BC patients revealed that 19 genes for oxylipin biosynthesis change their expression level, with CYP2C19, PTGS2, HPGD, and FAAH included in the list of DEGs in the analysis of transcriptomes and the list of SNPs associated with BC. Results allow us to suppose that oxylipin signatures reflect the organism's level of response to the disease. Our data regarding changes in oxylipins at the system level show that oxylipin profiles can be used to evaluate the early stages of breast cancer.

Exploiting photoredox catalysis for carbohydrate modification through C-H and C-C bond activation.

Photoredox catalysis has recently emerged as a powerful synthetic platform for accessing complex chemical structures through non-traditional bond disconnection strategies that proceed through free-radical intermediates. Such synthetic strategies have been used for a range of organic transformations; however, in carbohydrate chemistry they have primarily been applied to the generation of oxocarbenium ion intermediates in the ubiquitous glycosylation reaction. In this Review, we present more intricate light-induced synthetic strategies to modify native carbohydrates through homolytic C-H and C-C bond cleavage. These strategies allow access to glycans and glycoconjugates with profoundly altered carbohydrate skeletons, which are challenging to obtain through conventional synthetic means. Carbohydrate derivatives with such structural motifs represent a broad class of natural products integral to numerous biochemical processes and can be found in active pharmaceutical substances. Here we present progress made in C-H and C-C bond activation of carbohydrates through photoredox catalysis, focusing on the operational mechanisms and the scope of the described methodologies.

Stereoselective synthesis of unnatural α-amino acid derivatives through photoredox catalysis.

A protocol for stereoselective C-radical addition to a chiral glyoxylate-derived N-sulfinyl imine was developed through visible light-promoted photoredox catalysis, providing a convenient method for the synthesis of unnatural α-amino acids. The developed protocol allows the use of ubiquitous carboxylic acids as radical precursors without prior derivatization. The protocol utilizes near-stoichiometric amounts of the imine and the acid radical precursor in combination with a catalytic amount of an organic acridinium-based photocatalyst. Alternative mechanisms for the developed transformation are discussed and corroborated by experimental and computational studies.

Low JAK2 V617F Allele Burden in Ph-Negative Chronic Myeloproliferative Neoplasms Is Associated with Additional CALR or MPL Gene Mutations.

JAK2 (Janus kinase 2) V617F, CALR (Calreticulin) exon 9, and MPL (receptor for thrombopoietin) exon 10 mutations are associated with the vast majority of Ph-negative chronic myeloproliferative neoplasms (MPNs). These mutations affect sequential stages of proliferative signal transduction and therefore, after the emergence of one type of mutation, other types should not have any selective advantages for clonal expansion. However, simultaneous findings of these mutations have been reported by different investigators in up to 10% of MPN cases. Our study includes DNA samples from 1958 patients with clinical evidence of MPN, admitted to the National Research Center for Hematology for genetic analysis between 2016 and 2019. In 315 of 1402 cases (22.6%), CALR mutations were detected. In 23 of these 315 cases (7.3%), the JAK2 V617F mutation was found in addition to the CALR mutation. In 16 from 24 (69.6%) cases, with combined CALR and JAK2 mutations, V617F allele burden was lower than 1%. A combination of JAK2 V617F with MPL W515L/K was also observed in 1 out of 1348 cases, only. JAK2 allele burden in this case was also lower than 1%. Additional mutations may coexist over the low background of JAK2 V617F allele. Therefore, in cases of detecting MPNs with a low allelic load JAK2 V617F, it may be advisable to search for other molecular markers, primarily mutations in exon 9 of CALR. The load of the combined mutations measured at different time points may indicate that, at least in some cases, these mutations could be represented by different clones of malignant cells.

What Drives Racial Attitudes in Elementary School Children: Skin Tone, Facial Physiognomy, or Both?

This work examines whether racial attitudes-when measured by both explicit and implicit measures- are driven primarily by skin tone, facial physiognomy, or both in 5 to 12-year-old children. Participants evaluated faces varying in skin tone (from dark to light) and facial physiognomy (from Afrocentric to Eurocentric). In an explicit task, children rated how much they liked each face. In an implicit task, participants completed a child-friendly version of the Affect Misattribution Procedure, where they rated a Chinese character as "good" or "bad" following a racial prime. Results suggest that pro-White attitudes (especially those measured by the explicit task) are driven by both factors, vary by perceivers' race, and are present in both White and non-White children, though skin tone exerts a larger influence than other features, at least in explicit evaluations. Our results also raise the possibility that pro-White biases might be more internalized by non-White children in the American South.

Alcohol Priming and Attribution of Blame in an Acquaintance Rape Vignette.

Research on nonpharmacological effects of alcohol shows that exposure to alcohol-related cues (i.e., alcohol priming) can increase behaviors associated with actual alcohol consumption. Attributions of responsibility to female victims in sexual assault scenarios are affected by whether or not alcohol was consumed by a victim and/or perpetrator. Victims often receive higher levels of blame if they consume alcohol prior to the assault. This work extends the research on nonpharmacological effects of alcohol into a novel domain of blame attribution toward rape victims. In two studies, participants in lab settings (Study 1; N = 184) and online (Study 2; N = 421) were primed with alcohol or neutral beverage advertisements as part of a purportedly separate ad-rating task and then were presented with a vignette depicting an acquaintance rape where the characters consumed beer or soda. Participants subsequently completed a questionnaire assessing victim blame and perpetrator blame. Across both studies, participants blamed the victim most when they were exposed to both contextual (story) and noncontextual (ads) alcohol cues; this effect was especially prominent in males in Study 1. Findings for perpetrator blame were inconsistent across studies. Implications of nonpharmacological effects of alcohol on blame attribution toward rape victims are discussed in the context of courtroom situations and bystander intervention.

Association of CD200 expression in paternal lymphocytes with female Th1/Th2 balance and pregnancy establishment at immunotherapy of recurrent spontaneous abortion.

PROBLEM: We hypothesized that expression of transmembrane glycoprotein CD200 on paternal lymphocytes used for pre-gestational lymphocyte immunotherapy (LIT) of recurrent spontaneous abortion (RSA) can suppress the pro-inflammatory Th1-type immunity required for successful implantation. To reveal the association between CD200 expression, female immune background after LIT, and pregnancy establishment, we have performed this work. METHOD OF STUDY: Pre-gestational alloimmunizations were given to 37 women using paternal peripheral blood leukocytes, combined with additional alloimmunizations in case of pregnancy. Lymphocyte phenotypes were determined by flow cytometry. Cytokines produced by mitogen-stimulated female peripheral blood cells were estimated by FlowCytomix™ technology. RESULTS: We have shown that 78.4% (29/37) of women became pregnant within 12 menstrual cycles after pre-gestational LIT. Pregnancy establishment depends on the intensity of CD200 expression, which is significantly higher on the CD200+ lymphocytes administered to women who later did not achieve pregnancy (P < .05). The expression of CD200 negatively correlates with the ratios of Th1/Th2 cytokines produced by female peripheral blood cells (P < .05) and positively correlates with the frequency of female circulating regulatory T cells after LIT (P < .05). The ROC analysis showed that the intensity of CD200 expression and the Th1/Th2 ratios are the significant predictors of pregnancy establishment after pre-gestational LIT (P < .05 and P < .01, respectively). CONCLUSION: Elevated CD200 expression on allogeneic lymphocytes most likely suppresses the pro-inflammatory Th1-type immunity needed for successful embryo implantation. Therefore, a personalized approach of LIT should be applied to avoid negative effects of such immunomodulation on pregnancy establishment.

Divergent Synthesis of Natural Benzyl Salicylate and Benzyl Gentisate Glucosides.

Herein is reported the first total synthesis of benzyl salicylate and benzyl gentisate glucosides present in various plant species, in particular the Salix genus, such as Populus balsamifera and P. trichocarpa. The method permits the synthesis of several natural phenolic acid derivatives and their glucosides starting from salicylic or gentisic acid. The divergent approach afforded access to three different acetylated glucosides from a common synthetic intermediate. The key step in the total synthesis of naturally occurring glycosides-the selective deacetylation of the sugar moiety-was achieved in the presence of a labile benzyl ester group by employing mild deacetylation conditions. The protocol permitted synthesis of trichocarpine (4 steps, 40% overall yield), isotrichocarpine (3 steps, 51% overall yield), trichoside (6 steps, 40% overall yield), and deoxytrichocarpine (3 steps, 42% overall yield) for the first time (>95% purity). Also, the optimized mild deacetylation conditions allowed synthesis of 2-O-acetylated derivatives of all four glycosides (5-17% overall yield, 90-95% purity), which are rare plant metabolites.

Synthesis of Salicaceae Acetyl Salicins Using Selective Deacetylation and Acetyl Group Migration.

In the present work, the synthesis of acetylated salicins, which occur naturally in many Salicaceae species, is reported. The preparation of 2-O-acetylsalicin, 2-O-acetylchlorosalicin, and 2-O-acetylethylsalicin from peracetylated bromosalicin with selective acid-catalyzed deacetylation and one-pot nucleophilic substitution of bromine as the key steps is described. The base-catalyzed O-2 → O-6 acetyl migration afforded 6-O-acetylsalicin derivatives in good yields. Thus, the first synthesis of 6-O-acetylsalicin (fragilin) using acetyl group migration is reported as well as the synthesis of 6-O-acetylchlorosalicin and 6-O-acetylethylsalicin. The NaOMe-catalyzed deacetylation of acetylated glycosides gave salicin, chlorosalicin, and ethylsalicin recently reported from Alangium chinense.

Catalyst-free regioselective acetylation of primary hydroxy groups in partially protected and unprotected thioglycosides with acetic acid.

Highly regioselective acetylation of primary hydroxy groups in thioglycoside derivatives with gluco- and galacto-configurations was achieved by treatment with aqueous or anhydrous acetic acid (60-100% AcOH) at elevated temperatures (80-118 °C), avoiding complex, costly and time-consuming manipulations with protective groups. Acetylation of both 4,6-O-benzylidene acetals and the corresponding diols as well as the unprotected tetraol with AcOH was shown to lead selectively to formation of 6-O-acetyl derivatives. For example, the treatment of phenyl 1-thio-ß-d-glucopyranoside with anhydrous AcOH at 80 °C for 24 h gave the corresponding 6-O-acetylated derivative in 47% yield (71% based on the reacted starting material) and unreacted starting tetraol in 34% yield, which can easily be recovered by silica gel chromatography and reused in further acetylation.