Loss of UBE2S causes meiosis I arrest with normal spindle assembly checkpoint dynamics in mouse oocytes.

The timely degradation of proteins that regulate the cell cycle is essential for oocyte maturation. Oocytes are equipped to degrade proteins via the ubiquitin-proteasome system. In meiosis, anaphase promoting complex/cyclosome (APC/C), an E3 ubiquitin-ligase, is responsible for the degradation of proteins. Ubiquitin-conjugating enzyme E2 S (UBE2S), an E2 ubiquitin-conjugating enzyme, delivers ubiquitin to APC/C. APC/C has been extensively studied, but the functions of UBE2S in oocyte maturation and mouse fertility are not clear. In this study, we used Ube2s knockout mice to explore the role of UBE2S in mouse oocytes. Ube2s-deleted oocytes were characterized by meiosis I arrest with normal spindle assembly and spindle assembly checkpoint dynamics. However, the absence of UBE2S affected the activity of APC/C. Cyclin B1 and securin are two substrates of APC/C, and their levels were consistently high, resulting in the failure of homologous chromosome separation. Unexpectedly, the oocytes arrested in meiosis I could be fertilized and the embryos could become implanted normally, but died before embryonic day 10.5. In conclusion, our findings reveal an indispensable regulatory role of UBE2S in mouse oocyte meiosis and female fertility.

Restoration of CD3+CD56+ NKT-like cell function by TIGIT blockade in inactive carrier and immune tolerant patients of chronic hepatitis B virus infection.

Chronic hepatitis B (CHB) virus infection, which can be divided into immune-tolerant (IT), immune-active (IA), inactive carrier (IC) phases, and HBeAg-negative hepatitis (ENEG), can induce liver cirrhosis and eventually hepatocellular carcinoma (HCC). CD3+CD56+ NKT-like cells play an important role in antiviral immune response. However, the mechanism of NKT-like cells to mediate immune tolerance remains largely elusive. In this study, we observed circulating NKT-like cells from IC and IT CHB patients were phenotypically and functionally impaired, manifested by increased expression of inhibitory receptor TIGIT and decreased capacity of secreting antiviral cytokines. Besides, TIGIT+ NKT-like cells of IC and IT CHB patients expressed lower levels of cytotoxic cytokines than the TIGIT- subset. Furthermore, increased expression of CD155, the ligand of TIGIT, on plasmacytoid dendritic cells (pDCs) was detected in IC and IT CHB patients. Importantly, the co-culture of NKT-like cells and pDCs showed that NKT-like cells restored their antiviral ability after TIGIT blockade upon HBV peptide stimulation in IC and IT CHB patients. In conclusion, our findings suggest that the TIGIT pathway may mediate immune tolerance in IT CHB patients and lead to functional impairment in IC patients, indicating that TIGIT may be a potential therapeutic checkpoint for immunotherapy of CHB patients.

Phenotypic and functional exhaustion of circulating CD3+ CD56+ NKT-like cells in colorectal cancer patients.

CD3+ CD56+ NKT-like cells are crucial to antitumor immune surveillance and defense. However, research on circulating NKT-like cells in colorectal cancer (CRC) patients is limited. This investigation selected 113 patients diagnosed with primary CRC for preoperative peripheral blood collection. The blood from 106 healthy donors at the physical examination center was acquired as a healthy control (HC). The distribution of lymphocyte subsets, immunophenotype, and functional characteristics of NKT-like cells was comprehensively evaluated. Compared to HC, primary CRC patients had considerably fewer peripheral NKT-like cells in frequency and absolute quantity, and the fraction of NKT-like cells was further reduced in patients with vascular invasion compared to those without. The NKT-like cells in CRC patients had a reduced fraction of the activating receptor CD16, up-regulated expression of inhibitory receptors LAG-3 and NKG2A, impaired production of TNF-α and IFN-γ, as well as degranulation capacity. Moreover, the increased frequency of NKG2A+ NKT-like cells and the decreased expression of activation-related molecules were significantly correlated with tumor progression. In detail, NKG2A+ NKT-like cells indicated increased PD-1 and Tim-3 and reduced TNF-α than NKG2A- subgroup. Blocking NKG2A in vitro restored cytokine secretion capacity in NKT-like cells from CRC patients. Altogether, this research revealed that circulating NKT-like cells in CRC patients exhibited suppressive phenotype and functional impairment, which was more pronounced in NKG2A+ NKT-like cells. These findings suggest that NKG2A blockade may restore anti-tumor effector function in NKT-like cells, which provides a potential target for immunotherapy in CRC patients.

Electrocatalytic Generation of Singlet Oxygen via ROS-Mediated Redox Chain Reaction for Efficient Disinfection.

The risk of harmful microorganisms to ecosystems and human health has stimulated exploration of singlet oxygen (1O2)-based disinfection. It can be potentially generated via an electrocatalytic process, but is limited by the low production yield and unclear intermediate-mediated mechanism. Herein, we designed a two-site catalyst (Fe/Mo-N/C) for the selective 1O2 generation. The Mo sites enhance the generation of 1O2 precursors (H2O2), accompanied by the generation of intermediate •HO2/•O2-. The Fe site facilitates activation of H2O2 into •OH, which accelerates the •HO2/•O2- into 1O2. A possible mechanism for promoting 1O2 production through the ROS-mediated chain reaction is reported. The as-developed electrochemical disinfection system can kill 1 × 107 CFU mL-1 of E. coli within 8 min, leading to cell membrane damage and DNA degradation. It can be effectively applied for the disinfection of medical wastewater. This work provides a general strategy for promoting the production of 1O2 through electrocatalysis and for efficient electrochemical disinfection.

Reversible Fusion-Fission MXene Fiber-Based Microelectrodes for Target-Specific Gram-Positive and Gram-Negative Bacterium Discrimination.

Inaccurate or cumbersome clinical pathogen diagnosis between Gram-positive bacteria (G+) and Gram-negative (G-) bacteria lead to delayed clinical therapeutic interventions. Microelectrode-based electrochemical sensors exhibit the significant advantages of rapid response and minimal sample consumption, but the loading capacity and discrimination precision are weak. Herein, we develop reversible fusion-fission MXene-based fiber microelectrodes for G+/G- bacteria analysis. During the fissuring process, the spatial utilization, loading capacity, sensitivity, and selectivity of microelectrodes were maximized, and polymyxin B and vancomycin were assembled for G+/G- identification. The surface-tension-driven reversible fusion facilitated its reusability. A deep learning model was further applied for the electrochemical impedance spectroscopy (EIS) identification in diverse ratio concentrations of G+ and G- of (1:100-100:1) with higher accuracy (>93%) and gave predictable detection results for unknown samples. Meanwhile, the as-proposed sensing platform reached higher sensitivity toward E. coli (24.3 CFU/mL) and S. aureus (37.2 CFU/mL) in 20 min. The as-proposed platform provides valuable insights for bacterium discrimination and quantification.

Controllable Silver Release for Efficient Treatment of Drug-Resistant Bacterial-Infected Wounds.

The use of traditional Ag-based antibacterial agents is usually accompanied by uncontrollable silver release, which makes it difficult to find a balance between antibacterial performance and biosafety. Herein, we prepared a core-shell system of ZIF-8-derived amorphous carbon-coated Ag nanoparticles (Ag@C) as an ideal research model to reveal the synergistic effect and structure-activity relationship of the structural transformation of carbon shell and Ag core on the regulation of silver release behavior. It is found that Ag@C prepared at 600 °C (AC6) exhibits the best ion release kinetics due to the combination of relatively simple shell structure and lower crystallinity of the Ag core, thereby exerting stronger antibacterial properties (>99.999 %) at trace doses (20 µg mL-1) compared with most other Ag-based materials. Meanwhile, the carbon shell prevents the metal Ag from being directly exposed to the organism and thus endows AC6 with excellent biocompatibility. In animal experiments, AC6 can effectively promote wound healing by inactivating drug-resistant bacteria while regulating the expression of TNF-α and CD31. This work provides theoretical support for the scientific design and clinical application of controllable ion-releasing antibacterial agents.

Carbon dots for staining bacterial dead cells and distinguishing dead/alive bacteria.

The small molecular dyes such as propidium iodide (PI) always suffer from photo-bleaching and potential toxicity. To tackle the problems, a type of nontoxic carbon dots (CDs) was obtained for dead/alive bacterial distinguishing. This kind of carbon dots has an average size of 1.91 nm and owns carboxyl groups, emerging as excellent candidates for imaging bacterial cells. The negative charges of carboxyl groups lead their avoidance of alive cells while their small size facilitates penetration of dead cells. This kind of nontoxic CDs has effectively differentiated between and alive ones, presenting a highly promising green dye comparing with traditional small molecular dyes.

CD8+ T cells mediate antiviral response in severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS), which is caused by a novel Bunyavirus, has gradually become a threatening infectious disease in rural areas of Asia. Studies have identified a severe cytokine storm and impaired humoral immune response in SFTS. However, the cellular immune response to SFTS virus (SFTSV) infection remains largely unknown. Here we report that SFTS patients had a cytokine storm accompanied by high levels of chemokines. CD8+ T cells in peripheral blood mononuclear cells of SFTS patients exhibited a more activated phenotype and enhanced the antiviral responses. They increased the expression of CD69 and CD25, secreted a higher level of IFN-γ and granzyme, and had a stronger proliferative ability than in healthy controls. In convalescent SFTS patients, the expression of CD69 and CD25 on CD8+ T cells was reduced. In addition, we found the ratio and cellularity of CD14+ CD16+ intermediate monocytes were increased in peripheral blood of SFTS patients. Both the expression of C-X-C motif chemokine ligand 10 (CXCL10) on CD14+ CD16+ intermediate monocytes and the expression of C-X-C motif chemokine receptor 3 (CXCR3) on CD8+ T cells increased dramatically in SFTS patients. Our studies reveal a potential pathway that CD8+ T cells rapidly activate and are mostly recruited by intermediate monocytes through CXCL10 in SFTSV infection. Our results may be of clinical relevance for further treatment and discharge instructions in SFTSV infections.

Single substrate-functionalized molybdenum oxide nanozyme for specific colorimetric monitoring of xanthine oxidase activity.

Xanthine-functionalized molybdenum oxide nanodots (X-MoO3-x NDs) with peroxidase (POD)-like activity were developed for selective, sensitive, and facile colorimetric quantification of xanthine oxidase (XO). Xanthine functionalization can not only be favorable for the successful nanozyme preparation, but also for the specific recognition of XO as well as the simultaneous generation of hydrogen peroxide, which was subsequently transformed into hydroxyl radical to oxidize the chromogenic reagent based on the POD-like catalysis. Under the optimized conditions, the colorimetric biosensing platform was established for XO assay without addition of further substrates, showing good linearity relationship between absorbance difference (ΔA) and XO concentrations in the range 0.05-0.5 U/mL (R2 = 0.998) with a limit of detection (LOD) of 0.019 U/mL. The quantification of XO occurs in 25 min, which is superior to the previously reported and commercial XO assays. The proposed method has been successfully used in the assay of human serum samples, showing its high potential in the field of clinical monitoring.

Synthesis of γ-Cyclodextrin-Reduced Fe(III) Nanoparticles with Peroxidase-like Catalytic Activity for Bacteriostasis of Food.

Foodborne pathogens are a primary cause of human foodborne illness, making it imperative to explore novel antibacterial strategies for their control. In this study, Fe-γ-CD was successfully synthesized as a food antibacterial agent for use in milk and orange juice. The Fe-γ-CD consists of 6/11 Fe(II) and 5/11 Fe(III), which catalyze a Fenton-like catalytic reaction with H2O2 to generate •OH. Consequently, Fe-γ-CD exhibits exceptional peroxidase-like activity and broad-spectrum antibacterial efficacy. Fe-γ-CD not only disrupts the wall structure of ESBL-E. coli but also induces protein leakage and genetic destruction, ultimately leading to its death. Furthermore, Fe-γ-CD inhibits biofilm formation by MRSA and eradicates mature biofilms, resulting in MRSA's demise. Importantly, Fe-γ-CD demonstrates negligible cytotoxicity toward normal mammalian cells, making it an ideal candidate for application as an antibacterial agent in foodstuffs. These findings highlight that Fe-γ-CD is an effective tool for combating the spread of foodborne pathogens and food safety.

Spin-state Conversion by Asymmetrical Orbital Hybridization in Ni-doped Co3 O4 to Boost Singlet Oxygen Generation for Microbial Disinfection.

Singlet oxygen (1 O2 ) plays a significant role in environmental and biomedical disinfection fields. Electrocatalytic processes hold great potential for 1 O2 generation, but remain challenging. Herein, a facile Ni doping converted spin-state transition approach is reported for boosting 1 O2 production. Magnetic analysis and theoretical calculations reveal that Ni occupied at the octahedral site of Co3 O4 can effectively induce a low-to-high spin-state transition. The high-spin Ni-Co3 O4 generate appropriate binding strength and enhance electron transfer between the Co centers with oxygen intermediates, thereby improving the catalytic activity of Ni-Co3 O4 for effective generating 1 O2 . In neutral conditions, 1×106  CFU mL-1 Gram-negative ESBL-producing Escherichia coli (E. coli) could be inactivated by Ni-Co3 O4 system within 5 min. Further antibacterial mechanisms indicate that 1 O2 can lead to cell membrane damage and DNA degradation so as to irreversible cell death. Additionally, the developed Ni-Co3 O4 system can effectively inactivate bacteria from wastewater and bioaerosols. This work provides an effective strategy for designing high-spin electrocatalysis to boost 1 O2 generation for disinfection process.

Rapid and Sensitive Detection of Fungicide-Resistant Crop Fungal Pathogens Using an Isothermal Amplification Refractory Mutation System.

Fungicide abuse leads to the emergence of fungicide-resistant fungal pathogens, thus posing a threat to agriculture and food safety. Here, we developed an isothermal amplification refractory mutation system (termed iARMS) allowing us to resolve genetic mutations, enabling rapid, sensitive, and potentially field-applicable detection of fungicide-resistant crop fungal pathogens. iARMS yielded a limit of detection of 25 aM via a cascade signal amplification strategy of recombinase polymerase amplification (RPA) and Cas12a-mediated collateral cleavage at 37 °C within 40 min. Specificity for fungicide-resistant Puccinia striiformis (P. striiformis) detection was guaranteed by RPA primers and the flexible sequence of gRNA. The iARMS assay allowed us to detect as low as 0.1% cyp51-mutated P. striiformis that showed resistance to the demethylase inhibitor (DMI), which was 50 times more sensitive than the sequencing techniques. Thus, it is promising for the discovery of rare fungicide-resistant isolates. We applied iARMS to investigate the emergence of fungicide-resistant P. striiformis in western China and found that its proportion was over 50% in Qinghai, Sichuan, and Xinjiang Province. iARMS can serve as a molecular diagnostic tool for crop diseases and facilitate precision plant disease management.

Activity Regulating Strategies of Nanozymes for Biomedical Applications.

On accounts of the advantages of inherent high stability, ease of preparation and superior catalytic activities, nanozymes have attracted tremendous potential in diverse biomedical applications as alternatives to natural enzymes. Optimizing the activity of nanozymes is significant for widening and boosting the applications into practical level. As the research of the catalytic activity regulation strategies of nanozymes is boosting, it is essential to timely review, summarize, and analyze the advances in structure-activity relationships for further inspiring ingenious research into this prosperous area. Herein, the activity regulation methods of nanozymes in the recent 5 years are systematically summarized, including size and morphology, doping, vacancy, surface modification, and hybridization, followed by a discussion of the latest biomedical applications consisting of biosensing, antibacterial, and tumor therapy. Finally, the challenges and opportunities in this rapidly developing field is presented for inspiring more and more research into this infant yet promising area.

Infection pattern and immunological characteristics of Epstein-Barr virus latent infection in cervical squamous cell carcinoma.

Previous studies reported the association between Epstein-Barr virus (EBV) and cervical squamous cell carcinoma (CSCC), but its infection pattern and clinical significance unclear. This study aimed to comprehensively investigate the infection pattern, clinicopathology, outcomes, and immunology of this entity in central China. We evaluated a total of 104 untreated CSCC tumor tissue specimens using in situ hybridization for EBV-encoded small RNAs (EBERs), and by employing flowcytometry fluorescence hybridization for human papillomavirus (HPV) genotyping. The expression of EBV latency proteins and immune biomarkers was evaluated and quantified by immunohistochemistry. EBERs transcripts were detected in 21 (20.2%) cases overall (in malignant epithelial cells of 13 cases and in lymphocytes of 8 cases). EBV belonged to latency type I infection in CSCC. The high-risk (HR)-HPV was detected in all of EBV-positive CSCC, and the difference of detection rate of HR-HPV was significant when compared with EBV-negative CSCC (p = 0.001). The specific clinicopathology with increased frequency of advanced clinical stages, tumor-positive lymph nodes, neural invasion, and increased infiltration depth (all p value < 0.05) were observed in cases with EBV. However, EBV infection was found to have no impact on prognosis of patients with CSCC. Increased densities of forkhead box P3 (FoxP3)+-tumor infiltrating lymphocytes (TILs) (p = 0.005) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)+-TILs (p = 0.017) and higher expression of programmed cell death-1 (PD-1) (p = 0.002) and programmed cell death-1 ligand 1 (PD-L1) (p = 0.040) were associated with EBV latent infection in CSCC, and these immunological changes were more likely to be associated with the infection in lymphocytes rather than tumor cells. Moreover, in patients with HPV-positive CSCC, similar significant differences were still found. In conclusions, EBV-positive CSCC may have specific infection pattern and clinicopathology and can exhibit an immunosuppressive microenvironment dominated by Treg cells aggregation and immune checkpoint activation.

Pulmonary infection in patients with severe fever with thrombocytopenia syndrome: A multicentre observational study.

Co-infection in patients with severe fever with thrombocytopenia syndrome (SFTS) has been reported, posing a serious threat to survival and treatment. We aimed to systematically investigate the SFTS associated pulmonary infection, particularly invasive pulmonary fungal infection (IPFI). During April 2019 to October 2021, we conducted a multicentre observational study on adult hospitalized patients confirmed with SFTS from three tertiary hospital in central China. Demographic, clinical and laboratory data of patients were collected and re-assessed. A total of 443 patients (51.7% were male sex) were included for analysis with median age of 65-year-old. Among them, 190 (42.9%) patients met the criteria for pulmonary infection. Pulmonary infection was associated with shorter survival time (p < 0.0001 by log-rank test), and adjusted hazard ratio was 1.729 [95% confidence interval, 1.076-2.780] (p = 0.024). Age (odds ratio (OR) 1.040 [1.019-1.062], p < 0.001), time from onset to admission (OR 1.163 [1.070-1.264], p < 0.001), having severe status (OR 3.166 [2.020-4.962], p < 0.001) and symptoms of skin change (OR 2.361 [1.049-5.316], p < 0.001) at admission and receiving intravenous immunoglobin (OR 2.185 [1.337-3.569], p = 0.002) were independent risk factors for the occurrence of pulmonary infection. A total of 70 (15.8%) patients were defined as IPFI. Multivariate analysis showed that time from onset to admission (OR 1.117 [1.016-1.229], p = 0.022), severe status (OR 5.737 [3.054-10.779], p < 0.001), having smoking history (OR 3.178 [1.251-8.070], p = 0.015) and autoimmunity disease (OR 7.855 [1.632-37.796], p = 0.010), receiving intravenous immunoglobin (OR 3.270 [1.424-7.508], p = 0.005) were independent risk factors for the occurrence of IPFI. In SFTS patients with pulmonary infection, white blood count <2.09 × 109 per L (OR 11.064 [3.708-33.012], p < 0.001) and CD3+ CD4+ T cell count <104.0 per µL (OR 10.429 [3.395-32.038], p < 0.001) could independently predict IPFI. This study showed the high prevalence and poor outcomes of pulmonary infection and IPFI in patients with SFTS. These findings highlighted the need for active surveillance of fungal pathogens and early antifungal treatment in patients with SFTS.

Dysfunction of circulating CD3+CD56+ NKT-like cells in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is associated with increased incidence and mortality of many cancers and infectious diseases. CD3+CD56+ NKT-like cells play pivotal roles in tumor surveillance and infection control. However, little is known about potential alterations in circulating NKT-like cells in T2DM patients. In this study, we found that the frequency and absolute counts of circulating NKT-like cells were significantly lower in patients with T2DM compared to healthy volunteers. Moreover, in T2DM patients, NKT-like cells were impaired in their production of IFN-γ and TNF-α as well as degranulation capacity. The expression of activating receptor NKG2D was markedly decreased on NKT-like cells in T2DM patients, while the expression of inhibitory receptors Tim-3 and LAG-3 was upregulated. In detail, Tim-3+NKT-like cells expressed higher LAG-3 and less IFN-γ and TNF-α compared to Tim-3-NKT-like cells. Importantly, we further found that the expression of Tim-3 in NKT-like cells from T2DM patients correlated positively with glycated hemoglobin (HbA1c) and fasting blood glucose (FBG) levels, as well as with diabetes duration. In conclusion, these results indicate that NKT-like cells from T2DM patients display an exhausted phenotype and reduced functionality. Moreover, Tim-3 expression on NKT-like cells likely serves a novel biomarker for duration of T2DM.

FZD7 accelerates hepatic metastases in pancreatic cancer by strengthening EMT and stemness associated with TGF-ß/SMAD3 signaling.

BACKGROUND: Metastasis of malignant tumors accelerates systemic failure and hastens the deaths of pancreatic cancer patients. During the metastatic process, the physical translocation of cancer cells from the primary lesion to distant organs and is crucial. CSCs properties, such as self-renewal and multiple-direction differentiation capacity are essential for colonization in the microenvironment of distant organs and metastatic lesion formation. It is widely believed that EMT can cause cancer cells to penetrate blood vessels by undergoing phenotypic and cytoskeletal changes, so that they can infiltrate surrounding tissue and disseminate from the primary tumor to the blood circulation, where they are termed circulating tumor cells (CTCs), while CTCs often exhibit stemness properties. Accumulating evidence demonstrates that some EMT-related transcription factors are essential for CSCs self-renewal, so cancer cells that have undergone EMT typically acquire increased stemness properties. Abnormal activation of the WNT signaling pathway can drive a series of gene transcripts to promote EMT in multiple types of cancer, and among different Frizzled receptors of WNT signaling pathway, FZD7 expression is associated with distant organ metastasis, advanced clinical stages, and poor clinical prognosis. Objective of this study is to demonstrate that high FZD7 expression in pancreatic cancer can accelerate hepatic metastases and elucidate the related molecular mechanisms. METHODS: The expression of Frrizled receptor 7 (FZD7) in pancreatic ductal adenocarcinoma (PDAC) and relating survival rate were analyzed by bioinformatics, histochemistry assay and follow-up study. In vitro, FZD7 expression was silenced by lentiviral vectors carrying short hair RNA (shRNA) or upregulated by overexpression plasmid. Then, Wound-healing and Transwell experiment was used to analyze the abilities of migration and invasion; the levels of epithelial-to-mesenchymal transition (EMT) relating phenotype proteins, stemness relating phenotype proteins, and signaling molecular proteins were measured by Western-blot; cell stemness was evaluated by sphere forming ability of cells in suspension culture and detecting the proportion of CD24+CD44+ cells with flow cytometry. TGF-ß1 was used to induce EMT, and observe the effect of shRNA silencing FZD7 on which. RESULTS: High level of FZD7 expression in pancreatic cancer samples was associated with earlier hepatic metastasis. In vitro upregulation FZD7 can enable pancreatic cancer cells to obtain stronger migration and invasion ability and higher mesenchymal phenotype, and vice versa; the proportion of cancer stem cell (CSC) was also positively correlated with the level of FZD7; cells forming spheres in suspension culture showed stronger migration and invasion ability and higher level of mesenchymal phenotype than normal adherent cultured cells; the level of FZD7 was positively correlated with the level of activated ß-catenin. Silencing FZD7 expression can attenuate EMT induced by TGF-ß1 stimulating, and TGF-ß1 stimulating can also upregulate stemness phenotype expression, such as ABCG2, CD24, and CD44 by mediating of FZD7. CONCLUSIONS: High FZD7 expression in pancreatic cancer can accelerates hepatic metastases by promoting EMT and strengthening cell stemness, and FZD7 can work through the canonical Wingless-type (WNT) signaling pathway and participate in TGF-ß/SMAD3 signaling pathway also.

Antibacterial Copolypeptoids with Potent Activity against Drug Resistant Bacteria and Biofilms, Excellent Stability, and Recycling Property.

The preparation of a type of innovative cationic copolypeptoid antimicrobials containing various hydrophobic moieties that resemble both structure and membrane-lytic antibacterial mechanism of natural antimicrobial peptides (AMPs) is reported. By finely tuning the hydrophilic/hydrophobic balance, the polypeptoids exhibit a wide spectrum of antibacterial activity against both Gram-positive bacteria and Gram-negative bacteria with the lowest minimum inhibitory concentration (MIC) at only 2 µg mL-1 , whereas they also show low haemolytic properties. In particular, high selectivity (>128) is achieved from the polymers with butyl moieties. Moreover, the polypeptoids can readily inhibit the formation of biofilms and effectively eradicate the bacteria embedded in the mature biofilms, which is superior to many natural AMPs and vancomycin. Unlike conventional antibiotics, the polypeptoids possess potent activity against drug-resistant bacteria without visible resistance development after repeated usage. Notably, the polypeptoid antimicrobials not only have inherently fast bactericidal properties and excellent stability against incubation with human plasma, but also show excellent in vivo antibacterial effect. The prepared antimicrobials, coated onto magnetic nanospheres show recycling properties and enhanced antibacterial activity as combined with near-infrared (NIR)-induced photothermal antibacterial therapy.

Associated microbiota and treatment of severe fever with thrombocytopenia syndrome complicated with infections.

The purpose of this study is to assess the incidence and management of co-infections in hospitalized severe fever with thrombocytopenia syndrome bunyavirus (SFTSV) patients. We retrospectively evaluated the microbiological database records of the SFTS patients in the first affiliated hospital of Anhui Medical University from January 1, 2018, to December 1, 2021. According to the obtained results, co-infections including pulmonary infection, bloodstream infection, biliary tract infection, urinary tract infection, and abdominal infection were observed in SFTS patients. The incidence rate of fungal infections was found to be high in SFTS patients. Furthermore, we suggest that old age people should be evaluated for the risk of fungal infection. In comparison to the non-infection group, patients in the co-infection group were more likely to get mechanical ventilation, antibacterial treatment, antifungal treatment, and blood product therapy (p < 0.001), with a significantly longer length of stay (p < 0.05). In SFTS patients, the most prevalent strains were Aspergillus fumigatus, Aspergillus flavus, Candida, Klebsiella pneumonia, and Escherichia coli. In this investigation, 66.2% (106/160) of patients were given antibiotics, most often Piperacillin/tazobactam or minocycline. 15.6% (25/160) of patients were treated with antifungal drugs: 13.1% (21/160) with voriconazole. Patients with SFTS Associated Pulmonary Aspergillosis (SAPA) received active antifungal treatment, but the mortality rate was still 23.5% (8/34). Only 6 of the 11 patients with SFTS Associated Candidiasis were treated with antifungal drugs with no mortality. Due to the high frequency of fungal pulmonary infection in SFTS patients, more standardized fungal detection program should be strengthened.

MY11 exerts antitumor effects through activation of the NF-κB/PUMA signaling pathway in breast cancer.

Breast cancer is the most common malignancy in women worldwide, and the discovery of new effective breast cancer therapies with lower toxicity is still needed. We screened a series of chalcone derivatives and found that MY11 ((E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-piperazinylphenyl) prop-2-en-1-one) had the strongest anti-breast cancer activity. MY11 inhibited the growth of MDA-MB-231 and MCF-7 breast cancer cells by arresting the cell cycle and promoting apoptosis, through regulation of the cell cycle and apoptosis-related proteins. PDTC (Pyrrolidinedithiocarbamate ammonium), a specific inhibitor of the NF-κB pathway, abolished the inhibitory effect of MY11 treatment. NF-κB has been shown to regulate PUMA-dependent apoptosis. Our in vitro studies demonstrated that MY11 promoted breast cancer cell apoptosis by activating the NF-κB/PUMA/mitochondrial apoptosis pathway (including Bcl-2, Bax, and Caspase-9). MY11 also inhibited tumor growth in an orthotopic breast cancer mouse model by inducing apoptosis through the NF-κB signaling pathway, importantly, with minimal toxicity. In addition, MY11 was found by docking analysis to bind to p65, which might enhance the stability of the p65 protein. Taken together, our findings indicate that MY11 exerts a significant anticancer effect in breast cancer and that it may be a potential candidate for the treatment of breast cancer.