The receptor binding domain of SARS-CoV-2 Omicron subvariants targets Siglec-9 to decrease its immunogenicity by preventing macrophage phagocytosis.

The development of a vaccine specific to severe acute respiratory syndrome coronavirus 2 Omicron has been hampered due to its low immunogenicity. Here, using reverse mutagenesis, we found that a phenylalanine-to-serine mutation at position 375 (F375S) in the spike protein of Omicron to revert it to the sequence found in Delta and other ancestral strains significantly enhanced the immunogenicity of Omicron vaccines. Sequence FAPFFAF at position 371-377 in Omicron spike had a potent inhibitory effect on macrophage uptake of receptor-binding domain (RBD) nanoparticles or spike-pseudovirus particles containing this sequence. Omicron RBD enhanced binding to Siglec-9 on macrophages to impair phagocytosis and antigen presentation and promote immune evasion, which could be abrogated by the F375S mutation. A bivalent F375S Omicron RBD and Delta-RBD nanoparticle vaccine elicited potent and broad nAbs in mice, rabbits and rhesus macaques. Our research suggested that manipulation of the Siglec-9 pathway could be a promising approach to enhance vaccine response.

The ZAR1 resistosome is a calcium-permeable channel triggering plant immune signaling.

Nucleotide-binding, leucine-rich repeat receptors (NLRs) are major immune receptors in plants and animals. Upon activation, the Arabidopsis NLR protein ZAR1 forms a pentameric resistosome in vitro and triggers immune responses and cell death in plants. In this study, we employed single-molecule imaging to show that the activated ZAR1 protein can form pentameric complexes in the plasma membrane. The ZAR1 resistosome displayed ion channel activity in Xenopus oocytes in a manner dependent on a conserved acidic residue Glu11 situated in the channel pore. Pre-assembled ZAR1 resistosome was readily incorporated into planar lipid-bilayers and displayed calcium-permeable cation-selective channel activity. Furthermore, we show that activation of ZAR1 in the plant cell led to Glu11-dependent Ca2+ influx, perturbation of subcellular structures, production of reactive oxygen species, and cell death. The results thus support that the ZAR1 resistosome acts as a calcium-permeable cation channel to trigger immunity and cell death.

The FUS::DDIT3 fusion oncoprotein inhibits BAF complex targeting and activity in myxoid liposarcoma.

Mammalian SWI/SNF (mSWI/SNF or BAF) ATP-dependent chromatin remodeling complexes play critical roles in governing genomic architecture and gene expression and are frequently perturbed in human cancers. Transcription factors (TFs), including fusion oncoproteins, can bind to BAF complex surfaces to direct chromatin targeting and accessibility, often activating oncogenic gene loci. Here, we demonstrate that the FUS::DDIT3 fusion oncoprotein hallmark to myxoid liposarcoma (MLPS) inhibits BAF complex-mediated remodeling of adipogenic enhancer sites via sequestration of the adipogenic TF, CEBPB, from the genome. In mesenchymal stem cells, small-molecule inhibition of BAF complex ATPase activity attenuates adipogenesis via failure of BAF-mediated DNA accessibility and gene activation at CEBPB target sites. BAF chromatin occupancy and gene expression profiles of FUS::DDIT3-expressing cell lines and primary tumors exhibit similarity to SMARCB1-deficient tumor types. These data present a mechanism by which a fusion oncoprotein generates a BAF complex loss-of-function phenotype, independent of deleterious subunit mutations.

Spatiotemporal imaging of charge transfer in photocatalyst particles.

The water-splitting reaction using photocatalyst particles is a promising route for solar fuel production1-4. Photo-induced charge transfer from a photocatalyst to catalytic surface sites is key in ensuring photocatalytic efficiency5; however, it is challenging to understand this process, which spans a wide spatiotemporal range from nanometres to micrometres and from femtoseconds to seconds6-8. Although the steady-state charge distribution on single photocatalyst particles has been mapped by microscopic techniques9-11, and the charge transfer dynamics in photocatalyst aggregations have been revealed by time-resolved spectroscopy12,13, spatiotemporally evolving charge transfer processes in single photocatalyst particles cannot be tracked, and their exact mechanism is unknown. Here we perform spatiotemporally resolved surface photovoltage measurements on cuprous oxide photocatalyst particles to map holistic charge transfer processes on the femtosecond to second timescale at the single-particle level. We find that photogenerated electrons are transferred to the catalytic surface quasi-ballistically through inter-facet hot electron transfer on a subpicosecond timescale, whereas photogenerated holes are transferred to a spatially separated surface and stabilized through selective trapping on a microsecond timescale. We demonstrate that these ultrafast-hot-electron-transfer and anisotropic-trapping regimes, which challenge the classical perception of a drift-diffusion model, contribute to the efficient charge separation in photocatalysis and improve photocatalytic performance. We anticipate that our findings will be used to illustrate the universality of other photoelectronic devices and facilitate the rational design of photocatalysts.

Monocytes Release Pro-Cathepsin D to Drive Blood-to-Brain Transcytosis in Diabetes.

BACKGROUND: Microvascular complications are the major outcome of type 2 diabetes progression, and the underlying mechanism remains to be determined. METHODS: High-throughput RNA sequencing was performed using human monocyte samples from controls and diabetes. The transgenic mice expressing human CTSD (cathepsin D) in the monocytes was constructed using CD68 promoter. In vivo 2-photon imaging, behavioral tests, immunofluorescence, transmission electron microscopy, Western blot analysis, vascular leakage assay, and single-cell RNA sequencing were performed to clarify the phenotype and elucidate the molecular mechanism. RESULTS: Monocytes expressed high-level CTSD in patients with type 2 diabetes. The transgenic mice expressing human CTSD in the monocytes showed increased brain microvascular permeability resembling the diabetic microvascular phenotype, accompanied by cognitive deficit. Mechanistically, the monocytes release nonenzymatic pro-CTSD to upregulate caveolin expression in brain endothelium triggering caveolae-mediated transcytosis, without affecting the paracellular route of brain microvasculature. The circulating pro-CTSD activated the caveolae-mediated transcytosis in brain endothelial cells via its binding with low-density LRP1 (lipoprotein receptor-related protein 1). Importantly, genetic ablation of CTSD in the monocytes exhibited a protective effect against the diabetes-enhanced brain microvascular transcytosis and the diabetes-induced cognitive impairment. CONCLUSIONS: These findings uncover the novel role of circulatory pro-CTSD from monocytes in the pathogenesis of cerebral microvascular lesions in diabetes. The circulatory pro-CTSD is a potential target for the intervention of microvascular complications in diabetes.

DNA Damage Atlas: an atlas of DNA damage and repair.

DNA damage and its improper repair are the major source of genomic alterations responsible for many human diseases, particularly cancer. To aid researchers in understanding the underlying mechanisms of genome instability, a number of genome-wide profiling approaches have been developed to monitor DNA damage and repair events. The rapid accumulation of published datasets underscores the critical necessity of a comprehensive database to curate sequencing data on DNA damage and repair intermediates. Here, we present DNA Damage Atlas (DDA, http://www.bioinformaticspa.com/DDA/), the first large-scale repository of DNA damage and repair information. Currently, DDA comprises 6,030 samples from 262 datasets by 59 technologies, covering 16 species, 10 types of damage and 135 treatments. Data collected in DDA was processed through a standardized workflow, including quality checks, hotspots identification and a series of feature characterization for the hotspots. Notably, DDA encompasses analyses of highly repetitive regions, ribosomal DNA and telomere. DDA offers a user-friendly interface that facilitates browsing, searching, genome browser visualization, hotspots comparison and data downloading, enabling convenient and thorough exploration for datasets of interest. In summary, DDA will stand as a valuable resource for research in genome instability and its association with diseases.

Paternal USP26 mutations raise Klinefelter syndrome risk in the offspring of mice and humans.

Current understanding holds that Klinefelter syndrome (KS) is not inherited, but arises randomly during meiosis. Whether there is any genetic basis for the origin of KS is unknown. Here, guided by our identification of some USP26 variations apparently associated with KS, we found that knockout of Usp26 in male mice resulted in the production of 41, XXY offspring. USP26 protein is localized at the XY body, and the disruption of Usp26 causes incomplete sex chromosome pairing by destabilizing TEX11. The unpaired sex chromosomes then result in XY aneuploid spermatozoa. Consistent with our mouse results, a clinical study shows that some USP26 variations increase the proportion of XY aneuploid spermatozoa in fertile men, and we identified two families with KS offspring wherein the father of the KS patient harbored a USP26-mutated haplotype, further supporting that paternal USP26 mutation can cause KS offspring production. Thus, some KS should originate from XY spermatozoa, and paternal USP26 mutations increase the risk of producing KS offspring.

The impact of light and thioredoxins on the plant thiol-disulfide proteome.

Thiol-based redox regulation is a crucial posttranslational mechanism to acclimate plants to changing light availability. Here, we conducted a biotin switch-based redox proteomics study in Arabidopsis (Arabidopsis thaliana) to systematically investigate dynamics of thiol-redox networks in response to temporal changes in light availability and across genotypes lacking parts of the thioredoxin (Trx) or NADPH-Trx-reductase C (NTRC) systems in the chloroplast. Time-resolved dynamics revealed light led to marked decreases in the oxidation states of many chloroplast proteins with photosynthetic functions during the first 10 min, followed by their partial reoxidation after 2 to 6 h into the photoperiod. This involved f, m, and x-type Trx proteins showing similar light-induced reduction-oxidation dynamics, while NTRC, 2-Cys peroxiredoxins, and Trx y2 showed an opposing pattern, being more oxidized in light than dark. In Arabidopsis trxf1f2, trxm1m2, or ntrc mutants, most proteins showed increased oxidation states in the light compared to wild type, suggesting their light-dependent dynamics were related to NTRC/Trx networks. While NTRC deficiency had a strong influence in all light conditions, deficiencies in f- or m-type Trxs showed differential impacts on the thiol-redox proteome depending on the light environment, being higher in constant or fluctuating light, respectively. The results indicate plant redox proteomes are subject to dynamic changes in reductive and oxidative pathways to cooperatively fine-tune photosynthetic and metabolic processes in the light. The importance of the individual elements of the NTRC/Trx networks mediating these responses depend on the extent of light variability, with NTRC playing a crucial role to balance protein-redox states in rapidly fluctuating light.

METTL14 modulates glycolysis to inhibit colorectal tumorigenesis in p53-wild-type cells.

The frequency of p53 mutations in colorectal cancer (CRC) is approximately 40-50%. A variety of therapies are being developed to target tumors expressing mutant p53. However, potential therapeutic targets for CRC expressing wild-type p53 are rare. In this study, we show that METTL14 is transcriptionally activated by wild-type p53 and suppresses tumor growth only in p53-wild-type (p53-WT) CRC cells. METTL14 deletion promotes both AOM/DSS and AOM-induced CRC growth in mouse models with the intestinal epithelial cell-specific knockout of METTL14. Additionally, METTL14 restrains aerobic glycolysis in p53-WT CRC, by repressing SLC2A3 and PGAM1 expression via selectively promoting m6 A-YTHDF2-dependent pri-miR-6769b/pri-miR-499a processing. Biosynthetic mature miR-6769b-3p and miR-499a-3p decrease SLC2A3 and PGAM1 levels, respectively, and suppress malignant phenotypes. Clinically, METTL14 only acts as a beneficial prognosis factor for the overall survival of p53-WT CRC patients. These results uncover a new mechanism for METTL14 inactivation in tumors and, most importantly, reveal that the activation of METTL14 is a critical mechanism for p53-dependent cancer growth inhibition, which could be targeted for therapy in p53-WT CRC.

Carbon-Carbon Bond Cleavage for Late-Stage Functionalization.

Late-stage functionalization (LSF) introduces functional group or structural modification at the final stage of the synthesis of natural products, drugs, and complex compounds. It is anticipated that late-stage functionalization would improve drug discovery's effectiveness and efficiency and hasten the creation of various chemical libraries. Consequently, late-stage functionalization of natural products is a productive technique to produce natural product derivatives, which significantly impacts chemical biology and drug development. Carbon-carbon bonds make up the fundamental framework of organic molecules. Compared with the carbon-carbon bond construction, the carbon-carbon bond activation can directly enable molecular editing (deletion, insertion, or modification of atoms or groups of atoms) and provide a more efficient and accurate synthetic strategy. However, the efficient and selective activation of unstrained carbon-carbon bonds is still one of the most challenging projects in organic synthesis. This review encompasses the strategies employed in recent years for carbon-carbon bond cleavage by explicitly focusing on their applicability in late-stage functionalization. This review expands the current discourse on carbon-carbon bond cleavage in late-stage functionalization reactions by providing a comprehensive overview of the selective cleavage of various types of carbon-carbon bonds. This includes C-C(sp), C-C(sp2), and C-C(sp3) single bonds; carbon-carbon double bonds; and carbon-carbon triple bonds, with a focus on catalysis by transition metals or organocatalysts. Additionally, specific topics, such as ring-opening processes involving carbon-carbon bond cleavage in three-, four-, five-, and six-membered rings, are discussed, and exemplar applications of these techniques are showcased in the context of complex bioactive molecules or drug discovery. This review aims to shed light on recent advancements in the field and propose potential avenues for future research in the realm of late-stage carbon-carbon bond functionalization.

The structure and diversity of bacteria and fungi in the roots and rhizosphere soil of three different species of Geodorum.

Shepherd's crook (Geodorum) is a genus of protected orchids that are valuable both medicinally and ornamentally. Geodorum eulophioides (GE) is an endangered and narrowly distributed species, and Geodorum densiflorum (GD) and Geodorum attenuatum (GA) are widespread species. The growth of orchids depend on microorganisms. However, there are few studies on the microbial structure in Geodorum, and little is known about the roles of microorganisms in the endangered mechanism of G. eulophioides. This study analyzed the structure and composition of bacterial and fungal communities in the roots and rhizosphere soil of GE, GD, and GA. The results showed that Delftia, Bordetella and norank_f_Xanthobacteraceae were the dominant bacteria in the roots of Geodorum, while norank_f_Xanthobacteraceae, Gaiella and norank_f_norank_o_Gaiellales were the dominant bacteria in the rhizosphere soil of Geodorum. In the roots, the proportion of Mycobacterium in GD_roadside was higher than that in GD_understory, on the contrary, the proportion of Fusarium, Delftia and Bordetella in GD_roadside was lower than that in GD_understory. Compared with the GD_understory, the roots of GD_roadside had lower microbial diversity. In the endangered species GE, Russula was the primary fungus in the roots and rhizosphere soil, with fungal diversity lower than in the more widespread species. Among the widespread species, the dominant fungal genera in the roots and rhizosphere soil were Neocosmospora, Fusarium and Coprinopsis. This study enhances our understanding of microbial composition and diversity, providing fundamental information for future research on microbial contributions to plant growth and ecosystem function in Geodorum.

UCHL1 contributes to insensitivity to endocrine therapy in triple-negative breast cancer by deubiquitinating and stabilizing KLF5.

BACKGROUND: Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme that regulates ERα expression in triple-negative cancer (TNBC). This study aimed to explore the deubiquitination substrates of UCHL1 related to endocrine therapeutic responses and the mechanisms of UCHL1 dysregulation in TNBC. METHODS: Bioinformatics analysis was conducted using online open databases. TNBC representative MDA-MB-468 and SUM149 cells were used for in vitro and in-vivo studies. Co-immunoprecipitation was used to explore the interaction between UCHL1 and KLF5 and UCHL1-mediated KIF5 deubiquitination. CCK-8, colony formation and animal studies were performed to assess endocrine therapy responses. The regulatory effect of TET1/3 on UCHL1 promoter methylation and transcription was performed by Bisulfite sequencing PCR and ChIP-qPCR. RESULTS: UCHL1 interacts with KLF5 and stabilizes KLF5 by reducing its polyubiquitination and proteasomal degradation. The UCHL1-KLF5 axis collaboratively upregulates EGFR expression while downregulating ESR1 expression at both mRNA and protein levels in TNBC. UCHL1 knockdown slows the proliferation of TNBC cells and sensitizes the tumor cells to Tamoxifen and Fulvestrant. KLF5 overexpression partially reverses these trends. Both TET1 and TET3 can bind to the UCHL1 promoter region, reducing methylation of associated CpG sites and enhancing UCHL1 transcription in TNBC cell lines. Additionally, TET1 and TET3 elevates KLF5 protein level in a UCHL1-dependent manner. CONCLUSION: UCHL1 plays a pivotal role in TNBC by deubiquitinating and stabilizing KLF5, contributing to endocrine therapy resistance. TET1 and TET3 promote UCHL1 transcription through promoter demethylation and maintain KLF5 protein level in a UCHL1-dependent manner, implying their potential as therapeutic targets in TNBC.

Amyloid pathology mediates the associations between plasma fibrinogen and cognition in non-demented adults.

Though previous studies revealed the potential associations of elevated levels of plasma fibrinogen with dementia, there is still limited understanding regarding the influence of Alzheimer's disease (AD) biomarkers on these associations. We sought to investigate the interrelationships among fibrinogen, cerebrospinal fluid (CSF) AD biomarkers, and cognition in non-demented adults. We included 1996 non-demented adults from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study and 337 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The associations of fibrinogen with AD biomarkers and cognition were explored using multiple linear regression models. The mediation analyses with 10 000 bootstrapped iterations were conducted to explore the mediating effects of AD biomarkers on cognition. In addition, interaction analyses and subgroup analyses were conducted to assess the influence of covariates on the relationships between fibrinogen and AD biomarkers. Participants exhibiting low Aß42 were designated as A+, while those demonstrating high phosphorylated tau (P-tau) and total tau (Tau) were labeled as T+ and N+, respectively. Individuals with normal measures of Aß42 and P-tau were categorized as the A-T- group, and those with abnormal levels of both Aß42 and P-tau were grouped under A+T+. Fibrinogen was higher in the A+ subgroup compared to that in the A- subgroup (p = 0.026). Fibrinogen was higher in the A+T+ subgroup compared to that in the A-T- subgroup (p = 0.011). Higher fibrinogen was associated with worse cognition and Aß pathology (all p < 0.05). Additionally, the associations between fibrinogen and cognition were partially mediated by Aß pathology (mediation proportion range 8%-28%). Interaction analyses and subgroup analyses showed that age and ApoE ε4 affect the relationships between fibrinogen and Aß pathology. Fibrinogen was associated with both cognition and Aß pathology. Aß pathology may be a critical mediator for impacts of fibrinogen on cognition.

CCL4 contributes to aging related angiogenic insufficiency through activating oxidative stress and endothelial inflammation.

Aging is a natural process associated with chronic inflammation in the development of vascular dysfunction. We hypothesized that chemokine C-C motif ligands 4 (CCL4) might play a vital role in aging-related vascular dysfunction. Circulating CCL4 was up-regulated in elderly subjects and in aged animals. CCL4 inhibition reduced generation of reactive oxygen species (ROS), attenuated inflammation, and restored cell functions in endothelial progenitor cells from elderly subjects and in aged human aortic endothelial cells. CCL4 promoted cell aging, with impaired cell functioning, by activating ROS production and inflammation. CCL4 knockout mice and therapeutic administration of anti-CCL4 neutralizing antibodies exhibited vascular and dermal anti-aging effects, with improved wound healing, via the down-regulation of inflammatory proteins and the activation of angiogenic proteins. Altogether, our findings suggested that CCL4 may contribute to aging-related vascular dysfunction via activating oxidative stress and endothelial inflammation. CCL4 may be a potential therapeutic target for vascular protections during aging.

Heterologous overexpression of heat shock protein 20 genes of different species of yellow Camellia in Arabidopsis thaliana reveals their roles in high calcium resistance.

Yellow Camellia (Camellia sect. chrysantha) is a rare ornamental plant and an important germplasm resource globally. Camellia nitidissima thrives in normal acidic soils, while Camellia limonia can adapt to the calcareous soils found in karst areas. Our previous study on the karst adaptation of yellow camellias revealed that the expression levels of heat shock protein 20(HSP20) were higher in Camellia limonia than in Camellia nitidissima. However, the functions of the HSP20 gene of Camellia limonia remain unclear to data. In this study, the HSP20 genes of Camellia limonia (ClHSP20-OE lines) and Camellia. nitidissima (CnHSP20-OE lines) were cloned and overexpressed heterologously in Arabidopsis thaliana. Additionally, we overexpressed the HSP20 gene of Arabidopsis (AtHSP20-OE lines) was also overexpressed, and the T-DNA inserted mutants (athspmutant lines) were also used to determine the functions of HSP20 genes. Under high calcium stress, the chlorophyll, nitrogen, water content and humidity of leaves were increased in ClHSP20-OE lines, while those of other lines were declined. The size of the stomatal apertures, stomatal conductance, and the photosynthetic efficiency of ClHSP20-OE lines were higher than those of the other lines. However, the accumulation of H2O2 and O2- in the leaves of ClHSP20-OE lines was the lowest among all the lines. Energy spectrum scanning revealed that the percentage of calcium on the surfaces of the leaves of ClHSP20-OE lines was relatively low, while that of athspmutant lines was the highest. The ClHSP20 gene can also affected soil humidity and the contents of soil nitrogen, phosphorus, and potassium. Transcriptome analysis revealed that the expressions of FBA5 and AT5G10770 in ClHSP20-OE lines was significantly up-regulated compared to that of CnHSP20-OE lines. Compared to that of athspmutant lines, the expressions of DREB1A and AT3G30460 was significantly upregulated in AtHSP20-OE lines, and the expression of POL was down-regulated. Our findings suggest that the HSP20 gene plays a crucial role in maintained photosynthetic rate and normal metabolism by regulating the expression of key genes under high-calcium stress. This study elucidates the mechanisms underlying the karst adaptation in Camellia. limonia and provides novel insights for future research on karst plants.

Healthcare utilisation in people with long COVID: an OpenSAFELY cohort study.

BACKGROUND: Long COVID potentially increases healthcare utilisation and costs. However, its impact on the NHS remains to be determined. METHODS: This study aims to assess the healthcare utilisation of individuals with long COVID. With the approval of NHS England, we conducted a matched cohort study using primary and secondary care data via OpenSAFELY, a platform for analysing anonymous electronic health records. The long COVID exposure group, defined by diagnostic codes, was matched with five comparators without long COVID between Nov 2020 and Jan 2023. We compared their total healthcare utilisation from GP consultations, prescriptions, hospital admissions, A&E visits, and outpatient appointments. Healthcare utilisation and costs were evaluated using a two-part model adjusting for covariates. Using a difference-in-difference model, we also compared healthcare utilisation after long COVID with pre-pandemic records. RESULTS: We identified 52,988 individuals with a long COVID diagnosis, matched to 264,867 comparators without a diagnosis. In the 12 months post-diagnosis, there was strong evidence that those with long COVID were more likely to use healthcare resources (OR: 8.29, 95% CI: 7.74-8.87), and have 49% more healthcare utilisation (RR: 1.49, 95% CI: 1.48-1.51). Our model estimated that the long COVID group had 30 healthcare visits per year (predicted mean: 29.23, 95% CI: 28.58-29.92), compared to 16 in the comparator group (predicted mean visits: 16.04, 95% CI: 15.73-16.36). Individuals with long COVID were more likely to have non-zero healthcare expenditures (OR = 7.66, 95% CI = 7.20-8.15), with costs being 44% higher than the comparator group (cost ratio = 1.44, 95% CI: 1.39-1.50). The long COVID group costs approximately £2500 per person per year (predicted mean cost: £2562.50, 95% CI: £2335.60-£2819.22), and the comparator group costs £1500 (predicted mean cost: £1527.43, 95% CI: £1404.33-1664.45). Historically, individuals with long COVID utilised healthcare resources more frequently, but their average healthcare utilisation increased more after being diagnosed with long COVID, compared to the comparator group. CONCLUSIONS: Long COVID increases healthcare utilisation and costs. Public health policies should allocate more resources towards preventing, treating, and supporting individuals with long COVID.

Advances of Strategies to Increase the Surface Charge Density of Triboelectric Nanogenerators: A Review.

Triboelectric nanogenerators (TENGs) have manifested a remarkable potential for harvesting environmental energy and have the prospects to be utilized for various uses, for instance, self-powered sensing devices, flexible wearables, and marine corrosion protection. However, the potential for further development of TENGs is restricted on account of their low output power that in turn is determined by their surface charge density. The current review majorly focuses on the selection and optimization of triboelectric materials. Subsequently, various methods capable of enhancing the surface charge density of TENGs, including environmental regulation, charge excitation, charge pumping, electrostatic breakdown, charge trapping, and liquid-solid structure are comprehensively reviewed. Lastly, the review is concluded by highlighting the existing challenges in enhancing the surface charge density of TENGs and exploring potential opportunities for future research endeavors in this area.

Chimeric virus-like particles of human norovirus constructed by structure-guided epitope grafting elicit cross-reactive immunity against both GI.1 and GII.4 genotypes.

IMPORTANCE: Human norovirus (HuNoV) is highly infectious and can result in severe illnesses in the elderly and children. So far, there is no effective antiviral drug to treat HuNoV infection, and thus, the development of HuNoV vaccines is urgent. However, NoV evolves rapidly, and currently, at least 10 genogroups with numerous genotypes have been found. The genetic diversity of NoV and the lack of cross-protection between different genotypes pose challenges to the development of broadly protective vaccines. In this study, guided by structural alignment between GI.1 and GII.4 HuNoV VP1 proteins, several chimeric-type virus-like particles (VLPs) were designed through surface-exposed loop grafting. Mouse immunization studies show that two of the designed chimeric VLPs induced cross-immunity against both GI.1 and GII.4 HuNoVs. To our knowledge, this is the first designed chimeric VLPs that can induce cross-immune activities across different genogroups of HuNoV, which provides valuable strategies for the development of cross-reactive HuNoV vaccines.

Hepatic mitochondrial NAD + transporter SLC25A47 activates AMPKα mediating lipid metabolism and tumorigenesis.

BACKGROUND AIMS: SLC25A47 was initially identified as a mitochondrial HCC-downregulated carrier protein, but its physiological functions and transport substrates are unknown. We aimed to investigate the physiological role of SLC25A47 in hepatic metabolism. APPROACH RESULTS: In the treatment of hepatocytes with metformin, we found that metformin can transcriptionally activate the expression of Slc25a47 , which is required for AMP-activated protein kinase α (AMPKα) phosphorylation. Slc25a47 -deficient mice had increased hepatic lipid content, triglycerides, and cholesterol levels, and we found that Slc25a47 deficiency suppressed AMPKα phosphorylation and led to an increased accumulation of nuclear SREBPs, with elevated fatty acid and cholesterol biosynthetic activities. Conversely, when Slc25a47 was overexpressed in mouse liver, AMPKα was activated and resulted in the inhibition of lipogenesis. Moreover, using a diethylnitrosamine-induced mouse HCC model, we found that the deletion of Slc25a47 promoted HCC tumorigenesis and development through the activated mammalian target of rapamycin cascade. Employing homology modeling of SLC25A47 and virtual screening of the human metabolome database, we demonstrated that NAD + was an endogenous substrate for SLC25A47, and the activity of NAD + -dependent sirtuin 3 declined in Slc25a47 -deficient mice, followed by inactivation of AMPKα. CONCLUSIONS: Our findings reveal that SLC25A47, a hepatocyte-specific mitochondrial NAD + transporter, is one of the pharmacological targets of metformin and regulates lipid homeostasis through AMPKα, and may serve as a potential drug target for treating NAFLD and HCC.

Epidemiological characteristics and antibody kinetics of elderly population with booster vaccination following both Omicron BA.5 and XBB waves in China.

After the termination of zero-COVID-19 policy, the populace in China has experienced both Omicron BA.5 and XBB waves. Considering the poor antibody responses and severe outcomes observed among the elderly following infection, we conducted a longitudinal investigation to examine the epidemiological characteristics and antibody kinetics among 107 boosted elderly participants following the Omicron BA.5 and XBB waves. We observed that 96 participants (89.7%) were infected with Omicron BA.5, while 59 (55.1%) participants were infected with Omicron XBB. Notably, 52 participants (48.6%) experienced dual infections of both Omicron BA.5 and XBB. The proportion of symptomatic cases appeared to decrease following the XBB wave (18.6%) compared to that after the BA.5 wave (59.3%). Omicron BA.5 breakthrough infection induced lower neutralizing antibody titers against XBB.1.5, BA.2.86, and JN.1, while reinfection with Omicron XBB broadened the antibody responses against all measured Omicron subvariants and may alleviate the wild type-vaccination induced immune imprinting. Boosted vaccination type and comorbidities were the significant factors associated with antibody responses. Updated vaccines based on emerging severe acute respiratory syndrome coronavirus 2 variants are needed to control the Coronavirus Disease 2019 pandemic in the elderly.