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The spread of COVID-19 infection continues due to the emergence of multiple transmissible and immune-evasive variants of the SARS-CoV-2 virus. Although various vaccines have been developed and several drugs have been approved for the treatment of COVID-19, the development of new drugs to combat COVID-19 is still necessary. In this work, new 5′-O-ester derivatives of N4-hydroxycytidine based on carboxylic acids were developed and synthesized by Steglich esterification. The antiviral activity of the compounds was assessed in vitro—inhibiting the cytopathic effect of HCoV-229E, and three variants of SARS-CoV-2, on huh-7 and Vero E6 cells. Data have shown that most synthesized derivatives exhibit high activity against coronaviruses. In addition, the relationship between the chemical structure of the compounds and their antiviral effect has been established. The obtained results show that the most active compound was conjugate SN_22 based on 3-methyl phenoxyacetic acid. The results of this study indicate the potential advantage of the chemical strategies used to modify NHC as a promising avenue to be explored in vivo, which could lead to the development of drugs with improved pharmacological properties that potently inhibit SARS-CoV-2. [ABSTRACT FROM AUTHOR]

The North American low pathogenic H7N2 avian influenza A viruses, which lack the 220-loop in the hemagglutinin (HA), possess dual receptor specificity for avian- and human-like receptors. The purpose of this work was to determine which amino acid substitutions in HA affect viral antigenic and phenotypic properties that may be important for virus evolution. By obtaining escape mutants under the immune pressure of treatment with monoclonal antibodies, antigenically important amino acids were determined to be at positions 125, 135, 157, 160, 198, 200, and 275 (H3 numbering). These positions, except 125 and 275, surround the receptor binding site. The substitutions A135S and A135T led to the appearance of an N-glycosylation site at 133N, which reduced affinity for the avian-like receptor analog and weakened binding with tested monoclonal antibodies. Additionally, the A135S substitution is associated with the adaptation of avian viruses to mammals (cat, human, or mouse). The mutation A160V decreased virulence in mice and increased affinity for the human-type receptor analog. Conversely, substitution G198E, in combination with 157N or 160E, displayed reduced affinity for the human-type receptor analog. [ABSTRACT FROM AUTHOR]

Here, we report the results of our 1H nuclear magnetic resonance study of the dynamics of water molecules confined in zeolites (mordenite and ZSM-5 structures) with hierarchical porosity (micropores in zeolite lamella and mesopores formed by amorphous SiO2 in the inter-lamellar space). 1H nuclear magnetic resonance (NMR) spectra show that water experiences complex behavior within the temperature range from 173 to 298 K. The temperature dependence of 1H spin-lattice relaxation evidences the presence of three processes with different activation energies: freezing (about 30 kJ/mol), fast rotation (about 10 kJ/mol), and translational motion of water molecules (23.6 and 26.0 kJ/mol for pillared mordenite and ZSM-5, respectively). For translational motion, the activation energy is markedly lower than for water in mesoporous silica or zeolites with similar mesopore size but with disordered secondary porosity. This indicates that the process of water diffusion in zeolites with hierarchical porosity is governed not only by the presence of mesopores, but also by the mutual arrangement of meso- and micropores. The translational motion of water molecules is determined mainly by zeolite micropores. [ABSTRACT FROM AUTHOR]

Abstract. In the «fight for minds» of the Russian youth the modern education system should rely on active and initiative representatives of a new generation of researches. For this purpose creation of the effective tool by means of which they can interact with themselves, administration of university, authorities and future employers is necessary. The recipe of such tool originates in the Soviet era N the youth self-government organizations. Adaptation of this tool to modern, rapidly changing conditions is the most important task of educational and scientific community.

In South Africa, the problem of service delivery cuts across all municipalities as manifested by citizen protests across the country on almost daily basis. To mitigate the costs associated with the protests, the South African government has placed emphasis on the role played by human resources management through instituting legislative frameworks, such as the the White Paper on Human Resource Management in the Public Service (1997). Despite this effort, the human resource management practices of municipalities continue to be criticized, by both municipal internal staff and citizenry. Service delivery in the South African context is regarded as one of the cornerstone indicators of how the government affords its citizens access to quality life as enshrined in its constitution. This paper is one of the studies based on the South African context attempting to explain the problem of service delivery by looking at perceived fairness in human resource management (HRM) practices by employees of municipalities and how such perceptions affect their motivation to work. Using the tenets of the organizational justice theory, the authors hypothesize that perceived HRM practices of municipalities can be predictors of employee motivation. Quantitative data collected from employees of nine randomly selected municipalities in the Free State Province are used to create indices for the different HRM practices as well as employee motivation. Significant correlation tests are performed. Results show a positive correlation between perceived fairness in the HRM practices of municipalities and employees’ motivation at .05 and .01 levels of significance. This means that fair HRM practices of municipalities promote employee motivation

A series of 108 novel quaternary bis-ammonium pyridoxine derivatives carrying various substituents at the quaternary nitrogen’s and acetal carbon was synthesized. Thirteen compounds exhibited antibacterial and antifungal activity (minimum inhibitory concentration (MIC) 0.25–16 µg/mL) comparable or superior than miramistin, benzalkonium chloride, and chlorhexidine. A strong correlation between the lipophilicity and antibacterial activity was found. The most active compounds had logP values in the range of 1–3, while compounds with logP > 6 and logP < 0 were almost inactive. All active compounds demonstrated cytotoxicity comparable with miramistin and chlorhexidine on HEK-293 cells and were three-fold less toxic when compared to benzalkonium chloride. The antibacterial activity of leading compound 5c12 on biofilm-embedded Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli or Pseudomonas aeruginosa was comparable or even higher than that of the benzalkonium chloride. In vivo 5c12 was considerably less toxic (LD50 1705 mg/kg) than benzalkonium chloride, miramistine, and chlorhexidine at oral administration on CD-1 mice. An aqueous solution of 5c12 (0.2%) was shown to be comparable to reference drugs efficiency on the rat’s skin model. The molecular target of 5c12 seems to be a cellular membrane as other quaternary ammonium salts. The obtained results make the described quaternary bis-ammonium pyridoxine derivatives promising and lead molecules in the development of the new antiseptics with a broad spectrum of antimicrobial activity.

Induction of a robust and long-lived mucosal immune response during vaccination is critical to achieve protection against numerous pathogens. However, traditional injected vaccines are generally poor inducers of mucosal immunity. One of the effective strategies to improve vaccine efficacy is incorporation of adjuvant molecules that enhance and polarize adaptive immune reactions. Effects of Syk-coupled lectin receptor agonists as adjuvants to induce mucosal immune reactions during parenteral immunization are not fully studied. We now report that the agonists trehalose-6,6-dibehenate (TDB), curdlan, and furfurman, which stimulate Dectin-1, Dectin-2, and Mincle, respectively, activate transcription factors (NF-κB, NFAT, and AP-1) to various extents in murine RAW 264.7 macrophages, even though similar pathways are activated. The agonists also elicit differential expression of maturation markers in bone marrow-derived dendritic cells, as well as differential cytokine secretion from these cells and from splenic mononuclear cells. In vivo assays also show that agonists of Dectin-1 and Dectin-2, but not Mincle, induce heavy IgA secretion in intestinal mucosa even when delivered parenterally. Strikingly, this effect appears to be formulation-independent. Collectively, the data suggest that adjuvants based on Dectin-1 and Dectin-2 agonists may significantly improve the efficacy of parenteral vaccines by inducing robust local immune reactions in intestinal mucosa.

Dual‐ion battery (DIB) is a promising energy storage system because it can provide high power. However, the stability and rate performance of the battery depend strongly on the type of salt and solvents in the electrolyte. Herein, the use of lithium bis(fluorosulfonyl)imide (LiFSI) is studied, which has better high‐temperature stability, as salt in the DIB and develop a 3 m LiFSI fluoroethylene carbonate/methyl 2,2,2‐trifluoroethyl carbonate (FEC/FEMC) = 3:7 electrolyte, which stabilizes graphite–lithium DIB with 94.1% capacity retention after 2000 cycles at 5C. The DIB also exhibits excellent rate performance with 100.4 mAh g−1 capacity at 30C, with a utilization of 96.3% compared to capacity at 2C. The outstanding electrochemical performance is attributed to the thin cathode electrolyte interface (CEI) layer and fast FSI− transport kinetics, confirmed by X‐ray photoelectron spectroscopy and activation energy calculation. Superior cycle and rate performances are also obtained from a graphite–graphite full cell. Though, increasing salt concentration to 5 and 6 m leads to sluggish FSI− de‐intercalation reaction and lower capacity, which is attributed to solvent co‐intercalation. The research suggests that the electrolyte plays an important role in ion transport, surface film formation, and stability of DIB. [ABSTRACT FROM AUTHOR]

The gene therapy has been successful in treatment of spinal cord injury (SCI) in several animal models, although it still remains unavailable for clinical practice. Surprisingly, regardless the fact that multiple reports showed motor recovery with gene therapy, little is known about molecular and cellular changes in the post-traumatic spinal cord following viral vector- or cell-mediated gene therapy. In this study we evaluated the therapeutic efficacy and changes in spinal cord after treatment with the genes encoding vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF), angiogenin (ANG), and neuronal cell adhesion molecule (NCAM) applied using both approaches. Therapeutic genes were used for viral vector- and cell-mediated gene therapy in two combinations: (1) VEGF+GDNF+NCAM and (2) VEGF+ANG+NCAM. For direct gene therapy adenoviral vectors based on serotype 5 (Ad5) were injected intrathecally and for cell-mediated gene delivery human umbilical cord blood mononuclear cells (UCB-MC) were simultaneously transduced with three Ad5 vectors and injected intrathecally 4 h after the SCI. The efficacy of both treatments was confirmed by improvement in behavioral (BBB) test. Molecular and cellular changes following post-traumatic recovery were evaluated with immunofluorescent staining using antibodies against the functional markers of motorneurons (Hsp27, synaptophysin, PSD95), astrocytes (GFAP, vimentin), oligodendrocytes (Olig2, NG2, Cx47) and microglial cells (Iba1). Our results suggest that both approaches with intrathecal delivery of therapeutic genes may support functional recovery of post-traumatic spinal cord via lowering the stress (down regulation of Hsp25) and enhancing the synaptic plasticity (up regulation of PSD95 and synaptophysin), supporting oligodendrocyte proliferation (up regulation of NG2) and myelination (up regulation of Olig2 and Cx47), modulating astrogliosis by reducing number of astrocytes (down regulation of GFAP and vimetin) and microglial cells (down regulation of Iba1).

The bacterium Clostridium botulinum is the causative agent of botulism—a severe intoxication caused by botulinum neurotoxin (BoNT) and characterized by damage to the nervous system. In an effort to develop novel C. botulinum immunotherapeutics, camelid single-domain antibodies (sdAbs, VHHs, or nanobodies) could be used due to their unique structure and characteristics. In this study, VHHs were produced using phage display technology. A total of 15 different monoclonal VHHs were selected based on their comlementarity-determining region 3 (CDR3) sequences. Different toxin lethal dose (LD50) challenges with each selected phage clone were conducted in vivo to check their neutralizing potency. We demonstrated that modification of neutralizing VHHs with a human immunoglobulin G (IgG)1 Fc (fragment crystallizable) fragment (fusionbody, VHH-Fc) significantly increased the circulation time in the blood (up to 14 days). At the same time, VHH-Fc showed the protective activity 1000 times higher than monomeric form when challenged with 5 LD50. Moreover, VHH-Fcs remained protective even 14 days after antibody administration. These results indicate that this VHH-Fc could be used as an effective long term antitoxin protection against botulinum type A.