Key Fragments Research Articles

Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation.

Curcumin shows a broad spectrum of activities of relevance in the treatment of Alzheimer’s disease (AD); however, it is poorly absorbed and is also chemically and metabolically unstable, leading to a very low oral bioavailability. A small library of hybrid compounds designed as curcumin analogues and incorporating the key structural fragment of piperlongumine, a natural neuroinflammation inhibitor, were synthesized by a two-step route that combines a three-component reaction between primary amines, β-ketoesters and α-haloesters and a base-promoted acylation with cinnamoyl chlorides. These compounds were predicted to have good oral absorption and CNS permeation, had good scavenging properties in the in vitro DPPH experiment and in a cellular assay based on the oxidation of dichlorofluorescin to a fluorescent species. The compounds showed low toxicity in two cellular models, were potent inductors of the Nrf2-ARE phase II antioxidant response, inhibited PHF6 peptide aggregation, closely related to Tau protein aggregation and were active against the LPS-induced inflammatory response. They also afforded neuroprotection against an oxidative insult induced by inhibition of the mitochondrial respiratory chain with the rotenone-oligomycin A combination and against Tau hyperphosphorylation induced by the phosphatase inhibitor okadaic acid. This multitarget pharmacological profile is highly promising in the development of treatments for AD and provides a good hit structure for future optimization efforts.

High-Performance Smart Hydrogels with Redox-Responsive Properties Inspired by Scallop Byssus.

Smart hydrogels with versatile properties, including a tunable gelation time, nonswelling attributes, and biocompatibility, are in great need in the biomedical field. To meet this urgent demand, we explored novel biomaterials with the desired properties from sessile marine organisms. To this end, a novel protein, Sbp9, derived from scallop byssus was extensively investigated, which features typical epidermal growth factor-like (EGFL) multiple repetitive motifs. Our current work demonstrated that the key fragment of Sbp9 (calcium-binding domain (CBD) and 4 EGFL repeats (CE4)) was able to form a smart hydrogel driven by noncovalent interactions and facilitated by disulfide bonds. More importantly, this smart hydrogel demonstrates several desirable and beneficial features, which could offset the drawbacks of typical protein-based hydrogels, including (1) a redox-responsive gelation time (from <1 to 60 min); (2) tunable mechanical properties, nonswelling abilities, and an appropriate microstructure; and (3) good biocompatibility and degradability. Furthermore, proof-of-concept demonstrations showed that the newly discovered hydrogel could be used for anticancer drug delivery and cell encapsulation. Taken together, a smart hydrogel inspired by marine sessile organisms with desirable properties was generated and characterized and demonstrated to have extensive applicability potential in biomedical applications, including tissue engineering and drug release.

Professor of History Vitaliy Stetskevich : notes to intellectual portrait

The aim of the article is to characterize the key fragments of life and career of the famous military historian of contemporary Ukraine proffessor V. V. Stetskevych. Research methods: chronological, historical-genetic, historical-biographical. Sources: archival documents of special origin, unpublished epistolary materials and memorials of the scholar, current historiography. Main results. The most distinctive biographical dates, events, facts of V. V. Stetskevych’s life from his birth till nowadays are identified and briefly characterized; his formation as a scientist and an educator at Dnipropetrovsk classical university are specified; the progress of his further career development in the leading technical higher educational institution of Kryvyi Rig (KMU–KTU), which became an integral part of his almost half-century professional activity, is investigated. An attempt is made to discover and outline the factors which determined his choice of the scientific research strategies, at first within the framework of special historical reproduction of Ukrainian life at the final stage of the war of 1941–1945, and then, historiographical understanding of historical science in its most difficult first period. The overall creative heritage of the scientist is preliminary summed up (initiated and implemented scientific projects, published works, defended dissertations, organized conferences etc.).Conclusions. V. V. Stetskevych left a noticeable mark in the professional environment of Dnipro region and Ukraine of the late 20th – first quarter of the 21st century as an authoritative scholar in the field of national history of the Second World War. He went through a difficult path of professional self-improvement, theoretical and methodological transformation, the so-called “paradigm shift”, thanks to which he was able to create intellectual products corresponding to the modern era. Practical value. The material of the article can be used in research projects devoted to the history of war, in the educational process of history departments of universities. Scientific novelty. Some traits of the intellectual portrait of the distinctive historian are foregrounded and defined for the first time. Type of the article: research.

A data transmission approach based on ant colony optimization and threshold proxy re-encryption in WSNs

Wireless sensor networks have become increasingly popular due to the rapid growth of the Internet of Things. As open wireless transmission mediums are easy to attack, security is one of the primary design concerns for wireless sensor networks. Current solutions consider routing and data encryption as two isolated issues, providing incomplete security. Therefore, in this paper we divide the WSN communication process into a data path selection phase and a data encryption phase. By proposing an improved transmission method based on ant colony optimization and threshold proxy re-encryption for wireless sensor networks,named as ACOTPRE, it resists internal and external attacks and ensures safe and efficient data transmission. In the data path selection stage, the ant colony optimization algorithm is used for network routing. The improvement of the pheromone concentration is proposed. In order to resist attacks from external attackers, proxy re-encryption is extended to WSN in the data encryption stage. The threshold secret sharing algorithm is introduced to generate a set of re-encryption key fragments composed of random numbers at the source node. We confirm the performance of our model via simulation studies.

Structures of Endocrine-Disrupting Chemicals Correlate with the Activation of 12 Classic Nuclear Receptors.

Endocrine-disrupting chemicals (EDCs) can inadvertently interact with 12 classic nuclear receptors (NRs) that disrupt the endocrine system and cause adverse effects. There is no widely accepted understanding about what structural features make thousands of EDCs able to activate different NRs as well as how these structural features exert their functions and induce different outcomes at the cellular level. This paper applies the hierarchical characteristic fragment methodology and high-throughput screening molecular docking to comprehensively explore the structural and functional features of EDCs for the 12 NRs based on more than 7000 chemicals from curated datasets. EDCs share three levels of key fragments. The primary and secondary fragments are associated with the binding of EDCs to four groups of receptors: steroidal nuclear receptors (SNRs, including androgen, estrogen, glucocorticoid, mineralocorticoid, and progesterone), retinoic acid receptors, thyroid hormone receptors, and vitamin D receptors. The tertiary fragments determine the activity type by interacting with two key locations in the ligand-binding domains of NRs (N-H5-H3-C and N-H7-H11-C for SNRs and N-H5-H5'-H2'-H3-C and N-H6'-H11-C for non-SNRs). The resulting compiled structural fragments of EDCs together with elucidated compound NR binding modes provide a framework for understanding the interactions between EDCs and NRs, facilitating faster and more accurate screening of EDCs for multiple NRs in the future.

Theoretical Insights into Mutation and Histidine Tautomerism Effects on Tau Proteins.

Research on misfolding of tau proteins will help to better understand the formation process of neurofibrillary tangles, a hallmark of Alzheimer's disease. Mutation and histidine tautomeric effects have been considered the two most important inherent factors for tau protein misfolding. In current research, replica-exchange molecular dynamics (REMD) were performed to characterize the structural properties of the key fragment R3 of tau protein under the collective effects of P332L mutation and histidine tautomerism. Simulation results suggest that though the content β-sheet of P332L R3 εδ isomer is slightly lower than that of the WT P332L R3 fragment, the total stable secondary structures including β-sheet and helix of P332L R3 isomers are generally more prevalent than those of wild type R3, which may be the reason that P332L R3 has a higher aggregation tendency. Further analysis showed that the hydrogen bond networks are affected by the mutation and histidine tautomerism. Furthermore, the interactions between N-terminus and C-terminus play a crucial role in β-hairpin formation in all isomers. The current study will contribute to revealing the collective effects of P332L and histidine tautomerism on the misfolding of tau proteins.

Identification of Potent and Selective Inhibitors of Fat Mass Obesity-Associated Protein Using a Fragment-Merging Approach.

Fat mass obesity-associated protein (FTO) is a DNA/RNA demethylase involved in the epigenetic regulation of various genes and is considered a therapeutic target for obesity, cancer, and neurological disorders. Here, we aimed to design novel FTO-selective inhibitors by merging fragments of previously reported FTO inhibitors. Among the synthesized analogues, compound 11b, which merges key fragments of Hz (3) and MA (4), inhibited FTO selectively over alkylation repair homologue 5 (ALKBH5), another DNA/RNA demethylase. Treatment of acute monocytic leukemia NOMO-1 cells with a prodrug of 11b decreased the viability of acute monocytic leukemia cells, increased the level of the FTO substrate N6-methyladenosine in mRNA, and induced upregulation of MYC and downregulation of RARA, which are FTO target genes. Thus, Hz (3)/MA (4) hybrid analogues represent an entry into a new class of FTO-selective inhibitors.

Selectivity in atomically precise etching: Thermal atomic layer etching of a CoFeB alloy and its protection by MgO

• Atomic layer etching (ALE) has been demonstrated for CoFeB alloy. • This ALE process maintains the atomic concentration on the alloy surface. • This ALE process maintains a nearly atomically smooth surface. • The process of ALE is demonstrated to stop by MgO. The central unit in an integrated memory device is a magnetic tunnel junction (MTJ) consisting of two ferromagnetic layers, often using complex alloys such as CoFeB, separated by an insulating barrier such as MgO. Atomic level precision is required to fabricate miniaturized devices, and atomic layer etching (ALE) is one of the most promising methods to do this. However, at the nanoscale, it is imperative to maintain the concentration of each element in an alloy during etching, and it is important to not affect the insulating barrier, i.e. the etching process should stop at MgO. Here we use thermal dry etching of CoFeB alloy thin films with sequential doses of chlorine and 2,4-pentanedione (acetylacetone, acacH). Patterned samples are modified with atomic level precision, and the process is completely selective to the removal of CoFeB alloy in ALE regime without changing the alloy composition and without etching MgO that is used as a protecting layer. The etching process was investigated by comparing the film thickness on a patterned surface before and after ALE process using atomic force microscopy (AFM). The viable key features of the reaction mechanism were proposed by detection of key desorbing fragments during a heating ramp via temperature-programmed desorption (TPD) experiments. Ex-situ X-ray photoelectron spectroscopy (XPS) was performed to characterize the surface during ALE process.

Flow-Assisted Synthesis of Alkyl Citrate Natural Products.

The development of a flow-assisted synthesis of alkyl citrate natural products is described. The flow route harnesses a number of steps including the generation of ketene silyl acetal, a formal [2 + 2] cycloaddition, and a methanolysis cascade to efficiently generate a highly substituted, and stereodefined tetrahydrofuran intermediate. A heterogeneous pseudo-Finkelstein reaction and zinc-mediated elimination furnish a key alkene alkyl citrate fragment in high yield over a multistep sequence that provides direct entry to compounds such as (-)-CJ-13982 (1), (-)-CJ-13,981 (2), L-731,120 (3), and related natural products. The flow methodology developed in this study enables a new machine-assisted approach toward the efficient and scalable synthesis of the alkyl citrate family of natural products.

Development of a Concise and Robust Route to a Key Fragment of MCL-1 Inhibitors via Stereoselective Defluoroborylation.

MCL-1 is an attractive target for cancer therapy. We recently discovered highly potent and selective MCL-1 inhibitors containing a fluoroalkene fragment for which an efficient route to the main chiral gem-fluoro-BPin fragment was needed. The key step of this synthesis is a highly stereoselective defluoroborylation of a gem-difluorovinyl intermediate. The latter is reached via a copper-catalyzed diastereoselective opening of dimethyloxirane. These two features allowed a 30-fold improvement in yield, a shorter synthesis, and a decrease in the cost of this crucial building block.

A multimodal metabolomics approach using imaging mass spectrometry and liquid chromatography-tandem mass spectrometry for spatially characterizing monoterpene indole alkaloids secreted from roots.

Plants release specialized (secondary) metabolites from their roots to communicate with other organisms, including soil microorganisms. The spatial behavior of such metabolites around these roots can help us understand roles for the communication; however, currently, they are unclear because soil-based studies are complex. Here, we established a multimodal metabolomics approach using imaging mass spectrometry (IMS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to spatially assign metabolites under laboratory conditions using agar. In a case study using Catharanthus roseus, we showed that 58 nitrogen (N)-containing metabolites are released from the roots into the agar. For the metabolite assignment, we used 15N-labeled and non-labeled LC-MS/MS data, previously reported. Four metabolite ions were identified using authentic standard compounds as derived from monoterpene indole alkaloids (MIAs) such as ajmalicine, catharanthine, serpentine, and yohimbine. An alkaloid network analysis using dot products and spinglass methods characterized five clusters to which the 58 ions belong. The analysis clustered ions from the indolic skeleton-type MIAs to a cluster, suggesting that other communities may represent distinct metabolite groups. For future chemical assignments of the serpentine community, key fragmentation patterns were characterized using the 15N-labeled and non-labeled MS/MS spectra.

A Multi-Source Big Data Security System of Power Monitoring Network Based on Adaptive Combined Public Key Algorithm

The multi-source data collected by the power Internet of Things (IoT) provide the data foundation for the power big data analysis. Due to the limited computational capability and large amount of data collection terminals in power IoT, the traditional security mechanism has to be adapted to such an environment. In order to ensure the security of multi-source data in the power monitoring networks, a security system for multi-source big data in power monitoring networks based on the adaptive combined public key algorithm and an identity-based public key authentication protocol is proposed. Based on elliptic curve cryptography and combined public key authentication, the mapping value of user identification information is used to combine the information in a public and private key factor matrix to obtain the corresponding user key pair. The adaptive key fragment and combination method are designed so that the keys are generated while the status of terminals and key generation service is sensed. An identification-based public key authentication protocol is proposed for the power monitoring system where the authentication process is described step by step. Experiments are established to validate the efficiency and effectiveness of the proposed system. The results show that the proposed model demonstrates satisfying performance in key update rate, key generation quantity, data authentication time, and data security. Finally, the proposed model is experimentally implemented in a substation power IoT environment where the application architecture and security mechanism are described. The security evaluation of the experimental implementation shows that the proposed model can resist a series of attacks such as counterfeiting terminal, data eavesdropping, and tampering.

Application of QSAR for the identification of key molecular fragments and reliable predictions of effects of textile dyes on growth rate and biomass values of Raphidocelis subcapitata.

The current quantitative structure-activity relationship (QSAR) study seeks to explore the underlying causes of fluctuations in growth rate and biomass of microalgae mainly due to textile dyes. The derived QSAR models cover two endpoints: ErC50 (growth rate) and EbC50 (biomass) of Raphidocelis subcapitata. In order to extract the structural features involved, multiple PLS (partial least squares) models have been developed with easy to interpret and uncomplicated 2D descriptors having proper physico-chemical meaning. These descriptors were calculated from Dragon, SiRMS, and PaDEL-descriptor software. Then, the models were developed initially using stepwise regression followed by partial least squares (PLS) regression, and the model development procedure for both the endpoints (ErC50 and EbC50) followed the stringent Organization for Economic Cooperation and Development (OECD) rules. Later on, the model validation was carried out with statistically significant and internationally accepted metrics (both internally and externally) in both the cases. Next, we have used the "Intelligent Consensus Predictor" tool (available from http://teqip.jdvu.ac.in/QSAR_Tools/DTCLab/) to test the prediction quality with an "intelligent" approach to select multiple models. The estimated prediction quality for the appropriate test sets reveals that the consensus models (CM) surpass the quality shown by individual models (IM) for both the endpoints (ErC50 and EbC50). Finally, the developed models were able to identify the major contributing features (hydrophobic units, unsaturation, saturation, electronegativity, branched atoms and charged fragments) related to aquatic toxicity of textile dyes.

Rapid identification of chemical constituents of Rhodiola crenulata using liquid chromatography-mass spectrometry pseudotargeted analysis.

Rhodiola crenulata (R. crenulata), is a famous traditional Chinese medicine, with observable effects such as anti-high-altitude illness and fatigue resistance. Nevertheless, comprehensive and systematic structural identification of its components remains a challenge. In this study, a pseudotargeted analytical method, involving key fragment filtering by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry and ultra-high performance liquid chromatography-linear ion trap-Orbitrap mass spectrometry, was developed for rapid detection and identification of the chemical constituents of R. crenulata. The process consists of three steps: (i) acquiring sufficient mass spectral data, (ii) constructing a key fragments schedule and discovering the substructures rapidly by pseudotargeted key fragment filtering, and (iii) further identification of the compound structures based on accurate masses, fragment ions, related literatures, and authentic standards. As a result, 104 compounds were identified and divided into five categories, among which three potentially new and 59 ones were reported for the first time in R. crenulata. These results indicated that the major types of components are flavanols and gallic acid derivatives, organic acids, alcohols and their glycosides, flavonoids and their glycosides. This study enhances the understanding of R. crenulata and provides a reference for rapid and comprehensive identification of constituents in other herbal medicines.

Mesenchymal stem cell exosomal tsRNA-21109 alleviate systemic lupus erythematosus by inhibiting macrophage M1 polarization

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with M1-type macrophage activation. Mesenchymal stem cells (MSCs) therapies have shown promise in models of pathologies relevant to SLE, while the function and mechanism of MSC-derived exosomes (MSC-exo) were still unclear. We aimed to interrogate the effect of MSC-exo on M1-type polarization of macrophage and investigate mechanisms underlying MSC-exo. Exosomes were isolated from MSC and the effect of MSC-exo on macrophage polarization was evaluated. The key tRNA-derived fragments (tRFs) carried by exosomes were identified by small RNA sequencing and verified in clinical samples. The effect of exosomal-tRFs on macrophage polarization was examined. In this study, MSC-exo dramatically suppressed expression of M1 markers, and reduced the levels of TNF-α and IL-1β, while increased M2 markers in macrophages. A total of 243 differently expressed tRFs (DEtRFs) were identified between MSC-exo treated and untreated macrophage, among which 103 DEtRFs were up-regulated in response to MSC-exo treatment, including tsRNA-21109. The target genes of tsRNA-21109 were mainly enriched in DNA transcription-related GO function, and mainly involved in inflammatory-related pathways, including Rap1, Ras, Hippo, Wnt, MAPK, TGF-beta signaling pathway. The tsRNA-21109 was lowly expressed in clinical samples and was associated with the patient data in SLE. Compared to the normal MSC-exo, the tsRNA-21109-privative MSC-exo up-regulated M1 marker (CD80, NOS2, MCP1) and down-regulated M2 marker (CD206, ARG1, MRC2), also increased the levels of TNF-α and IL-1β in macrophages. Western blot and immunofluorescence confirmed that the proportion of CD80/ARG-1 was increased in macrophages treated with tsRNA-21109-privatived MSC-exo compared to that with control MSC-exo. In conclusion, MSC-exo inhibited the M1-type polarization of macrophages, possibly through transferring tsRNA-21109, which may develop as a novel therapeutic target for SLE.

Computed Tomography and Pathobiomechanical-Based Treatment of Volar Distal Radius Fractures.

Today, there are various classifications for distal radius fractures (DRF). However, they are primarily based on plain radiographs and do not provide sufficient information on the best treatment option. There are newer classifications that simultaneously consider the pathobiomechanical basis of the fracture mechanism and analysis of computed tomography images. Main determinants of which type of DRFs occurs are the strength/direction of the applied forces on the carpus and radius, and the position of the wrist relative to the radius during the fall. Reconstruction of the mechanism of injury provides information about which anatomic structures are involved, such as torn ligaments, bone fragments, and the dislocated osteoligamentous units. This article attempts to combine and modify current pathobiomechanically oriented classifications with an improved understanding of the "key fragments" to subsequently offer a treatment approach to stabilize these critical fragments through specific types of internal fixation.

Stereoselective and Divergent Aza-Adenosine and Aza-Guanosine Syntheses from Xylofuranose, the Key Fragments of a STING Cyclic Dinucleotide Agonist.

The stereoselective and divergent synthesis of two aza-nucleosides is reported. Starting from xylofuranose 9, aza-adenosine 2 was prepared in 13 steps and 7% overall yield, and aza-guanosine 3 was prepared in 13 steps and 7.8% overall yield. Compared to the original syntheses, some advantages of these new routes are significant yield improvement, overall step-count reduction, an optimized protecting group strategy, the development of a versatile platform for nitrogenous base incorporation, and the elimination of hazardous reagents (e.g., benzyl isocyanate, Et3N·HF).

Minireview: Remdesivir, A Prominent Nucleotide/Nucleoside Antiviral Drug

Nucleotide analogues are the divergent scaffolds that are reliable potential therapeutic drugs to treat the wide range of diseases including viral infections. For instance, Remdesivir is a biologically important nucleotide analogue prodrug that can act as a key drug target for the diseases Ebola and COVID-19. Remdesivir is a structurally chiral aryloxy-phosphoramidate prodrug as it is metabolized into nucleoside triphosphate (active drug form) inside the cell through sequential reactions by ester mediated-hydrolysis. Thus, the current minireview focuses on the earlier reported synthetic approaches of key fragments of remdesivir and their developments to attain the scale-up yields of the drug for clinical/commercial applies. Further, this review serves as a template for the design and development of other complex organic molecules.

Assessments of Organic Carbon Stabilization Using the Spectroscopic Characteristics of Humic Acids Separated from Soils of the Lena River Delta

In the Arctic zone, where up to 1024 × 1013 kg of organic matter is stored in permafrost-affected soils, soil organic matter consists of about 50% humic substances. Based on the analysis of the molecular composition of humic acids, we assessed the processes of accumulation of the key structural fragments, their transformations and the stabilization rates of carbon pools in soils in general. The landscape of the Lena River delta is the largest storage of stabilized organic matter in the Arctic. There is active accumulation and deposition of a significant amount of soil organic carbon from terrestrial ecosystems in a permafrost state. Under ongoing climate change, carbon emission fluxes into the atmosphere are estimated to be higher than the sequestration and storing of carbon compounds. Thus, investigation of soil organic matter stabilization mechanisms and rates is quite an urgent topic regarding polar soils. For study of molecular elemental composition, humic acids were separated from the soils of the Lena River delta. Key structural fragments of humic matter were identified and quantified by CP/MAS 13C NMR spectroscopy: carboxyl (–COOR); carbonyl (–C=O); CH3–; CH2–; CH-aliphatic; –C-OR alcohols, esters and carbohydrates; and the phenolic (Ar-OH), quinone (Ar = O) and aromatic (Ar–) groups as benchmark Cryosols of the Lena delta river terrestrial ecosystem. Under the conditions of thermodynamic evolutionary selection, during the change between the dry and wet seasons, up to 41% of aromatic and carboxyl fragments accumulated in humic acids. Data obtained showed that three main groups of carbon played the most important role in soil organic matter stabilization, namely C, H-alkyls ((CH2)n/CH/C and CH3), aromatic compounds (C-C/C-H, C-O) and an OCH group (OCH/OCq). The variations of these carbon species’ content in separated humics, with special reference to soil–permafrost organic profiles’ recalcitrance in the current environment, is discussed.

Deep Learning Insights into Lanthanides Complexation Chemistry.

Modern structure–property models are widely used in chemistry; however, in many cases, they are still a kind of a “black box” where there is no clear path from molecule structure to target property. Here we present an example of deep learning usage not only to build a model but also to determine key structural fragments of ligands influencing metal complexation. We have a series of chemically similar lanthanide ions, and we have collected data on complexes’ stability, built models, predicting stability constants and decoded the models to obtain key fragments responsible for complexation efficiency. The results are in good correlation with the experimental ones, as well as modern theories of complexation. It was shown that the main influence on the constants had a mutual location of the binding centers.