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ABSTRACT The development of novel treatments for Staphylococcus aureus infections remains a high priority worldwide. We previously reported compounds 0147 and 0186, novel bacterial topoisomerase inhibitors (NBTIs) with potent antibacterial activity against S. aureus, including methicillin-resistant S. aureus. Here, we further investigated the in vitro activity of 0147 and 0186 against S. aureus ATCC 29213. Both compounds demonstrated bactericidal activity against planktonic and biofilm S. aureus, which then translated into significant inhibition of biofilm formation. Combinations of NBTIs and glycopeptides yielded indifferent interactions against planktonic S. aureus, but several had synergistic effects against S. aureus biofilms. This work reinforces the potential of NBTIs as future therapeutics for S. aureus infections. IMPORTANCE The pathogen Staphylococcus aureus contributes substantially to infection-related mortality. Biofilms render bacteria more recalcitrant to antibacterial therapy. The manuscript describes the potent activity of a new class of antibacterial agents against both planktonic and biofilm populations of Staphylococcus aureus.

Novel bacterial topoisomerase inhibitors (NBTIs) are an emerging class of antibacterials that target gyrase and topoisomerase IV. A hallmark of NBTIs is their ability to induce gyrase/topoisomerase IV-mediated single-stranded DNA breaks and suppress the generation of double-stranded breaks. However, a previous study reported that some dioxane-linked amide NBTIs induced double-stranded DNA breaks mediated by Staphylococcus aureus gyrase. To further explore the ability of this NBTI subclass to increase double-stranded DNA breaks, we examined the effects of OSUAB-185 on DNA cleavage mediated by Neisseria gonorrhoeae gyrase and topoisomerase IV. OSUAB-185 induced single-stranded and suppressed double-stranded DNA breaks mediated by N. gonorrhoeae gyrase. However, the compound stabilized both single- and double-stranded DNA breaks mediated by topoisomerase IV. The induction of double-stranded breaks does not appear to correlate with the binding of a second OSUAB-185 molecule and extends to fluoroquinolone-resistant N. gonorrhoeae topoisomerase IV, as well as type II enzymes from other bacteria and humans. The double-stranded DNA cleavage activity of OSUAB-185 and other dioxane-linked NBTIs represents a paradigm shift in a hallmark characteristic of NBTIs and suggests that some members of this subclass may have alternative binding motifs in the cleavage complex.

The study of NAD+ dependent ADP-ribosylation can be challenging. Here the authors report on the development of NAD+ analogues, using chemo-enzymatic methods, which can be used as probes to label the substrate proteins of poly-ADP-ribose polymerase.

Abstract Epstein-Barr virus (EBV) infects more than 95% of adults worldwide and is closely associated with various malignancies. Considering the complex life cycle of EBV, developing vaccines targeting key entry glycoproteins to elicit robust and durable adaptive immune responses may provide better protection. EBV gHgL-, gB- and gp42-specific antibodies in healthy EBV carriers contributed to sera neutralizing abilities in vitro, indicating that they are potential antigen candidates. To enhance the immunogenicity of these antigens, we formulate three nanovaccines by co-delivering molecular adjuvants (CpG and MPLA) and antigens (gHgL, gB or gp42). These nanovaccines induce robust humoral and cellular responses through efficient activation of dendritic cells and germinal center response. Importantly, these nanovaccines generate high levels of neutralizing antibodies recognizing vulnerable sites of all three antigens. IgGs induced by a cocktail vaccine containing three nanovaccines confer superior protection from lethal EBV challenge in female humanized mice compared to IgG elicited by individual NP-gHgL, NP-gB and NP-gp42. Importantly, serum antibodies elicited by cocktail nanovaccine immunization confer durable protection against EBV-associated lymphoma. Overall, the cocktail nanovaccine shows robust immunogenicity and is a promising candidate for further clinical trials.

Abstract Wound infection is a major factor affecting the speed and quality of wound healing. While hydrogen peroxide (H2O2) is recognized for its antibacterial capacity and facilitation of wound healing, its administration requires careful dosage differentiation. Inappropriately matched dosages can protract the healing of infected wounds. Herein, a calcium peroxide‐based hydrogel (CPO‐Alg hydrogel) is fabricated to enable a biphasic tapered release of H2O2, ensuring robust initial antimicrobial activity followed by sustained promotion of cellular proliferation of wound healing. The design of the hydrogel allowed for the calcium peroxide nanoparticles (CPO NPs) being in two spatial niches within the gel framework. When applied to infectious wounds, CPO NPs with weak constraints are promptly released out of the gel, penetrating into infected regions to serve as antibacterial agents that eliminate bacteria and biofilms at high concentrations. Conversely, the entrapped CPO NPs structurally integrated into the gel remain confined, thus gradually degrading and allowing a mild release of H2O2 through hydrolysis in a moist environment that contributes to the cell growth in the later stage. The CPO‐Alg hydrogel represents an innovative and practical solution for the antimicrobial protection of chronic wounds, offering promising prospects for advancing wound healing.

Epstein–Barr virus (EBV) infection has been related to multiple epithelial cancers and lymphomas. Current efforts in developing a prophylactic EBV vaccine have focused on inducing neutralizing antibodies. However, given the lifelong and persistent nature of EBV infection following primary infection, it is rationalized that an ideal vaccine should elicit both humoral and cellular immune responses targeting multiple stages of the EBV lifecycle. This study used a DNA vector and a TianTan vaccinia virus to express key EBV antigens, including BZLF1, EBNA1, EBNA3B, and gH/gL, to generate multi-antigen vaccines. The multi-antigen vaccine expressing all four antigens and the multi-antigen vaccine expressing BZLF1, EBNA1, and EBNA3B showed comparable protection effects and prevented 100% and 80% of humanized mice, respectively, from EBV-induced fatal B cell lymphoma by activating BZLF1, EBNA1, and EBNA3B specific T cell. The vaccine expressing lytic protein BZLF1 elicited stronger T cell responses and conferred superior protection compared to vaccines targeting single latent EBNA1 or EBNA3B. The vaccine solely expressing gH/gL exhibited no T cell protective effects in our humanized mice model. Our study implicates the potential of EBV vaccines that induce potent cellular responses targeting both latent and lytic phases of the EBV life cycle in the prevention of EBV-induced B cell lymphoma.

The hinterland of the Qinghai-Xizang （Tibet） Plateau is affected by two major circulation systems， Westerly Wind and Indian Ocean monsoon.The average altitude of the region is high， and the terrain is complex and changeable.It is extremely complicated that the temperature and precipitation conditions in this region as a comparison to other areas of the Qinghai-Xizang （Tibet） Plateau.In order to accurately obtain the temporal and spatial changes of temperature and precipitation in this region and predict future temperature and precipitation changes， based on the CN05.1 observation dataset， the ability of CMIP6 data to simulate temperature and precipitation in the hinterland of the Qinghai-Xizang （Tibet） Plateau was evaluated.CMIP6 was corrected using Spatial Disaggregation and Equidistant Cumulative Distribution Functions Method Temperature and precipitation conditions of 5 climate models and 7 scenarios in 2015-2100 were estimated.The results show that： （1） In the historical period （from 1961 to 2014）， the temperature and precipitation observation values of CMIP6 data have little deviation from the simulation values， and have strong space-time correlation.（2） In the future （from 2021 to 2100）， the annual average temperature and precipitation will show an overall upward trend.The percentage of temperature anomaly and precipitation anomaly in 2021-2100 of SSP3-7.0 and SSP5-8.5 scenarios increased significantly.The high value of temperatures anomaly is concentrated in the Qaidam Basin， and the high value of precipitation anomaly is located at the source of the Lancang River in the southeast.（3） In the future， the temperature will continue to increase in the four seasons， the precipitation will also show an overall trend of rise in four seasons.However， the degree of precipitation increase is distinct in different seasons and different scenarios.In the four seasons， the temperature increase of SSP5-8.5 scenario is the largest.The temperature of SSP5-8.5 scenario increases fastest in autumn； The precipitation of SSP3-7.0 scenario increases fastest in summer and winter， while that of SSP5-8.5 scenario increases fastest in spring and autumn.（4） Except for the SSP1-1.9 scenario， the temperature of each scenario from the recent period to the end of the period shows strong temporal and spatial similarity.Against to the historical period， the spatial distribution of temperature in spring and winter showed a consistently rising tendency is similar， and that in summer and autumn is similar.The precipitation increase is the largest in summer and the smallest in winter.Compared with the historical period， the spatial distribution of precipitation anomaly percentage shows a strong seasonality and regional feature.The high value area is mainly distributed in the southeast of the study area.

Epstein-Barr Virus (EBV) is closely linked to nasopharyngeal carcinoma (NPC), notably prevalent in southern China. Although type II latency of EBV plays a crucial role in the development of NPC, some lytic genes and intermittent reactivation are also critical for viral propagation and tumor progression. Since T cell-mediated immunity is effective in targeted killing of EBV-positive cells, it is important to identify EBV-derived peptides presented by highly prevalent human leukocyte antigen class I (HLA-I) molecules throughout the EBV life cycle. Here, we constructed an EBV-positive NPC cell model to evaluate the presentation of EBV lytic phase peptides on streptavidin-tagged specific HLA-I molecules. Utilizing a mass spectrometry (LC-MS/MS)-based immunopeptidomic approach, we characterized eleven novel EBV peptides as well as two previously identified peptides. Furthermore, we determined these peptides were immunogenic and could stimulate PBMCs from EBV VCA/NA-IgA positive donors in an NPC endemic southern Chinese population. Overall, this work demonstrates that highly prevalent HLA-I-specific EBV peptides can be captured and functionally presented to elicit immune responses in an in vitro model, which provides insight into the epitopes presented during EBV lytic cycle and reactivation. It expands the range of viral targets for potential NPC early diagnosis and treatment.