Добірка наукової літератури з теми "Backbone Modification"

Peptide modifications via C–C bond formation have emerged as valuable tools for the preparation and alteration of non-proteinogenic amino acids and the corresponding peptides. Modification of glycine subunits in peptides allows for the incorporation of unusual side chains, often in a highly stereoselective manner, orchestrated by the chiral peptide backbone. Moreover, modifications of peptides are not limited to the peptidic backbone. Many side-chain modifications, not only by variation of existing functional groups, but also by C–H functionalization, have been developed over the past decade. This account highlights the synthetic contributions made by our group and others to the field of peptide modifications and their application in natural product syntheses.1 Introduction2 Peptide Backbone Modifications via Peptide Enolates2.1 Chelate Enolate Claisen Rearrangements2.2 Allylic Alkylations2.3 Miscellaneous Modifications3 Side-Chain Modifications3.1 C–H Activation3.1.1 Functionalization via Csp3–H Bond Activation3.2.2 Functionalization via Csp2–H Bond Activation3.2 On Peptide Tryptophan Syntheses4 Conclusion

AbstractThe diverse activity of flavoenzymes in organic transformations has fascinated researchers for a long time. However, when applied outside an enzyme environment, the isolated flavin cofactor only shows largely reduced activity. This highlights the importance of embedding the reactive isoalloxazine core of flavins in defined surroundings. The latter include crucial non-covalent interactions with amino acid side chains or backbone as well as controlled access to reactants such as molecular oxygen. Nevertheless, molecular flavins are increasingly applied in the organic laboratory as valuable organocatalysts. Chemical modification of the parent isoalloxazine structure is of particular interest in this context in order to achieve reactivity and selectivity in transformations, which are so far only known with flavoenzymes or even unprecedented. This review aims to give a systematic overview of the reported designed flavin catalysts and highlights the impact of each structural alteration. It is intended to serve as a source of information when comparing the performance of known catalysts, but also when designing new flavins. Over the last few decades, molecular flavin catalysis has emerged from proof-of-concept reactions to increasingly sophisticated transformations. This stimulates anticipating new flavin catalyst designs for solving contemporary challenges in organic synthesis.1 Introduction2 N1-Modification3 N3-Modification4 N5-Modification5 C6–C9-Modification6 N10-Modification7 Conclusion

Modifications of the nucleic acid backbone are essential for the development of oligonucleotide-derived bioactive agents. The NAA-modification represents a novel artificial internucleotide linkage which enables the site-specific introduction of positive charges into the otherwise polyanionic backbone of DNA oligonucleotides. Following initial studies with the introduction of the NAA-linkage at T–T sites, it is now envisioned to prepare NAA-modified oligonucleotides bearing the modification at X–T motifs (X = A, C, G). We have therefore developed the efficient and stereoselective synthesis of NAA-linked 'dimeric' A–T phosphoramidite building blocks for automated DNA synthesis. Both the (S)- and the (R)-configured NAA-motifs were constructed with high diastereoselectivities to furnish two different phosphoramidite reagents, which were employed for the solid phase-supported automated synthesis of two NAA-modified DNA oligonucleotides. This represents a significant step to further establish the NAA-linkage as a useful addition to the existing 'toolbox' of backbone modifications for the design of bioactive oligonucleotide analogues.

Deficient stability towards nuclease-mediated degradation is one of the most relevant tasks in the development of oligonucleotide-derived biomedical agents. This hurdle can be overcome through modifications to the native oligonucleotide backbone structure, with the goal of simultaneously retaining the unique hybridization properties of nucleic acids. The nucleosyl amino acid (NAA)-modification is a recently introduced artificial cationic backbone linkage. Partially zwitterionic NAA-modified oligonucleotides had previously shown hybridization with DNA strands with retained base-pairing fidelity. In this study, we report the significantly enhanced stability of NAA-modified oligonucleotides towards 3′- and 5′-exonuclease-mediated degradation as well as in complex biological media such as human plasma and whole cell lysate. This demonstrates the potential versatility of the NAA-motif as a backbone modification for the development of biomedically active oligonucleotide analogues.

The synthesis and spectroscopic characterization of two novel cationic silicon–sulfur Lewis pairs with a chiral 4,4′-disubstituted binaphthyl silepine backbone are described. Both Lewis acids induce significant enantioselectivity in the model Diels–Alder reaction of cyclohexa-1,3-diene and chalcone but additional substitution of the binaphthyl backbone exerts a minimal effect on enantioinduction compared to previously reported Lewis acids. Another silicon cation with a chiral spirocyclic backbone induces enantioselectivity in the same range but its synthesis is laborious.

Traditional macrocyclic molecules encode recognition sites in their structural backbones, which limits the variation of the recognition sites and thus, would restrict the adjustment of recognition properties. Here, we report a new oligoamide-based macrocycle capable of varying the recognition functional groups by post-synthesis modification on its structural backbone. Through six steps of common reactions, the parent macrocycle (9) can be produced in gram scale with an overall yield of 31%. The post-synthesis modification of 9 to vary the recognition sites are demonstrated by producing four different macrocycles (10–13) with distinct functional groups, 2-methoxyethoxyl (10), hydroxyl (11), carboxyl (12) and amide (13), respectively. The 1H NMR study suggests that the structure of these macrocycles is consistent with our design, i.e., forming hydrogen bonding network at both rims of the macrocyclic backbone. The 1H-1H NOESY NMR study indicates the recognition functional groups are located inside the cavity of macrocycles. At last, a preliminary molecular recognition study shows 10 can recognize n-octyl-β-D-glucopyranoside (14) in chloroform.

Hybrid peptides whose N-terminal residues are activated in the form of α-methylisoserine cyclic sulfamidates exhibit rich reactivity as electrophiles, allowing site- and stereoselective modifications at different backbone and side chain positions.

The idea and methods of methylvinylsilicone rubber modification are present. Polyhedral oligomeric silsesquioxanes (POSS) functionalized by vinyl-, carboxyl or amino-organic groups were used with the goal of modifying the rubber matrix. Additionally, oxazoline derivative and itaconic acid were used as the coupling agents. Generally, the process of modification contributed to increasing of rubber-filler interactions, however the useful properties of composites depended on a kind of active groups and way of modifications. It has been shown how grafting of POSS molecules to silicone backbone affects the cross-link density, rheometrical and mechanical properties, hysteresis and relaxation rates of the methylvinylsilicone rubber vulcanizates. Moreover, both the presence of silsesquioxanes and the way of composites preparing affect the improvement of filler dispersion degree in the rubber matrix, as indicated by SEM images. The most significant effect was observed for vinylisobutyl-POSS grafting to the silicone backbone which resulted in the considerably improved mechanical properties of the resulting network.

Antisense oligonucleotides are short strands of DNA, which bind to their complementary mRNA target to prevent protein translation. Although conceptually appealing, for their practical use as drugs, these oligonucleotides must have better cellular uptake, resistance to enzymatic degradation, and target selectivity. In this work, new synthetic chemistry is established to prepare a novel group of chemically modified oligonucleotides. The anionic phosphodiester backbone is partially replaced with a neutral triazole and, at the same time, the 2'-position of the ribose sugar is functionalised with pyrene, anthraquinone, or guanidine moieties. Being unnatural, the triazole backbone is inherently resistant to enzymatic degradation, while the reduced negative charge potentially improves cell penetration. The limitation of introduction of a triazole backbone into the antisense strand is its destabilising effect on the duplex formation with their complementary target. In this study, the 2'-modifications are used to restore the lost duplex stability and they have been found to be very efficient stabilising moieties. To evaluate the viability of this strategy, reporter gene assays based on splice-switching model are used. Promisingly, these modified oligonucleotides have successfully shown antisense splice-switching activity, suggesting there is further scope for their improvement.

Doutoramento em Bioquímica
Os polissacarídeos são os componentes maioritários dos grãos de café verde e torrado e da bebida de café. Os mais abundantes são as galactomananas, seguindo-se as arabinogalactanas. Durante o processo de torra, as galactomananas e arabinogalactanas sofrem modificações estruturais, as quais estão longe de estar completamente elucidadas devido à sua diversidade e à complexidade estrutural dos compostos formados. Durante o processo de torra, as galactomananas e arabinogalactanas reagem com proteínas, ácidos clorogénicos e sacarose, originando compostos castanhos de alto peso molecular contendo nitrogénio, designados de melanoidinas. As melanoidinas do café apresentam diversas atividades biológicas e efeitos benéficos para a saúde. No entanto, a sua estrutura exata e os mecanismos envolvidos na sua formação permanecem desconhecidos, bem como a relação estrutura-atividade biológica. A utilização de sistemas modelo e a análise por espectrometria de massa permitem obter uma visão global e, simultaneamente, detalhada das modificações estruturais nos polissacarídeos do café promovidas pela torra, contribuindo para a elucidação das estruturas e mecanismos de formação das melanoidinas. Com base nesta tese, oligossacarídeos estruturalmente relacionados com a cadeia principal das galactomananas, (β1→4)-Dmanotriose (Man3), e as cadeias laterais das arabinogalactanas, (α1→5)-Larabinotriose (Ara3), isoladamente ou em misturas com ácido 5-Ocafeoilquínico (5-CQA), o ácido clorogénico mais abundante nos grãos de café verde, e péptidos compostos por tirosina e leucina, usados como modelos das proteínas, foram sujeitos a tratamento térmico a seco, mimetizando o processo de torra. A oxidação induzida por radicais hidroxilo (HO•) foi também estudada, uma vez que estes radicais parecem estar envolvidos na modificação dos polissacarídeos durante a torra. A identificação das modificações estruturais induzidas por tratamento térmico e oxidativo dos compostos modelo foi feita por estratégias analíticas baseadas principalmente em espectrometria de massa, mas também em cromatografia líquida. A cromatografia de gás foi usada na análise de açúcares neutros e ligações glicosídicas. Para validar as conclusões obtidas com os compostos modelo, foram também analisadas amostras de polissacarídeos do café obtidas a partir de resíduo de café e café instantâneo. Os resultados obtidos a partir dos oligossacarídeos modelo quando submetidos a tratamento térmico (seco), assim como à oxidação induzida por HO• (em solução), indicam a ocorrência de despolimerização, o que está de acordo com estudos anteriores que reportam a despolimerização das galactomananas e arabinogalactanas do café durante a torra. Foram ainda identificados outros compostos resultantes da quebra do anel de açúcares formados durante o tratamento térmico e oxidativo da Ara3. Por outro lado, o tratamento térmico a seco dos oligossacarídeos modelo (individualmente ou quando misturados) promoveu a formação de oligossacarídeos com um maior grau de polimerização, e também polissacarídeos com novos tipos de ligações glicosídicas, evidenciando a ocorrência de polimerização através reações de transglicosilação não enzimática induzidas por tratamento térmico a seco. As reações de transglicosilação induzidas por tratamento térmico a seco podem ocorrer entre resíduos de açúcares provenientes da mesma origem, mas também de origens diferentes com formação de estruturas híbridas, contendo arabinose e manose como observado nos casos dos compostos modelo usados. Os resultados obtidos a partir de amostras do resíduo de café e de café instantâneo sugerem a presença de polissacarídeos híbridos nestas amostras de café processado, corroborando a ocorrência de transglicosilação durante o processo de torra. Além disso, o estudo de misturas contendo diferentes proporções de cada oligossacarídeo modelo, mimetizando regiões do grão de café com composição distinta em polissacarídeos, sujeitos a diferentes períodos de tratamento térmico, permitiu inferir que diferentes estruturas híbridas e não híbridas podem ser formadas a partir das arabinogalactanas e galactomananas, dependendo da sua distribuição nas paredes celulares do grão e das condições de torra. Estes resultados podem explicar a heterogeneidade de estruturas de melanoidinas formadas durante a torra do café. Os resultados obtidos a partir de misturas modelo contendo um oligossacarídeo (Ara3 ou Man3) e 5-CQA sujeitas a tratamento térmico a seco, assim como de amostras provenientes do resíduo de café, mostraram a formação de compostos híbridos compostos por moléculas de CQA ligadas covalentemente a um número variável de resíduos de açúcar. Além disso, os resultados obtidos a partir da mistura contendo Man3 e 5-CQA mostraram que o CQA atua como catalisador das reações de transglicosilação. Por outro lado, nas misturas modelo contendo um péptido, mesmo contendo também 5-CQA e sujeitas ao mesmo tratamento, observou-se uma diminuição na extensão das reações transglicosilação. Este resultado pode explicar a baixa extensão das reações de transglicosilação não enzimáticas durante a torra nas regiões do grão de café mais ricas em proteínas, apesar dos polissacarídeos serem os componentes maioritários dos grãos de café. A diminuição das reações de transglicosilação na presença de péptidos/proteínas pode dever-se ao facto de os resíduos de açúcares redutores reagirem preferencialmente com os grupos amina de péptidos/proteínas por reação de Maillard, diminuindo o número de resíduos de açúcares redutores disponíveis para as reações de transglicosilação. Além dos compostos já descritos, uma diversidade de outros compostos foram formados a partir dos sistemas modelo, nomeadamente derivados de desidratação formados durante o tratamento térmico a seco. Em conclusão, a tipificação das modificações estruturais promovidas pela torra nos polissacarídeos do café abre o caminho para a compreensão dos mecanismos de formação das melanoidinas e da relação estrutura-atividade destes compostos.
Polysaccharides are the major components of green and roasted coffee beans, and coffee brew. The most abundant ones are galactomannans, followed by arabinogalactans. During the roasting process, galactomannans and arabinogalactans undergo structural modifications that are far to be completely elucidated due to their diversity and complexity of the compounds formed. During the roasting process, galactomannans and arabinogalactans react with proteins, chlorogenic acids, and sucrose, originating high molecular weight brown compounds containing nitrogen, known as melanoidins. Several biological activities and beneficial health effects have been attributed to coffee melanoidins. However, their exact structures and the mechanisms involved in their formation remain unknown, as well as the structure-biological activity relationship. The use of model systems and mass spectrometry analysis allow to obtain an overall view and, simultaneously, detailed, of the structural modifications in coffee polysaccharides promoted by roasting, contributing to the elucidation of the structures and formation mechanisms of melanoidins. Based on this thesis, oligosaccharides structurally related to the backbone of galactomannans, (β1→4)-D-mannotriose, and the side chains of arabinogalactans, (α1→5)-Larabinotriose, alone or in mixtures with 5-O-caffeoylquinic acid, the most abundant chlorogenic acid in green coffee beans, and dipeptides composed by tyrosine and leucine, used as models of proteins, were submitted to dry thermal treatments, mimicking the coffee roasting process. The oxidation induced by hydroxyl radicals (HO•) was also studied, since these radicals seem to be involved in the modification of the polysaccharides during roasting. The identification of the structural modifications induced by thermal and oxidative treatment of the model compounds was performed mostly by mass spectrometry-based analytical strategies, but also using liquid chromatography. Gas chromatography was used in the analysis of neutral sugars and glycosidic linkages. To validate the conclusions achieved with the model compounds, coffee polysaccharide samples obtained from spent coffee grounds and instant coffee were also analysed. The results obtained from the model oligosaccharides when submitted to thermal treatment (dry) or oxidation induced by HO• (in solution) indicate the occurrence of depolymerization, which is in line with previous studies reporting the depolymerization of coffee galactomannans and arabinogalactans during roasting. Compounds resulting from sugar ring cleavage were also formed during thermal treatment and oxidative treatment of Ara3. On the other hand, the dry thermal treatment of the model oligosaccharides (alone or when mixed) promoted the formation of oligosaccharides with a higher degree of polymerization, and also polysaccharides with new type of glycosidic linkages, evidencing the occurrence of polymerization via non-enzymatic transglycosylation reactions induced by dry thermal treatment. The transglycosylation reactions induced by dry thermal treatment can occur between sugar residues from the same origin, but also of different origins, with formation of hybrid structures, containing arabinose and mannose in the case of the model compounds used. The results obtained from spent coffee grounds and instant coffee samples suggest the presence of hybrid polysaccharides in these processed coffee samples, corroborating the occurrence of transglycosylation during the roasting process. Furthermore, the study of mixtures containing different proportions of each model oligosaccharide, mimicking coffee bean regions with distinct polysaccharide composition, subjected to different periods of thermal treatment, allowed to infer that different hybrid and non-hybrid structures may be formed from arabinogalactans and galactomannans, depending on their distribution in the bean cell walls and on roasting conditions. These results may explain the heterogeneity of melanoidins structures formed during coffee roasting. The results obtained from model mixtures containing an oligosaccharide (Ara3 or Man3) and 5-CQA and subjected to dry thermal treatment, as well as samples derived from spent coffee grounds, showed the formation of hybrid compounds composed by CQA molecules covalently linked to a variable number of sugar residues. Moreover, the results obtained from the mixture containing Man3 and 5-CQA showed that CQA acts as catalyst of transglycosylation reactions. On the other hand, in the model mixtures containing a peptide, even if containing 5-CQA and subjected to the same treatment, it was observed a decrease in the extent of transglycosylation reactions. This outcome can explain the low extent of non-enzymatic transglycosylation reactions during roasting in coffee bean regions enriched in proteins, although polysaccharides are the major components of the coffee beans. The decrease of transglycosylation reactions in the presence of peptides/proteins can be related with the preferential reactivity of reducing residues with the amino groups of peptides/proteins by Maillard reaction, decreasing the number of reducing residues available to be directly involved in the transglycosylation reactions. In addition to the compounds already described, a diversity of other compounds were formed from model systems, namely dehydrated derivatives formed during dry thermal treatment. In conclusion, the identification of the structural modifications in coffee polysaccharides promoted by roasting pave the way to the understanding of the mechanisms of formation of melanoidins and structure-activity relationship of these compounds.

The first part of the work presented in the thesis deals with CH-pi interaction, which is a lesser-known non-covalent interaction in proteins. We identified several CH-pi donor-acceptor pairs involving amino acids side chains and less polarized C-H bonds at a solvent-exposed site between the strands of a model beta-hairpin peptide. Therein, we observe a distance-dependent induction of CH-pi interaction within the aliphatic-aromatic amino acid pair. Our results also suggest an interplay of hydrophobicity and CH-pi interaction in dictating the stability of beta-hairpin. In the second part, we have attempted to establish thioamidation, which is a single atom ‘O’ to ‘S’ substitution, as a chemical strategy for amide bond desolvation. Thioamide substitution on a model and a bioactive cyclic peptide has led to an enhancement in membrane permeability and metabolic stability which are the two major deterrents of peptide bioavailability. We observed improved plasma exposure of the thioamidated peptides upon oral intake. Thioamidation could successfully improve the pharmacokinetic properties of the peptides and subsequently, their oral bioavailability. Additionally, thioamidated somatostatin agonists displayed prolonged inhibition of growth hormone release in vivo. Altogether, the work done in this thesis highlights the roles of both side chains and amide backbone in modulating conformations and other functional properties of peptides and proteins. Our strategies underscore how these local components can be fine-tuned to achieve the desired biophysical properties and activities to design next generation peptide-based therapeutics.
MoE

The peptide backbone holds a protein together and plays a crucial role in guiding its three-dimentional structure. The tertiary structure of proteins regulates several biological processes. Therefore, peptide bond modification has gained significant attention to influence protein folding, stability, and functions. However, it is a challenging task to mimic the peptide (amide) bond due to its unique properties, such as planar structure, hydrogen bond donor, and acceptor properties. Thioamide, a single O to S substitution in an amide bond, is the closest isostere and has shown promising results on small peptides. The recent discovery of thioamide in natural protein, methyl-coenzyme M reductase (MCR), raises an important fundamental question of its role in protein conformation and stability. However, the synthesis of thio modified peptides/proteins is challenging. Therefore, we first focused on the synthetic procedure for the synthesis of thioamidated peptides and proteins. We have shown the compatibility of our synthetic method in incorporating the thionated derivative of all the 20 naturally occurring amino acids onto a growing peptide chain. We also report the use of a 2% DBU + 5% piperazine cocktail for fast Fmoc-deprotection that allowed us to synthesize thioamidated Pin1 WW domain and GB1 directly on a solid support. Next, we demonstrated the role of a single n→π* interaction on protein stability by engineering n→π* interaction at the β-turn. Our experimental results at the i+2 residue of type-II’ β-turn in GB1 variants suggest that amino acid side-chain identity and the rotamer conformation can modulate the strength of an n→π* interaction. The altered rotamer conformation as a result of local structural changes within a protein can amplify/weaken an n→π* interaction affecting the backbone torsion angles (phi, psi), and thereby influencing its stability. Further, we amplified the strength of n→π* interaction by replacing i+1 donor carbonyl with thiocarbonyl and validated that the n→π* interaction can indeed influence the structural stability of proteins. We also highlighted the potential impact of a single atom substitution in stabilizing the β-sheet protein. It broadens the scope of this backbone mutation approach in designing/stabilizing the protein scaffold.

Regular starches contain two principal types of glucan polymers: amylopectin and amylose. The structure of amylopectin is characterized according to the unit chain length profile and the nature of the branching pattern, which determine the alignment of glucan chains during biosynthesis. The organization of glucan chains in amylopectin and their impact on the structure of starch are still open to debate. The location of amylose and its exact contribution to the assembly of crystalline lamellae in regular and high-amylose starch granules also remain unknown. The primary focus of this thesis is the organization and flexibility of glucan chains in crystalline lamellae. The organization and flexibility of glucan chains in native, annealed (ANN), and heat-moisture treated (HMT) normal, waxy, hylon V, hylon VII, and hylon VIII corn starches were examined. This study has shown for the first time that increased amounts of apparent amylose in B-type starches hinder the polymorphic transition (from B to A+B) during HMT. The research has also demonstrated that an iodine-glucan complex transformed the B-type polymorphic pattern of hylon starches into a V-type pattern. The differential scanning calorimetry (DSC) results showed that ANN- and HMT-induced changes were most pronounced in hylon starches. These findings suggest that the glucan tie chains influences the assembly of crystalline lamellae in high-amylose starches. The relationship between the internal unit chain composition of amylopectin, and the thermal properties and annealing of starches from four different structural types of amylopectin was investigated by DSC. The onset gelatinization temperature (To) correlated negatively with the number of building blocks in clusters (NBbl) and positively with the inter-block chain length (IB-CL). The enthalpy of gelatinization (∆H) correlated positively with the external chain length of amylopectin. Annealing results showed that starches with a short IB-CL were most susceptible to ANN, as evidenced by a greater increase in the To and Tm. The increase in enthalpy was greater in starches with long external chains and IB-CLs. These data suggest that the internal organization of glucan chains in amylopectin determines the alignment of chains within the crystalline lamellae and thereby the thermal properties and annealing of the starch granules.

Unambiguous and homogeneous geodetic reference frames are essential to the proper determination of locations and heights. The reference frames used in the Netherlands are the Rijksdriehoekmeting (RD) for locations and the Normaal Amsterdamse Peil (NAP) for heights. The RD has traditionally been managed by the Kadaster; the NAP by Rijkswaterstaat. The emergence of satellite positioning has resulted in drastic changes to these geodetic reference frames. A surveyor is now offered one instrument, GPS (the Global Positioning System), capable of the simultaneous determination of locations and heights. This is possible by virtue of one three-dimensional geodetic reference system - the European Terrestrial Reference System (ETRS89) - which in the Netherlands is maintained in a collaborative arrangement between the Kadaster and Rijkswaterstaat. GPS has been advanced as a practical measurement technique by linking the definition of the RD grid to ETRS89. Nevertheless the introduction of GPS also revealed distortions in the RD grid, which are modelled in the RDNAPTRANSTM2004 transformation. Furthermore, the use of the geoid model has become essential to the use of GPS in determining the height in comparison to NAP. Subsidence that has disrupted the backbone of the NAP gave cause to the need for a large-scale adjustment of the heights of the underground benchmarks and, in so doing, of the grid. Consequently new NAP heights have been introduced at the beginning of 2005; a new definition of the RD grid that had already been introduced in 2000 was once again modified in 2004. During the past few years two NCG subcommissions have devoted a great deal of time to these modifications. This publication lays down ETRS89, the RD and the NAP, together with their mutual relationships. In addition to reviewing the history of the reference frames and the manner in which they are maintained (including, for example, the use of AGRS.NL as the basis for the Dutch geometric infrastructure), the publication also discusses the status of the frames as at 1 January 2005. This encompasses the realisation of ETRS89 via AGRS.NL, the revision and new definition of the RD grid in 2004, and the new NAP publication in 2005. The publication also describes the mutual relationships between the frames in the modernized RDNAPTRANSTM2004 transformation consisting of the new NLGEO2004 geoid model and a model for the distortions of the RD grid. In conclusion, the publication also devotes attention to the future maintenance of the ETRS89, RD and NAP. The continuity of the link between the traditional frames and the three-dimensional frames is of great importance, and ETRS89 will continue to fulfil this linking role. The GPS base network and AGRS.NL reference stations will increasingly assume the leading role in the maintenance of the RD frame. The maintenance of the NAP will continue to be necessary, although during the coming decades the the primary heights will not need revision. In so doing the high quality of the geodetic reference frames required for their use in actual practice will continue to be guaranteed.

AbstractThis introduction charts the history of the development of the major chemical modifications that have influenced the development of nucleic acids therapeutics focusing in particular on antisense oligonucleotide analogues carrying modifications in the backbone and sugar. Brief mention is made of siRNA development and other applications that have by and large utilized the same modifications. We also point out the pitfalls of the use of nucleic acids as drugs, such as their unwanted interactions with pattern recognition receptors, which can be mitigated by chemical modification or used as immunotherapeutic agents.

AbstractImprovement methods constitute the backbone of most metaheuristics. These methods repeatedly perform slight, local modifications on a current solution to the problem. Hence, for any solution, a set of neighbor solutions must be defined. Clearly, the definition of this set depends on the problem modeling. However, a natural neighborhood may turn out to be either too small to lead to quality solutions or too large, inducing prohibitive calculation times. Various approaches have been proposed to enlarge the neighborhood, such as the filter and fan method or the ejection chains. For reducing the neighborhood size, typical strategies are the granular search and the candidate list.

A new kind of optical material with a high potential for various high quality low cost devices has been optimized and applicated for optical waveguides. In order to meet the requirements of thermal and long-term stability inorganic and organic components were combined in an optical material consisting of a stable inorganic backbone and an additional organic modification with polymerizable organic groupings.

JB4730-94 “nondestructive inspection of pressure vessels” is a mandatory backbone standard for Chinese pressure equipment sector. However, several problems have also been found in the course of its implementation. Chinese government decided to make revision to JB4730 standard and officially promulgated JB/T4730-2005 “Nondestructive inspection of pressure equipment” in July 2005 and published its English version at the same time. The new standard has made significant modification based on 94 edition, it extends the scope of application to the entire category of pressure equipment, the standard covers such five conventional NDT techniques as RT, UT, MT, PT and eddy-current inspection, adds the content of the types of defects (point defect, surface defect) determined by UT, and UT of austenitic stainless steel welds is also included. As the major drafting unit of the standard, in this paper the modification condition, modification content and modification reason of this standard are exhaustively introduced, which provides certain help and guidance in learning the development and present situation of NDT techniques of Chinese pressure equipment sector. Exhaustive introduction provides certain help and guidance for learning the development and present situation of NDT technology of Chinese pressure-bearing equipment sector.

Calculations form the backbone of every design. Engineers and designers rely on calculations to support the technical adequacy of any system, structure or component (SSC). Without representative calculations, the design, construction, operation, maintenance or modification of any SSC would remain unanalyzed, non-configured and potentially unsafe. In today’s nuclear generating plants, calculations that form the design basis and how that design is translated into drawings and procedures are especially important. Federal regulations mandate that all nuclear generating plant licensees establish a method of design control to assure that regulatory requirements are met. The purpose of this paper is to describe one such method by which a nuclear plant licensee (Southern Nuclear) controls its calculations.

Abstract The two most common challenges on the oil and gas production today are the flowing production under natural pressure depletion and the surface facility capacity limitation. Ujung Pangkah field is no exception regarding finding a method to overcome this problem. It compelled to embolden many strategies to ensure the continuity of oil and gas production. Production enhancement initiatives were delivered through both Subsurface and Surface sides. SAKA Energi Indonesia, as the operator of Pangkah PSC, proved that Surface Modification approach increased the oil and gas production. Historically, gas lift injection dependency in all production wells force a continuous operation of Gas Lift Compressor (GLC) unit to supply gas lift. However, GLC as a production backbone is no longer sustainable, it has reached its maximum limit and unable to fulfil the gas lift rate requirement for all wells. Furthermore, the changing flowing conditions – low gas feeding - from wells are relatable to most of the critical surface equipment. Considering all the challenges faced in Ujung Pangkah field, SAKA developed initiatives on MP Compressor and GLC configuration by performing compressors restaging. The equipment modifications started out with restaging the MP Compressor (MPC) that led to MP Separator operating pressure reduction – from 22 barg down to 16 barg. Pressure changes on MP Separator also directly affected the GLC system since it works on the same pipeline header. Technical assessment analysis for other corresponding equipment were performed to verify if each of the equipment's operating boundary could accommodate lower pressure at the facility. Compressor restaging has direct and indirect impacts. The direct impacts are decrease in suction pressure, increase in gas lift rates, and decrease in flowing of suction pressure due to the pressure at wellhead. The indirect impact is production gain from wells by lowering the wellhead pressure. Particularly in the pressure depletion case, this initiative could extend the lifetime of the wells. Production gain was quantified after compressor restaging and pressure system lower to 16 barg. The gain from this method was 3 MMscfd and ~400 BOPD.

Stacked dilated convolutions used in Wavenet have been shown effective for generating high-quality audios. By replacing pooling/striding with dilation in convolution layers, they can preserve high-resolution information and still reach distant locations. Producing high-resolution predictions is also crucial in music source separation, whose goal is to separate different sound sources while maintain the quality of the separated sounds. Therefore, in this paper, we use stacked dilated convolutions as the backbone for music source separation. Although stacked dilated convolutions can reach wider context than standard convolutions do, their effective receptive fields are still fixed and might not be wide enough for complex music audio signals. To reach even further information at remote locations, we propose to combine a dilated convolution with a modified GRU called Dilated GRU to form a block. A Dilated GRU receives information from k-step before instead of the previous step for a fixed k. This modification allows a GRU unit to reach a location with fewer recurrent steps and run faster because it can execute in parallel partially. We show that the proposed model with a stack of such blocks performs equally well or better than the state-of-the-art for separating both vocals and accompaniment.

Humic substances (HS) are abundant in the environment. They penetrate through water, soil, and air. They have plentiful fossil and renewable resources including oxidized brown coal, peat, sapropel, spent sulphite liquor, composts, and other organic waste. HS govern many vitally important ecosystem processes like maintenance of soil fertility, nutrients delivery to plants, mitigation of abiotic stresses, etc. Numerous examples on their beneficial effects to plants and other living organisms are reported. Still, due to complexity of humic molecular assemblies, they have been very limitedly tapped for practical needs. Here we introduce a concept of ecoadaptive chemistry, which implies molecular and functional studies of life-sustaining processes in nature aimed at their further transfer into ecoadaptive technologies via rational design of nature-like chemicals, materials, and processes (Perminova 2019). We show how the disclosed mechanisms of self-purification and self-healing implied by natural systems can be applied to molecular design of humics-based products (chemicals, materials) with the tailored properties. The examples will be given for direct chemical modification of HS by incorporation of phenolic units into molecular backbone of HS, for preparation of interpolyelectrolyte complexes with aminoorganolanes , for HS assisted synthesis of nanoparticles with the needed properties (iron (hydr)oxides, silver, gold), for preparation of HS-based hybrid nanomaterials. The possibilities for practical applications of the obtained humic derivatives, polyelectrolyte complexes, HS-stabilized nanoparticles and hybrid materials will be demonstrated. They include novel humics-based biocatalytic systems for manipulation of microbial metabolism (suppression of methane synthesis by methanogens), solid HS-clay emulsion stabilizers for eliminating of oil slicks, humics-based non-lactam inhibitors of beta-lactamases, HS-based nanomaterials for wound-healing. The developed approaches open a way for broad innovative applications of humics-based chemicals and materials both in the field of environmental protection, biotechnology, human and environmental health. They also contribute to further elaboration and development of the concept of ecoadaptive chemistry and technology. References Perminova, I.V. From green chemistry and nature-like technologies towards ecoadaptive chemistry and technology. Pure and Applied Chemistry 2019, 91(5), 851-864. DOI: 10.1515/pac2018-1110 Acknowledgement: This research was supported by the Russian Science Foundation 20-63- 47070. The studies were conducted in the framework of the Interdisciplinary Scientific and Educational School of M. V. Lomonosov Moscow State University “Future Planet and Global Environ-mental Change”.

Novel amorphous nonlinear optical (NLO) polymers with modified polyimide backbones and functionalized azo chromophores have been synthesized for applications as electro-optic materials. The most attractive aspects of these polymers are the ease of modification of the NLO side-chain chromophores and the high thermal stability provided by glass transition temperatures in excess of 140 °C. The dispersion of the linear and nonlinear optical properties of these polymers has been determined. The time-temperature behaviour of the chromophore relaxation has been modeled to obtain estimates of the lifetimes of electro-optic devices using these polymers.

The current US DoD has recognized that their asymmetric advantage is eroding1. Adversaries have had over 25 years to counter the US playbook and weapon systems (Ref. [1]). The US Army Future Vertical Lift (FVL) programs have identified several key tenets that their airborne weapon systems need to ensure they maintain asymmetric advantage. (1) New and upgraded mission capabilities of their airborne platforms need to get to the field faster (Ref. [2]). One of the current roadblocks to achieving this is the extensive full-system regression testing that ends up being required when there are mission system changes (Ref. [3]). (2) More competition is needed to help generate "quicker, better, faster" capabilities (Ref. [4]). "Vendor lock" inherent in current system designs hinders the speed at which technology advances (Ref. [4, 5]). (3) Improved portability of mission capability across the FVL and enduring fleet (Ref. [6, 7]). The ability to more easily reuse technology will help maintain advantage by eliminating the time needed to develop platform specific solutions (Ref. [4, 6]). The request for Modular Open System Architecture (MOSA) solutions has been a practice to try to address the items above (Ref. [8]). Most air vehicle and mission system providers are today providing MOSA solutions but the required benefits have not yet been fully realized. MOSA standards as they exist today do a very good job of identifying electronics hardware and software architectures. However, they fall short on physical aircraft integration and consistency in architecture among aircraft systems. Minimizing aircraft wiring and structural modifications, increasing speed to fielding, and portability among multiple systems types are all part of integrating highly MOSA compliant solutions. The US Army FVL programs have required a "digital backbone" (Ref. [7, 9, 10]) to address these integration issues and ensure that they can maintain asymmetric advantage. Unique requirements affecting the digital backbone include: - Power and power distribution (Ref. [9]) - Thermal management (Ref. [9, 11]) - Packaging and installation (Ref. [9]) - Air Vehicle data distribution (Ref. [9]) - Mission System data distribution (Ref. [9]) - Isolation of air vehicle and mission system (Ref. [9]) This paper will provide an introduction to the envisioned digital backbone for US Army, Future Vertical Lift aircraft. The paper will also offer discussion of digital backbone impacts on aircraft and avionics size, weight, power and cost, as well as technology considerations to address interoperability, safety, security, qualification, and accommodations for new, as well as, legacy avionics technology.

Abstract This paper describes a process for assessing multi-loop wearable devices that use a common slider to passively drive the exo-fingers for the physical training of people with limited hand mobility. Each finger design, except for the thumb, is based on an RRR serial chain, termed backbone, constrained into a multi-loop eight-bar slider mechanism using two RR constraints. The thumb utilizes a planar RR backbone chain constrained into a parallel four bar slider. During the physical task acquisition experiments, the subject’s tip finger trajectories are captured using an optical motion capture and its dimensions are set such that they match each of the fingers kinematics as closely as possible. The dimensional synthesis procedure can yield a variety of design candidates that fulfill the desired fingertip precision grasping trajectory. Once it is ensured that the synthesized fingertip motion is close to the physiological fingertip grasping trajectories, performance assessment criteria related to user-device interference and natural joint angle movement are taken into account. After the most preferred design for each finger is chosen, minor modifications related to substituting the backbone chain with the wearer’s limb to provide the skeletal structure of the customized passive device are made. To illustrate the proposed technique, the development of a 3D prototype model of a passively actuated Closed Loop Articulated Wearable (CLAW) hand is presented. The CLAW hand performance with respect to wear-ability and robustness was assessed. Preliminary test results with healthy subjects show that the CLAW hand is easy to operate and able to guide the user’s fingers without causing any discomfort, ensuring both, precision and power grasping in a natural manner. The lack of electrical actuators and sensors simplifies the control, resulting in a lightweight and cost-effective solution for grasping of a variety of objects with different sizes. This work establishes the importance of incorporating novel design candidate assessment techniques, based on human finger kinematic models, within the conceptual design level that can assist in finding robust design candidates with naturalistic joint motion.