Taiwan experienced two waves of imported infections with Coronavirus Disease 2019 (COVID-19). This study aimed at investigating the genomic variation of severe acute respiratory syndrome coronavirus ...2 (SARS-CoV-2) in Taiwan and compared their evolutionary trajectories with the global strains. We performed culture and full-genome sequencing of SARS-CoV-2 strains followed by phylogenetic analysis. A 382-nucleotides deletion in open reading frame 8 (ORF8) was found in a Taiwanese strain isolated from a patient on February 4, 2020 who had a travel history to Wuhan. Patients in the first wave also included several sporadic, local transmission cases. Genomes of 5 strains sequenced from clustered infections were classified into a new clade with ORF1ab-V378I mutation, in addition to 3 dominant clades ORF8-L84S, ORF3a-G251V and S-D614G. This highlighted clade also included some strains isolated from patients who had a travel history to Turkey and Iran. The second wave mostly resulted from patients who had a travel history to Europe and Americas. All Taiwanese viruses were classified into various clades. Genomic surveillance of SARS-CoV-2 in Taiwan revealed a new ORF8-deletion mutant and a virus clade that may be associated with infections in the Middle East, which contributed to a better understanding of the global SARS-CoV-2 transmission dynamics.
Non-alcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. The purpose of this study is to investigate the protective ...effects of ginsenoside Rg1 (Rg1), an active ingredient of a natural medicine, and further clarify its protective mechanisms, in a mouse model of NAFLD induced by a high-fat diet. Rg1 significantly reduced liver weight, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), liver free fatty acids (FFAs) and malondialdehyde (MDA) levels, and increased superoxide dismutase (SOD) activity. Rg1 also upregulated the expression of peroxisome proliferator-activated receptor-alpha (PPARα), which stimulated fatty acid beta oxidation and promoted the metabolism of FFAs and TG. It also suppressed the expression of CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP), cysteine-containing aspartate-specific proteases 12 (Caspase 12), and glucose-regulated protein78 (GRP78), which reduced endoplasmic reticulum (ER) stress. Furthermore, Rg1 alleviated liver inflammation by inhibiting the activation of nucleotide binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) and thus reduced the production of inflammatory cytokines, such as interleukin 1-beta (IL-1β) and interleukin 18 (IL-18). These results suggested that Rg1 may protect against NAFLD, through regulation of lipid peroxidation, ER stress and inflammasome activation.
Dihydropyrimidinase is a member of the cyclic amidohydrolase family, which also includes allantoinase, dihydroorotase, hydantoinase, and imidase. These metalloenzymes possess very similar active ...sites and may use a similar mechanism for catalysis. However, whether the substrates and inhibitors of other cyclic amidohydrolases can inhibit dihydropyrimidinase remains unclear. This study investigated the inhibition of dihydropyrimidinase by flavonoids and substrates of other cyclic amidohydrolases. Allantoin, dihydroorotate, 5-hydantoin acetic acid, acetohydroxamate, orotic acid, and 3-amino-1,2,4-triazole could slightly inhibit dihydropyrimidinase, and the IC50 values of these compounds were within the millimolar range. The inhibition of dihydropyrimidinase by flavonoids, such as myricetin, quercetin, kaempferol, galangin, dihydromyricetin, and myricitrin, was also investigated. Some of these compounds are known as inhibitors of allantoinase and dihydroorotase. Although the inhibitory effects of these flavonoids on dihydropyrimidinase were substrate-dependent, dihydromyricetin significantly inhibited dihydropyrimidinase with IC50 values of 48 and 40 μM for the substrates dihydrouracil and 5-propyl-hydantoin, respectively. The results from the Lineweaver-Burk plot indicated that dihydromyricetin was a competitive inhibitor. Results from fluorescence quenching analysis indicated that dihydromyricetin could form a stable complex with dihydropyrimidinase with the K(d) value of 22.6 μM. A structural study using PatchDock showed that dihydromyricetin was docked in the active site pocket of dihydropyrimidinase, which was consistent with the findings from kinetic and fluorescence studies. This study was the first to demonstrate that naturally occurring product dihydromyricetin inhibited dihydropyrimidinase, even more than the substrate analogs (>3 orders of magnitude). These flavonols, particularly myricetin, may serve as drug leads and dirty drugs (for multiple targets) for designing compounds that target several cyclic amidohydrolases.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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•Novel magnetically separable Ag2O/ZnFe2O4 p-n heterostructure photocatalysts were fabricated.•Ag2O/ZnFe2O4 composites display outstanding photoactivity for BPA degradation under ...visible light irradiation.•The band offsets in p-n heterostructure play a central role in promoting charge separation and performance enhancement.•Ag2O/ZnFe2O4 composites bring new insights into the comprehension and fabrication of novel p-n heterostructure photocatalysts.
The fabrication of highly efficient catalysts with easy recyclability has received great attention in the development of realistic photocatalytic applications. Herein, a magnetically separable Ag2O/ZnFe2O4 p-n heterostructure photocatalyst was fabricated and utilized for the degradation of BPA under visible light irradiation. Results show that the obtained AZ-3 composite possesses the optimal performance, which is about 2.33-fold and 34.45-fold higher than that of Ag2O and ZnFe2O4, respectively. The enhanced performance is attributed to the rapid separation of photogenerated electrons and holes caused by the built-in electric field between p-type Ag2O and n-type ZnFe2O4, as detailedly evidenced by photoelectrochemical measurements. Moreover, density functional theory (DFT) calculations show that the electrons around the contact interface of Ag2O and ZnFe2O4 will be redistributed after their hybridization, while the investigation on energy band alignment further indicates that a type-II band alignment with ΔECBO = 0.16 eV and ΔEVBO = 0.65 eV is formed in this p-n heterostructure, which provides a solid support for the reaction mechanism. This work gives deep insights into the charge transfer properties of p-n heterostructure systems and opens new vistas for the construction of highly efficient and magnetically separable photocatalysts.
The generation of molecular chirality in the absence of any molecular chiral inductor is challenging and of fundamental interest for developing a better understanding of homochirality. Here, we show ...the manipulation of molecular chirality through control of the handedness of helical metal nanostructures (referred to as nanohelices) that are produced by glancing angle deposition onto a substrate that rotates in either a clockwise or counterclockwise direction. A prochiral molecule, 2-anthracenecarboxylic acid, is stereoselectively adsorbed on the metal nanohelices as enantiomorphous anti-head-to-head dimers. The dimers show either Si-Si or Re-Re facial stacking depending on the handedness of the nanohelices, which results in a specific enantiopreference during their photoinduced cyclodimerization: a left-handed nanohelix leads to the formation of (+)-cyclodimers, whereas a right-handed one gives (-)-cyclodimers. Density functional theory calculations, in good agreement with the experimental results, point to the enantioselectivity mainly arising from the selective spatial matching of either Si-Si or Re-Re facial stacking at the helical surface; it may also be influenced by chiroplasmonic effects.
Defects can greatly influence the properties of oxide materials; however, facile defect engineering of oxides at room temperature remains challenging. The generation of defects in oxides is difficult ...to control by conventional chemical reduction methods that usually require high temperatures and are time consuming. Here, we develop a facile room-temperature lithium reduction strategy to implant defects into a series of oxide nanoparticles including titanium dioxide (TiO
), zinc oxide (ZnO), tin dioxide (SnO
), and cerium dioxide (CeO
). Our lithium reduction strategy shows advantages including all-room-temperature processing, controllability, time efficiency, versatility and scalability. As a potential application, the photocatalytic hydrogen evolution performance of defective TiO
is examined. The hydrogen evolution rate increases up to 41.8 mmol g
h
under one solar light irradiation, which is ~3 times higher than that of the pristine nanoparticles. The strategy of tuning defect oxides used in this work may be beneficial for many other related applications.
5-Fluorouracil (5-FU) stands as one of the most widely prescribed chemotherapeutics. Despite over 60 years of study, a systematic synopsis of how 5-FU binds to proteins has been lacking. ...Investigating the specific binding patterns of 5-FU to proteins is essential for identifying additional interacting proteins and comprehending their medical implications. In this review, an analysis of the 5-FU binding environment was conducted based on available complex structures. From the earliest complex structure in 2001 to the present, two groups of residues emerged upon 5-FU binding, classified as P- and R-type residues. These high-frequency interactive residues with 5-FU include positively charged residues Arg and Lys (P type) and ring residues Phe, Tyr, Trp, and His (R type). Due to their high occurrence, 5-FU binding modes were simplistically classified into three types, based on interactive residues (within <4 Å) with 5-FU: Type 1 (P-R type), Type 2 (P type), and Type 3 (R type). In summary, among 14 selected complex structures, 8 conform to Type 1, 2 conform to Type 2, and 4 conform to Type 3. Residues with high interaction frequencies involving the N1, N3, O4, and F5 atoms of 5-FU were also examined. Collectively, these interaction analyses offer a structural perspective on the specific binding patterns of 5-FU within protein pockets and contribute to the construction of a structural interactome delineating the associations of the anticancer drug 5-FU.
Single-stranded DNA-binding proteins (SSBs) play a crucial role in DNA metabolism by binding and stabilizing single-stranded DNA (ssDNA) intermediates. Through their multifaceted roles in DNA ...replication, recombination, repair, replication restart, and other cellular processes, SSB emerges as a central player in maintaining genomic integrity. These attributes collectively position SSBs as essential guardians of genomic integrity, establishing interactions with an array of distinct proteins. Unlike Escherichia coli, which contains only one type of SSB, some bacteria have two paralogous SSBs, referred to as SsbA and SsbB. In this study, we identified Staphylococcus aureus SsbA (SaSsbA) as a fresh addition to the roster of the anticancer drug 5-fluorouracil (5-FU) binding proteins, thereby expanding the ambit of the 5-FU interactome to encompass this DNA replication protein. To investigate the binding mode, we solved the complexed crystal structure with 5-FU at 2.3 Å (PDB ID 7YM1). The structure of glycerol-bound SaSsbA was also determined at 1.8 Å (PDB ID 8GW5). The interaction between 5-FU and SaSsbA was found to involve R18, P21, V52, F54, Q78, R80, E94, and V96. Based on the collective results from mutational and structural analyses, it became evident that SaSsbA’s mode of binding with 5-FU diverges from that of SaSsbB. This complexed structure also holds the potential to furnish valuable comprehension regarding how 5-FU might bind to and impede analogous proteins in humans, particularly within cancer-related signaling pathways. Leveraging the information furnished by the glycerol and 5-FU binding sites, the complexed structures of SaSsbA bring to the forefront the potential viability of several interactive residues as potential targets for therapeutic interventions aimed at curtailing SaSsbA activity. Acknowledging the capacity of microbiota to influence the host’s response to 5-FU, there emerges a pressing need for further research to revisit the roles that bacterial and human SSBs play in the realm of anticancer therapy.
The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) afatinib improves survival in nonsmall cell lung cancer (NSCLC) patients with EGFR mutation. We analysed the outcome between ...EGFR mutation subtypes in a large afatinib‐treated cohort in which 516 EGFR‐mutated NSCLC patients receiving afatinib as front‐line treatment. EGFR uncommon mutations include exon 20 insertion, de novo T790M of high or low allele frequency (dT790MHAF/dT790MLAF), non‐T790M compound mutation and others, where EGFR exon 20 insertion and dT790MHAF were defined as type‐I and the rest as type‐II uncommon mutation. Four hundred and sixty‐one (89.3%) and 55 (10.7%) patients were common and uncommon mutation, respectively. Exon 20 insertion and dT790MHAF patients demonstrated a significantly shortened progression‐free survival (PFS) (2.6 and 4.1 months) compared to EGFR common mutation, dT790MLAF and other uncommon mutation patients (15.1, 27.0 and 18.4 months; P = 3 × 10−8). Type‐I uncommon mutation was an independent predictor of PFS (HR 4.46 95% CI, 2.60‐7.64; P < .001) and OS (HR 2.56 95% CI, 1.37‐4.75; P = .003). EGFR L858R patients demonstrated a significantly higher CNS progression (cause‐specific HR, 3.16; 95% CI 1.24‐8.08; P = .016), and type‐I uncommon mutation patients exhibited a significantly higher systemic progression (cause‐specific HR, 4.95; 95% CI 2.30‐10.60; P = 4.3 × 10−5). Tendencies of higher CNS and lower systemic progression were observed in type‐II uncommon mutation patients. A PFS ≥ 12 months (OR 2.38 95% CI, 1.18‐4.89; P = .016) and uncommon EGFR mutation (OR 0.08 95% CI, 0.01‐0.48; P = .021) were independent predictors of secondary T790M. Afatinib‐treated NSCLC patients presented an EGFR genotype‐specific pattern of disease progression and outcome.
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For patients with nonsmall cell lung cancer (NSCLC), epidermal growth factor tyrosine kinase inhibitors (EGFR‐TKIs) can significantly improve survival. EGFG‐TKI effectiveness, however, is compromised by acquired EGFR mutations, especially de novo T790M mutations. Here, the impact of EGFR genotypes on the efficacy of afatinib, a second‐generation EGFR‐TKI, was investigated in a cohort of EGFR‐mutated NSCLC patients. Afatinib efficacy was associated with T790M allele quantity in patients with de novo T790M mutation. In particular, front‐line afatinib therapy was associated with favourable survival in EGFR‐mutated patients, whereas resistance was marked by a genotype‐specific pattern of disease progression, with secondary T790M development.
Congenital heart defects (CHDs) has a multifactorial causation with a strong genetic component and many environmental triggers. Emerging body of empirical studies suggest that air pollution is an ...important contributor to the development of CHDs, however, there still remains some controversy over the current evidence, and to the authors’ knowledge, no studies have reviewed the most recent evidence.
We performed a systematic review and meta-analysis of epidemiological literature to investigate the relationship between maternal air pollution exposure and CHDs risk in offspring. The presence of heterogeneity and publication bias across available studies were also examined.
An extensive literature search of epidemiological studies pertaining to air pollution and CHDs, published in English language, until August 1, 2019 was conducted. Summary risk estimates of pollution–outcome combinations were calculated for i) risk per specific increment of concentration and ii) risk at high versus low exposure level in each study using fixed-effect model or random-effects model.
A total of 26 studies were finally included. In the meta-analyses, high versus low carbon monoxide (CO) exposure was associated with an increased risk of tetralogy of Fallot odds ratio (OR) = 1.21, 95% confidence interval (CI): 1.04–1.41, yet particulate matter ≤ 5 μm (PM2.5) exposure was marginally associated with it. Increased risk of atrial septal defects (ASDs) was found for each 10 μg/m3 and 10 ppb increment in particulate matter ≤ 10 μm (PM10) and ozone (O3) exposure, respectively (OR = 1.04, 95% CI: 1.00–1.09; OR = 1.09, 95% CI: 1.02–1.17). Categorical nitrogen dioxide (NO2) exposure was associated with an increased risk of coarctation of the aorta (OR for high versus low = 1.14, 95% CI: 1.02–1.26). Analyses for other combinations yielded none statistically significant associations. Sensitive analyses showed similar findings.
The summary effect estimates from this study suggest statistically significant associations between increased risk of specific CHDs subtypes and PM2.5, PM10, NO2, CO, and O3 exposures. Further studies, especially conducted in developing countries, with improvements in exposure assessing, outcome harmonizing, and mechanistic understanding are needed to elaborate the suggestive associations.
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•Whether maternal exposure to air pollution contributes to the development of CHDs in offspring is a controversial question.•We conducted a systematic review and meta-analysis of epidemiological studies investigating this question.•Twenty-six studies met our eligibility criteria and were included in our systematic review and meta-analysis.•Overall, there was notable variability in CHDs definitions, air pollution exposure assessment and confounder adjustment.•The study suggests significant associations between maternal air pollution exposure and increased risk of specific CHDs subtypes in offspring.
Capsule: Air pollutants exposure could increase the risk of specific CHDs subtypes.
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