Calculation and Analysis of the Molecular Weight Characteristics of the Polymer in the Synthesis of Butyl Rubber

The article compiled a mathematical model of the cationic copolymerization of isobutylene and isoprene using a catalyst AlCl3 in a CH3Cl solution, including the reactions of initiation, chain growth, chain transfer to the monomer, and chain termination. The molecular weight characteristics of butyl rubber synthesized in methyl chloride using a catalytic system based on aluminum trichloride have been investigated. Relationships are obtained for calculating the moments of the molecular weight characteristics of butyl rubber. The effect of the concentration of the initiator on the conversion versus time was investigated.

Theoretical Study on Ethylene Polymerization Catalyzed by Half-Titanocenes Bearing Different Ancillary Groups

Half-titanocenes are well known to show high activity for ethylene polymerization and good capability for copolymerization of ethylene with other olefins, and the ancillary ligands can crucially affect the catalytic performance. In this paper, the mechanisms of ethylene polymerization catalyzed by three half-metallocenes, (η5-C5Me5)TiCl2(O-2,6-iPr2C6H3) (1), (η5-C5Me5)TiCl2(N=CtBu2) (2) and [Me2Si(η5-C5Me4)(NtBu)]TiCl2 (3), have been investigated by density functional theory (DFT) method. At the initiation stage, a higher free energy barrier was determined for complex 1, probably due to the presence of electronegative O atom in phenoxy ligand. At the propagation stage, front-side insertion of the second ethylene is kinetically more favorable than back-side insertion for complexes 1 and 2, while both side insertion orientations are comparable for complex 3. The energy decomposition showed that the bridged cyclopentadienyl amide ligand could enhance the rigidity of the active species as suggested by the lowest deformation energy derived from 3. At the chain termination stage, β-H transfer was calculated to be a dominant chain termination route over β-H elimination, presumably owing to the thermodynamic perspective.

Truncation of poly-N-acetylglucosamine (PNAG) polymerization with N-acetylglucosamine analogues

Bacteria require polysaccharides for structure, survival, and virulence. Despite the central role these structures play in microbiology few tools are available to manipulate their production. In E. coli the glycosyltransferase complex PgaCD produces poly-N-acetylglucosamine (PNAG), an extracellular matrix polysaccharide required for biofilm formation. We report that C6-substituted (H, F, N3, SH, NH2) UDP-GlcNAc substrate analogues are inhibitors of PgaCD. In vitro the inhibitors cause PNAG chain termination; consistent with the mechanism of PNAG polymerization from the non-reducing terminus. In vivo, expression of the GlcNAc-1-kinase NahK in E. coli provided a non-native GlcNAc salvage pathway that produced the UDP-GlcNAc analogue inhibitors in situ. The 6-fluoro and 6-deoxy derivatives were potent inhibitors of biofilm formation in the transformed strain, providing a tool to manipulate this key exopolysaccharide. Characterization of the UDP-GlcNAc pool and quantification of PNAG generation support PNAG termination as the primary in vivo mechanism of biofilm inhibition by 6-fluoro UDP-GlcNAc.

Pyronaridine Protects Against SARS-CoV-2 in Mouse

There are currently relatively few small-molecule antiviral drugs that are either approved or emergency approved for use against SARS-CoV-2. One of these is remdesivir, which was originally repurposed from its use against Ebola and functions by causing early RNA chain termination. We used this as justification to evaluate three molecules we had previously identified computationally with antiviral activity against Ebola and Marburg. Out of these we previously identified pyronaridine, which inhibited the SARS-CoV-2 replication in A549-ACE2 cells. Herein, the in vivo efficacy of pyronaridine has now been assessed in a K18-hACE transgenic mouse model of COVID-19. Pyronaridine treatment demonstrated a statistically significant reduction of viral load in the lungs of SARS CoV-2 infected mice. Furthermore, the pyronaridine treated group reduced lung pathology, which was also associated with significant reduction in the levels of pro-inflammatory cytokines/chemokine and cell infiltration. Notably, pyronaridine inhibited the viral PLpro activity in vitro (IC50 of 1.8 uM) without any effect on Mpro, indicating a possible molecular mechanism involved in its ability to inhibit SARS-CoV-2 replication. Interestingly, pyronaridine also selectively inhibits the host kinase CAMK1 (IC50 of 2.4 uM). We have also generated several pyronaridine analogs to assist in understanding the structure activity relationship for PLpro inhibition. Our results indicate that pyronaridine is a potential therapeutic candidate for COVID-19.

REverSe TRanscrIptase Chain Termination (RESTRICT) for Selective Measurement of Nucleotide Analogs Used in HIV Care and Prevention

Sufficient drug concentrations are required for efficacy of antiretroviral drugs used in human immunodeficiency virus (HIV) care and prevention. Measurement of nucleotide analogs, included in most HIV medication regimens, enables monitoring of short- and long-term adherence and the risk of treatment failure. The REverSe TRanscrIptase Chain Termination (RESTRICT) assay rapidly infers the concentration of intracellular nucleotide analogs based on the inhibition of DNA synthesis by HIV reverse transcriptase (RT) enzyme. Here, we introduce a probabilistic predictive model for RESTRICT and demonstrate selective measurement of multiple nucleotide analogs using DNA templates designed according to the chemical structure of each drug. We measure clinically relevant concentrations of tenofovir diphosphate (TFV-DP), emtricitabine triphosphate (FTC-TP), and azidothymidine triphosphate (AZT-TP) with agreement between experiment and theory. RESTRICT represents a new class of activity-based assays for therapeutic drug monitoring and precision dosing in HIV care and could be extended to other diseases treated with nucleotide analogs.

A unique genotype of pseudohypoaldosteronism type 1b in a highly consanguineous population

Context This study describes the molecular genetics of pseudohypoaldosteronism type 1b (PHA 1b) in the highly consanguineous population of two Arabian Gulf countries, Saudi Arabia and Oman. Patients and Methods This study enrolled 22 patients from 13 unrelated families (two families with five patients from Oman and 11 families with 17 patients from Saudi Arabia). All of these patients had presented within the first 10 days of life with nausea and vomiting, hyponatremia, hyperkalemia and hypotension. We isolated DNA from peripheral blood and PCR-sequenced all exons and exon-intron boundaries of SCNN1A and, if negative, SCNN1B and SCNN1G using the Dideoxy Chain termination method. Results We found a total of eight mutations in 13 families as follows: six mutations in SCNN1A, one in SCNN1B, and one in SCNN1G. All of these mutations were novel except one. SCNN1A mutations were: c.1496A>G, p.Q499R (novel) in one patient; c.1453C>T, p.Q485X (novel) in one patient; c.1322_1322delA, p.N441Tfs*41 (novel) in two patients of one family; c.876 + 2 delGAGT (novel) in three patients of one family; c.203_204 delTC, p.I68Tfs*76 (known mutation) in eight patients of five families; and whole SCNN1A gene deletion (novel) in two patients of two families. In addition, a nonsense SCNN1B mutation c.1694C>A, p.S565X (novel) was found in three siblings from one Omani family, and an SCNN1G deletion mutation c.527_528 delCA, p.T176Rfs*9 (novel) in two siblings form another Omani family. Conclusion We characterized a unique genotype of PHA 1b with several novel gene-structure disrupting mutations in SCNN1A, SCNN1B and SCNN1G in a consanguineous population.

SEARCH FOR UNCERTAINTY REGIONS OF KINETIC CONSTANTS IN MODELING PROCESSES OF NON-BREAK POLYMERIZATION OF DIENES

Рассматриваются процессы полимеризации на катализаторах Циглера-Натта. Исследован вопрос о механизме процессов как необходимом наборе элементарных стадий кинетической схемы. Приведена общая схема допустимых стадий процесса, включающая стадии инициирования, роста цепи, передач цепи и обрыва цепи. Указано, что часть элементарных реакций может быть убрана из кинетической схемы за счет способа приготовления самого катализатора, а часть - на основании получаемых кинетических зависимостей. Но гипотеза о наличии или отсутствии элементарных стадий может быть доказана не только экспериментальным, но и вычислительным путем. Приводимые в работе табличные данные свидетельствуют о практически нулевом значении константы скорости элементарной стадии материального обрыва цепи - дезактивации активных центров, что, в свою очередь, вызывает оптимизацию кинетической схемы. Тогда рассматриваемые процессы могут быть отнесены к типу безобрывной полимеризации. Составление кинетической и математической моделей для исследуемых процессов позволяет поставить прямые и обратные кинетические задачи. Решение последних может быть получено методом многократного решения прямых кинетических задач и сравнения расчетных значений молекулярных характеристик с их экспериментальными аналогами. Однако целесообразнее проводить предварительный этап нахождения областей локальных минимумов по оптимизируемым значениям констант путем построения базисной поверхности и при поиске допустимых наборов значений констант скоростей оперировать найденными областями минимумов This paper considers the processes of polymerization on Ziegler-Natta catalysts. The question of the mechanism of the processes as a necessary set of elementary stages of the kinetic scheme is investigated. A general scheme of the permissible stages of the process is given, including the stages of initiation, chain growth, chain transfers and chain termination. It is indicated that part of the elementary reactions can be removed from the kinetic scheme due to the method of preparation of the catalyst itself, and part on the basis of the obtained kinetic dependences. However, the hypothesis about the presence or absence of elementary stages can be proved not only experimentally but also computationally. The tabular data presented in the work indicate a practically zero value of the rate constant of the elementary stage of material chain termination - deactivation of active centers, which, in turn, leads to optimization of the kinetic scheme. Then the processes under consideration can be attributed to the type of non-break polymerization. Compilation of kinetic and mathematical models for the processes under study makes it possible to pose direct and inverse kinetic problems. The solution of the latter can be obtained by the method of multiple solution of direct kinetic problems and comparison of the calculated values of molecular characteristics with their experimental counterparts. However, it is more expedient to carry out the preliminary stage of finding the regions of local minima by the optimized values of the constants by constructing the base surface. When searching for admissible sets of values of the rate constants, operate with the found areas of minima