Protein aggregates and abnormal proteins are toxic and associated with neurodegenerative diseases. There are several mechanisms to help cells get rid of aggregates but little is known on how cells ...prevent aggregate-prone proteins from being synthesised. The EBNA1 of the Epstein-Barr virus (EBV) evades the immune system by suppressing its own mRNA translation initiation in order to minimize the production of antigenic peptides for the major histocompatibility (MHC) class I pathway. Here we show that the emerging peptide of the disordered glycine-alanine repeat (GAr) within EBNA1 dislodges the nascent polypeptide-associated complex (NAC) from the ribosome. This results in the recruitment of nucleolin to the GAr-encoding mRNA and suppression of mRNA translation initiation in cis. Suppressing NAC alpha (NACA) expression prevents nucleolin from binding to the GAr mRNA and overcomes GAr-mediated translation inhibition. Taken together, these observations suggest that EBNA1 exploits a nascent protein quality control pathway to regulate its own rate of synthesis that is based on sensing the nascent GAr peptide by NAC followed by the recruitment of nucleolin to the GAr-encoding RNA sequence.
Flavone and isoflavone derivatives have drawn much attention because of their antioxidant radical scavenging capacity. Based on computational methods, we now present the antioxidant potential results ...of flavone norartocarpetin (1) and isoflavone 2′-hydroxygenistein (2). The optimized structures of the neutral and radical forms have been carried out by DFT-B3LYP method with the 6-311++G (d,p) basis set. From the findings and thermodynamic point of view, ring B system of either flavone or isoflavone is considered as an active centre in facilitating antioxidant reactions. Antioxidant activities are mostly driven by the O–H bond dissociation enthalpy (BDE) following hydrogen atom transfer (HAT) mechanism. In all studied environments, the lowest BDE values are found in 4′-OH and 2′-OH of compounds 1-2, respectively. Isoflavone 2 possesses a higher antioxidant capacity than that of flavone 1. Of extensive analysis, intramolecular hydrogen bonds and solvents not only greatly influence on antioxidant aspect but also directly affect the structural properties, especially spectroscopic outcomes.
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•Antioxidant activities of flavonoids are mostly driven by hydrogen atom transfer (HAT) mechanism.•The results make a good agreement between experience and theoretical calculation.•Isoflavone showed antioxidant capacity better than flavone.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The Epstein-Barr virus (EBV) is the first oncogenic virus described in human. EBV infects more than 90% of the human population worldwide, but most EBV infections are asymptomatic. After the primary ...infection, the virus persists lifelong in the memory B cells of the infected individuals. Under certain conditions the virus can cause several human cancers, that include lymphoproliferative disorders such as Burkitt and Hodgkin lymphomas and non-lymphoid malignancies such as 100% of nasopharyngeal carcinoma and 10% of gastric cancers. Each year, about 200,000 EBV-related cancers emerge, hence accounting for at least 1% of worldwide cancers. Like all gammaherpesviruses, EBV has evolved a strategy to escape the host immune system. This strategy is mainly based on the tight control of the expression of its Epstein-Barr nuclear antigen-1 (EBNA1) protein, the EBV-encoded genome maintenance protein. Indeed, EBNA1 is essential for viral genome replication and maintenance but, at the same time, is also highly antigenic and T cells raised against EBNA1 exist in infected individuals. For this reason, EBNA1 is considered as the Achilles heel of EBV and the virus has seemingly evolved a strategy that employs the binding of nucleolin, a host cell factor, to RNA G-quadruplex (rG4) within EBNA1 mRNA to limit its expression to the minimal level required for function while minimizing immune recognition. This review recapitulates in a historical way the knowledge accumulated on EBNA1 immune evasion and discusses how this rG4-dependent mechanism can be exploited as an intervention point to unveil EBV-related cancers to the immune system.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This paper provides a novel application of the multi-criteria decision-making (MCDM) method to the multi-objective optimization problem (MOOP) of creating a two-stage helical gearbox (TSHG) with ...second-stage double gear sets (SDGSs). The aim of the study is to determine the optimum major design components for enhancing the gearbox efficiency while reducing the gearbox volume. In this work, three primary design parameters are chosen to accomplish this: the gear ratio of the first stage and the coefficients of the wheel face width (CWFW) of the first and second stages. Additionally, the study is conducted with two distinct objectives in mind: the lowest gearbox volume and the maximum gearbox efficiency. Moreover, phase 1 and phase 2, respectively, are the two stages of the MOOP. Phase 2 handles the MOOP to identify the ideal primary design factors as well as the single-objective optimization problem to minimize the difference between the variable levels. Additionally, the Multi-Attributive Ideal–Real Comparative Analysis (MAIRCA) approach is selected to deal with the MOOP. The results of the study are utilized to determine the ideal values for three crucial design parameters in order to create a TSHG with SDGSs.
Abstract
BCL-x is a master regulator of apoptosis whose pre-mRNA is alternatively spliced into either a long (canonical) anti-apoptotic Bcl-xL isoform, or a short (alternative) pro-apoptotic Bcl-xS ...isoform. The balance between these two antagonistic isoforms is tightly regulated and overexpression of Bcl-xL has been linked to resistance to chemotherapy in several cancers, whereas overexpression of Bcl-xS is associated to some forms of diabetes and cardiac disorders. The splicing factor RBM25 controls alternative splicing of BCL-x: its overexpression favours the production of Bcl-xS, whereas its downregulation has the opposite effect. Here we show that RBM25 directly and specifically binds to GQ-2, an RNA G-quadruplex (rG4) of BCL-x pre-mRNA that forms at the vicinity of the alternative 5′ splice site leading to the alternative Bcl-xS isoform. This RBM25/rG4 interaction is crucial for the production of Bcl-xS and depends on the RE (arginine-glutamate-rich) motif of RBM25, thus defining a new type of rG4-interacting domain. PhenDC3, a benchmark G4 ligand, enhances the binding of RBM25 to the GQ-2 rG4 of BCL-x pre-mRNA, thereby promoting the alternative pro-apoptotic Bcl-xS isoform and triggering apoptosis. Furthermore, the screening of a combinatorial library of 90 putative G4 ligands led to the identification of two original compounds, PhenDH8 and PhenDH9, superior to PhenDC3 in promoting the Bcl-xS isoform and apoptosis. Thus, favouring the interaction between RBM25 and the GQ-2 rG4 of BCL-x pre-mRNA represents a relevant intervention point to re-sensitize cancer cells to chemotherapy.
Graphical Abstract
Graphical Abstract
The antioxidative activities of the original compound dehydro-δ-viniferin (
1
) and its three designated derivatives, 5-(2-(4-hydroxyphenyl)benzofuran-3-yl)benzene-1,3-diol (
2
), (
E
...)-5-(2-(2-(4-hydroxyphenyl)benzofuran-5-yl)vinyl)benzene-1,3-diol (
3
), and (
E
)-5-(2-(3-(3,5-dihydroxyphenyl)benzofuran-5-yl)vinyl)benzene-1,3-diol (
4
), are extensively studied, mainly based on density functional theory (DFT) calculations using the hybrid functional B3LYP and the 6-311G(d,p) basis set. The O-H bond breakage is reasonably responsible for the antioxidative activity, whereas the environment greatly influences results. In solvents, namely water, methanol, and especially acetone, the SPL-ET mechanism (sequential proton loss-electron transfer) is mainly likely to be a antioxidative route for four studied compounds; however, the HAT mechanism (hydrogen atom transfer) is assigned to these compounds in the gaseous phase. Benzofuran-stilbene hybrid compound
3
with a planar structure is the best antioxidative agent; its 4′-OH induced the lowest PA values in liquid solvents as well as the lowest BDE value in the gas solvent. The kinetic investigation of the interactions of compounds
1-4
with HOO&z.rad; radicals evidently provides the lowest Gibbs activation energy Δ
G
#
= 4.7 kcal mol
−1
and the highest rate constant
K
= 5.702 × 10
10
L mol
−1
s
−1
, which again are assigned to
3
-4′-OH. At the theoretical level of B3LYP/6-311G(d,p)/LANL2DZ, the complex La(compound
3
)
3
in gas induces a redshift in the UV-Vis spectrum.
The kinetic reaction of the benzofuran-stilbene hybrid compound 5-(2-(2-(4-hydroxyphenyl)benzofuran-5-yl)vinyl)benzene-1,3-diol captures the HOO&z.rad; free radical.
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IJS, KILJ, NUK, UL, UM, UPUK
The oncogenic Epstein-Barr virus (EBV) evades the immune system but has an Achilles heel: its genome maintenance protein EBNA1. Indeed, EBNA1 is essential for viral genome maintenance but is also ...highly antigenic. Hence, EBV seemingly evolved a system in which the glycine-alanine repeat (GAr) of EBNA1 limits the translation of its own mRNA to the minimal level to ensure its essential function, thereby, at the same time, minimizing immune recognition. Therefore, defining intervention points at which to interfere with GAr-based inhibition of translation is an important step to trigger an immune response against EBV-carrying cancers. The host protein nucleolin (NCL) plays a critical role in this process via a direct interaction with G-quadruplexes (G4) formed in the GAr-encoding sequence of the viral EBNA1 mRNA. Here we show that the C-terminal arginine-glycine-rich (RGG) motif of NCL is crucial for its role in GAr-based inhibition of translation by mediating interaction of NCL with G4 of EBNA1 mRNA. We also show that this interaction depends on the type I arginine methyltransferase family, notably PRMT1 and PRMT3: drugs or small interfering RNA that target these enzymes prevent efficient binding of NCL on G4 of EBNA1 mRNA and relieve GAr-based inhibition of translation and of antigen presentation. Hence, this work defines type I arginine methyltransferases as therapeutic targets to interfere with EBNA1 and EBV immune evasion.
Abstract We tested a candidate live, oral, rotavirus vaccine (Rotavin-M1™) derived from an attenuated G1P 8 strain (KH0118-2003) isolated from a child in Vietnam. The vaccine was tested first for ...safety in 29 healthy adults. When deemed safe, it was further tested for safety and immunogenicity in 160 infants (4 groups) aged 6–12 weeks in a dose and schedule ranging study. The vaccine was administered in low titer (106.0 FFU/dose) on a 2-dose schedule given 2 months apart (Group 2L) and on a 3-dose schedule given 1 month apart (Group 3L) and in high titer (106.3 FFU/dose) in 2 doses 2 months apart (Group 2H) and in 3 doses 1 month apart (Group 3H). For comparison, 40 children (group Rotarix™) were given 2 doses of the lyophilized Rotarix™ vaccine (106.5 CCID50 /dose) 1 month apart. All infants were followed for 30 days after each dose for clinical adverse events including diarrhea, vomiting, fever, abdominal pain, irritability and intussusception. Immunogenicity was assessed by IgA seroconversion and viral shedding was monitored for 7 days after administration of each dose. Two doses of Rotavin-M1 (106.3 FFU/dose) were well tolerated in adults. Among infants (average 8 weeks of age at enrollment), administration of Rotavin-M1 was safe and did not lead to an increased rate of fever, diarrhea, vomiting or irritability compared to Rotarix™, indicating that the candidate vaccine virus had been fully attenuated by serial passages. No elevation of levels of serum transaminase, blood urea, or blood cell counts were observed. The highest rotavirus IgA seroconversion rate (73%, 95%CI (58–88%)) was achieved in group 2H (2 doses – 106.3 FFU/dose, 2 months apart). The 2 dose schedules performed slightly better than the 3 dose schedules and the higher titer doses performed slightly better than the lower titer doses. These rates of seroconversion were similar to that of the Rotarix™ group (58%, 95%CI (42–73%)). However more infants who received Rotarix™ (65%) shed virus in their stool after the first dose than those who received Rotavin-M1 (44–48%) ( p < 0.05) and the percent shedding decreased after subsequent doses of either vaccine. Rotavin-M1 vaccine is safe and immunogenic in Vietnamese infants. A trial in progress will assess the safety, immunogenicity and efficacy of Rotavin-M1 (2 doses at 106.3 FFU/dose) in a larger number of infants. The trial registration numbers are NCT01375907 and NCT01377571.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Two new hopan-type triterpenoids, namely tinctoric acid A-B (
), were isolated from the lichen
(Despr. ex Nyl.) Hale. Their structures were elucidated by extensive spectroscopic analyses (1D and 2D ...NMR). The absolute configuration at C-22 of
was established through DP4 probability. Compounds
were evaluated for their inhibitory activity against
glucosidase and found to be more potent than those of positive control (acarbose, IC
168 µM) with values IC
74.7 and 98.2 µM, respectively. Both of these compounds interacted well with enzyme α-glucosidase MAL32 through H-bonds and hydrophobic interaction.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
A second cluster of COVID-19 cases imported from Europe occured in Vietnam from early March 2020. We describe 44 SARS-CoV-2 RT-PCR positive patients (cycle threshold value <30) admitted to the ...National Hospital for Tropical Diseases in Hanoi between March 6 and April 15 2020. Whole SARS-CoV-2 genomes from these patients were sequenced using Illumina Miseq and analysed for common genetic variants and relationships to local and globally circulating strains. Results showed that 32 cases were Vietnamese with a median age of 37 years (range 15-74 years), and 23 were male. Most cases were acquired outside Vietnam, mainly from the UK (n = 15), other European countries (n = 14), Russia (n = 6) and countries in Asia (n = 3). No cases had travelled from China. Forty-one cases had symptoms at admission, typically dry cough (n = 36), fever (n = 20), sore throat (n = 14) and diarrhoea (n = 12). Hospitalisation was long with a median of 25 days, most commonly from 20-29 days. All SARS-CoV-2 genomes were similar (92-100% sequence homology) to the reference sequence Wuhan_1 (NC_045512), and 32 strains belonged to the B.1.1 lineage. The three most common variants were linked, and included C3037T, C14408T (nsp12: P323L) and A23403G (S: D614G) mutations. This group of mutations often accompanied variant C241T (39/44 genomes) or GGG 28881..28883 AAC (33/44 genomes). The prevalence of the former reflected probable European origin of viruses, and the transition D614G was dominant in Vietnam. New variants were identified; however, none could be associated with disease severity.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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