Structural and functional characterizations of infectivity and immune evasion of SARS-CoV-2 Omicron.

The SARS-CoV-2 Omicron variant with increased fitness is spreading rapidly worldwide. Analysis of cryo-EM structures of the spike (S) from Omicron reveals amino acid substitutions forging interactions that stably maintain an active conformation for receptor recognition. The relatively more compact domain organization confers improved stability and enhances attachment but compromises the efficiency of the viral fusion step. Alterations in local conformation, charge, and hydrophobic microenvironments underpin the modulation of the epitopes such that they are not recognized by most NTD- and RBD-antibodies, facilitating viral immune escape. Structure of the Omicron S bound with human ACE2, together with the analysis of sequence conservation in ACE2 binding region of 25 sarbecovirus members, as well as heatmaps of the immunogenic sites and their corresponding mutational frequencies, sheds light on conserved and structurally restrained regions that can be used for the development of broad-spectrum vaccines and therapeutics.

Convergent evolution of SARS-CoV-2 XBB lineages on receptor-binding domain 455-456 synergistically enhances antibody evasion and ACE2 binding.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) XBB lineages have achieved dominance worldwide and keep on evolving. Convergent evolution of XBB lineages on the receptor-binding domain (RBD) L455F and F456L is observed, resulting in variants with substantial growth advantages, such as EG.5, FL.1.5.1, XBB.1.5.70, and HK.3. Here, we show that neutralizing antibody (NAb) evasion drives the convergent evolution of F456L, while the epistatic shift caused by F456L enables the subsequent convergence of L455F through ACE2 binding enhancement and further immune evasion. L455F and F456L evade RBD-targeting Class 1 public NAbs, reducing the neutralization efficacy of XBB breakthrough infection (BTI) and reinfection convalescent plasma. Importantly, L455F single substitution significantly dampens receptor binding; however, the combination of L455F and F456L forms an adjacent residue flipping, which leads to enhanced NAbs resistance and ACE2 binding affinity. The perturbed receptor-binding mode leads to the exceptional ACE2 binding and NAb evasion, as revealed by structural analyses. Our results indicate the evolution flexibility contributed by epistasis cannot be underestimated, and the evolution potential of SARS-CoV-2 RBD remains high.

Metagenomic insights into comparative study of nitrogen metabolic potential and microbial community between primitive and urban river sediments.

As a result of anthropogenic pollution, the nitrogen nutrients load in urban rivers has increased, potentially raising the risk of river eutrophication. Here, we studied how anthropogenic impacts alter nitrogen metabolism in river sediments by comparing the metagenomic function of microbial communities between relatively primitive and human-disturbed sediments. The contents of organic matter (OM), total nitrogen (TN), NO3--N and NO2--N were higher in primitive site than in polluted sites, which might be due to vegetation density, sediment type, hydrology, etc. Whereas, NH4+-N content was higher in midstream and downstream, indicating that nitrogen loading increased in the anthropogenic regions and subsequently leading higher NH4+-N. Hierarchical cluster analyses revealed significant changes in the community structure and functional potential between the primitive and human-affected sites. Metagenomic analysis demonstrated that Demequina, Streptomyces, Rubrobacter and Dechloromonas were the predominant denitrifiers. Ardenticatena and Dechloromonas species were the most important contributors to dissimilatory nitrate reduction. Furthermore, anthropogenic pollution significantly increased their abundance, and resulting in a decrease in NO3-, NO2--N and an increase in NH4+-N contents. Additionally, the SOX metabolism of Dechloromonas and Sulfuritalea may involve in the sulfur-dependent autotrophic denitrification process by coupling the conversion of thiosulfate to sulfate with the reduction of NO3--N to N2. From pristine to anthropogenic pollution sediments, the major nitrifying bacteria harboring Hao transitioned from Nitrospira to Nitrosomonas. This study sheds light on the consequences of anthropogenic activities on nitrogen metabolism in river sediments, allowing for better management of nitrogen pollution and eutrophication in river.

Mitochondrial changes in fish cells in vitro in response to serum deprivation.

Mitochondria are critical to cellular activity that implicated in expansive networks to maintain organismal homeostasis under external stimuli of nutrient variability, a common and severe stress to fish performance during the intensive culture conditions. In the present study, zebrafish embryonic fibroblast cells were used to investigate the fish mitochondrial changes upon serum deprivation. Results showed that mitochondrial content and membrane potential were significantly reduced with increased intracellular ROS level in the serum deprivation treated fish cells. And the impaired mitochondria were characterized by rough and fracted outer membrane, and more fused mitochondria were frequently observed with the upregulated mRNA expressions of mitochondrial fusion genes (mfn1b, mfn2, and opa1). Besides, the mitochondrial DNA (mtDNA) copy numbers of mtatp6, mtcox1, mtcytb, mtnd4, and mtnd6 were overall showing the highly significant reduction, together with the mRNA expressions of these genes significantly increased, exhibiting the compensatory effects in mitochondria. Furthermore, the methyl-cytosine of whole mtDNA was compared and the methyl-reads numbers were distinctly increased in the treatment group, reflecting the instability of fish mtDNA with mitochondrial dysfunction under nutrient fluctuations. Collectively, current findings could facilitate the integrated research between fish mitochondrial response and external variables that indicates the potentially profound and durative deficits in fish health during the aquaculture processes.

Multisite Mutation of the Escherichia coli cAMP Receptor Protein: Enhancing Xylitol Biosynthesis by Activating Xylose Catabolism and Improving Strain Tolerance.

The bioproduction of xylitol from hemicellulose hydrolysate has good potential for industrial development. However, xylitol productivity has always been limited due to corncob hydrolysate toxicity and glucose catabolic repression. To address these challenges, this work selected the S83 and S128 amino acid residues of the cyclic AMP receptor protein (CRP) as the modification target. By introducing multisite mutation in CRP, this approach successfully enhanced xylose catabolism and improved the strain's tolerance to corncob hydrolysate. The resulting mutant strain, designated as CPH (CRP S83H-S128P), underwent fermentation in a 20 L bioreactor with semicontinuous feeding of corncob hydrolysate. Remarkably, xylitol yield and xylitol productivity for 41 h fermentation were 175 and 4.32 g/L/h, respectively. Therefore, multisite CRP mutation was demonstrated as an efficient global regulatory strategy to effectively improve xylitol productivity from lime-pretreated corncob hydrolysates.

Comparing T- and B-cell responses to COVID-19 vaccines across varied immune backgrounds.

The emergence of adapted variants of the SARS-CoV-2 virus has led to a surge in breakthrough infections worldwide. A recent analysis of immune responses in people who received inactivated vaccines has revealed that individuals with no prior infection have limited resistance to Omicron and its sub-lineages, while those with previous infections exhibit a significant amount of neutralizing antibodies and memory B cells. However, specific T-cell responses remain largely unaffected by the mutations, indicating that T-cell-mediated cellular immunity can still provide protection. Moreover, the administration of a third dose of vaccine has resulted in a marked increase in the spectrum and duration of neutralizing antibodies and memory B cells in vivo, which has enhanced resistance to emerging variants such as BA.2.75 and BA.2.12.1. These results highlight the need to consider booster immunization for previously infected individuals and the development of novel vaccination strategies. The rapid spread of adapted variants of the SARS-CoV-2 virus presents a significant challenge to global health. The findings from this study underscore the importance of tailoring vaccination strategies based on individual immune backgrounds and the potential need for booster shots to combat emerging variants. Continued research and development are crucial to discovering new immunization strategies that will effectively protect public health against the evolving virus.

Comparative genomic analysis reveals the evolution and environmental adaptation of Acinetobacter johnsonii.

Genome plasticity is a key determinant that Acinetobacter johnsonii could widely distribute in natural and clinical environments. However, little attention has been paid to figure out the changes in the genome during A. johnsonii's evolution. Here, a comparative genomic analysis of A. johnsonii isolated from clinical and environmental sources was conducted. In this study, we found A. johnsonii has an open pan-genome and has great adaptability to different environments. Based on the results of the phylogenetic tree, ANI value and the distribution of accessory genes, we found that strains from the same habitat had a high degree of similarity. Though genes associated with the fundamental process were mostly conserved in evolution, clinical-derived isolates accumulate more genes associated with translational modification, ß-lactamase and defense mechanisms, whereas environmental-derived isolates enriched more genes related to substances degradation. In addition, clinical-derived strains harbored some "strong" virulence islands and resistance islands. This study highlights the evolutionary relationship of A. johnsonii isolates from clinical and environmental sources.

Identification of dibucaine derivatives as novel potent enterovirus 2C helicase inhibitors: In vitro, in vivo, and combination therapy study.

Enterovirus A71 (EV-A71) is a human pathogen causing hand, foot and mouth disease (HFMD) which seriously threatened the safety and lives of infants and young children. However, there are no licensed direct antiviral agents to cure the HFMD. In this study, a series of quinoline formamide analogues as effective enterovirus inhibitors were developed, subsequent systematic structure-activity relationship (SAR) studies demonstrated that these quinoline formamide analogues exhibited good potency to treat EV-A71 infection. As described, the most efficient EV-A71 inhibitor 6i showed good anti-EV-A71 activity (EC50 = 1.238 µM) in RD cells. Furthermore, compound 6i could effectively prevent death of virus infected mice at dose of 6 mg/kg. When combined with emetine (0.1 mg/kg), this treatment could completely prevent the clinical symptoms and death of virus infected mice. Mechanism study indicated that compound 6i inhibited EV-A71 via targeting 2C helicase, thus impeding RNA remodeling and metabolism. Taken together, these data indicated that 6i is a promising EV-A71 inhibitor and worth extensive preclinical investigation as a lead compound.

Inverse Relationship Between Coarse Food Grain Intake and Blood Pressure Among Young Chinese Adults.

BACKGROUND: Coarse food grains are rich in dietary fiber and contain a wide range of nutrients with potential health benefits, such as blood pressure control. Coarse food grains are very popular in China, where hypertension is a major challenge. We evaluated the associations between coarse food grain consumption and blood pressure among young Chinese adults. METHODS: A total of 104 men and women aged 18-35 years, who participated in a pilot study of the Carbohydrate Alternatives and Metabolic Phenotypes study, were included in the present analysis. Food frequency questionnaires were used to collect dietary intake data. Blood pressure was measured using a digital monitor. A multivariate general linear model was used to evaluate the putative associations. RESULTS: Overall, 12.5% of our participants have regular habits of coarse food grain intake (at least 4 days/week). Age was positively associated with both systolic blood pressure (SBP) and diastolic blood pressure (DBP) (all Ps for trend < 0.05). With multivariable adjustment, including for body mass index and physical activity level, the frequency of coarse food grain intake was inversely associated with both SBP and DBP (all Ps for trend < 0.05). Similar associations were observed for estimated daily coarse food grain intake with SBP (ß coefficient ± SE = -0.039 ± 0.017, P = 0.024) and DBP (ß coefficient ± SE = -0.033 ± 0.013, P = 0.016). CONCLUSIONS: In our sample of young Chinese adults, higher coarse food grain intake was associated with lower SBP and DBP.