Earth-abundant catalyst for modification of wheat straw to enhance ammonia mitigation from fertilized alkaline soil.

In this study, inexpensive earth-abundant catalyst of Co/TiO2 is coupled with a low-temperature modification approach to enhance NH3 adsorption capacity on wheat straw (WS). The highest NH3 uptake achieved is 111.9 mg/g, with 80.8 % retention even after 3 h of desorption. Mechanistic investigation indicates that the enhanced adsorption capacity stems from Co/TiO2, which facilitates generation of reactive oxygen species, leading improved ultra-micropore structure that enhances the interaction between NH3 and oxygen-containing functional groups through a trapping effect. The robust stability of adsorbed NH3 is attributed to the formation of amides or amines. Incorporation of only 1 wt% WS-Co to urea-fertilized alkaline soil reduced NH3 volatilization by 83.1 %. The significant effect is primarily attributed to the excellent adsorption capacity of WS-Co, rather than alterations in the relative abundance of the microbial community. These findings present a novel approach for development of effective fertiliser additive to mitigate NH3 volatilization from alkaline soil.

Small HBV surface antigen drives regorafenib resistance in HCC via KIAA1429-dependent m6A modification of CCR9.

A substantial body of literature, including our own, points to a connection between hepatitis B virus (HBV) infection and the development of drug resistance in hepatocellular carcinoma (HCC), particularly against sorafenib. However, the influence of HBV on resistance to regorafenib, another therapeutic agent, has been less studied. In this study, we used the GEO database (GSE87630) and clinical samples to demonstrate that C-C motif chemokine receptor 9 (CCR9) was highly expressed in HBV-related HCC and predicted poor overall survival. Its overexpression correlated with HBsAg-positive HCC patients. Both univariate and multivariable Cox regression analysis elucidated CCR9 was an independent risk factor for poor overall survival in HCC patients. Our in vitro findings further revealed that HBV structural proteins, small HBV surface antigen (SHBs), triggered an upregulation of CCR9. Functional assays showed that SHBs enhanced HCC cell proliferation, migration, and invasion, increased ABCB1 and ABCC1 expression, and promoted regorafenib resistance via CCR9. Intriguingly, overexpression of HBV plasmid and an AAV-HBV mouse model both exhibited a significant elevation in global N6-methyladenosine (m6A) levels. Further investigations revealed that SHBs elevated these m6A levels, upregulated CCR9 and stabilized CCR9 mRNA through KIAA1429-mediated m6A modification, with sites 1373 and 1496 on CCR9 mRNA being critical for modification. In conclusion, SHBs promoted HCC progression and regorafenib resistance via KIAA1429-mediated m6A modification of CCR9. Our findings suggested that CCR9 could be a potential prognostic biomarker and a valuable molecular therapeutic target of regorafenib resistance in HBV-related HCC.

Determining the Disinfectants Resistance Genes and the Susceptibility to Common Disinfectants of Extensively Drug-Resistant Carbapenem-Resistant Klebsiella pneumoniae Strains at a Tertiary Hospital in China.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) infection has become a significant threat to global health. The application of chemical disinfectants is an effective infection control strategy to prevent the spread of CRKP in hospital environments. However, bacteria have shown reduced sensitivity to clinical disinfectants in recent years. Furthermore, bacteria can acquire antibiotic resistance due to the induction of disinfectants, posing a considerable challenge to hospital infection prevention and control. This study collected 68 CRKP strains from the Fifth Affiliated Hospital of Xinjiang Medical University in China from 2023 to 2024. These strains were isolated from the sputum, urine, and whole blood samples of patients diagnosed with CRKP infection. Antibiotic susceptibility tests were performed on CRKP strains. Concurrently, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of disinfectants (benzalkonium bromide, 1% iodophor disinfectant, alcohol, and chlorine-containing disinfectant) against the test isolates were determined by the broth microdilution method. The efflux pump genes (cepA, qacE, qacEΔ1, qacEΔ1-SUL1, oqxA, and oqxB) were detected using polymerase chain reaction. The results showed that 21 out of the 68 CRKP strains exhibited extensive drug resistance, whereas 47 were nonextensively drug-resistant. The MIC value for benzalkonium bromide disinfectants displayed statistically significant differences (p < 0.05) between extensively drug-resistant (XDR) and non-XDR strains. Additionally, the MBC values for benzalkonium bromide disinfectants and 1% iodophor disinfectants displayed statistically significant differences (p < 0.05) between XDR and non-XDR strains. The detection rates for the efflux pump genes were as follows: cepA 52.9%, qacE 39.7%, qacEΔ1 35.2%, qacEΔ1-SUL1 52.9%, oqxA 30.8%, and oqxB 32.3%. The detection rate of the qacEΔ1-SUL1 gene in XDR CRKP strains was significantly higher than in non-XDR CRKP strains (p < 0.05). This indicates a potential link between CRKP bacterial disinfectant efflux pump genes and CRKP bacterial resistance patterns. Ongoing monitoring of the declining sensitivity of XDR strains against disinfectants is essential for the effective control and prevention of superbug.

A LDH-Derived Metal Sulfide Nanosheet-Functionalized Bioactive Glass Scaffold for Vascularized Osteogenesis and Periprosthetic Infection Prevention/Treatment.

Periprosthetic infection and prosthetic loosing stand out as prevalent yet formidable complications following orthopedic implant surgeries. Synchronously addressing the two complications is long-time challenging. Herein, a bioactive glass scaffold (BGS) functionalized with MgCuFe-layered double hydroxide (LDH)-derived sulfide nanosheets (BGS/MCFS) is developed for vascularized osteogenesis and periprosthetic infection prevention/treatment. Apart from the antibacterial cations inhibiting bacterial energy and material metabolism, the exceptional near-infrared-II (NIR-II) photothermal performance empowers BGS/MCFS to eliminate periprosthetic infections, outperforming previously reported functionalized BGS. The rough surface topography and the presence of multi-bioactive metal ions bestow BGS/MCFS with exceptional osteogenic and angiogenic properties, with 8.5-fold and 2.3-fold enhancement in bone mass and neovascularization compared with BGS. Transcriptome sequencing highlights the involvement of the TGF-ß signaling pathway in these processes, while single-cell sequencing reveals a significant increase in osteoblasts and endothelial cells around BGS/MCFS compared to BGS.

Phytochemical profiling and evaluation of antimicrobial activities of common culinary spices: Syzygium aromaticum (clove) and Piper nigrum (black pepper).

Background: The increasing resistance of microbial pathogens to conventional antibiotics necessitates the exploration of alternative antimicrobial agents. This study aims to evaluate the antimicrobial potential and phytochemical properties of Syzygium aromaticum (clove) and Piper nigrum (black pepper) extracts, both of which are known for their historical use in traditional medicine and culinary applications. Methods: Hydroalcoholic and aqueous extracts of clove and black pepper were prepared. The antimicrobial activity of these extracts was assessed using the disk diffusion method against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger. Minimum inhibitory concentration (MIC) was determined using the broth dilution method. Qualitative phytochemical screening identified the presence of key bioactive compounds, while quantitative analysis measured total phenolic and flavonoid contents. LC-HRMS/MS analysis of ethanolic extracts was performed. Results: Both spices extracts exhibited significant antimicrobial activity, with inhibition zones ranging from 14 to 18 mm. clove showed superior antimicrobial efficacy compared to black paper, particularly against fungi. MIC values ranged between 3 mg/mL and 6 mg/mL for both spices. Phytochemical analysis revealed higher total phenolic and flavonoid contents in clove, with hydroalcoholic extracts showing greater concentrations than aqueous extracts. HPLC quantified higher eugenol content in clove extracts and higher piperine content in black pepper extracts. The differences in bioactive compound content were statistically significant (p < 0.05). Conclusion: The study confirms that both spices possess significant antimicrobial properties, attributable to their rich phytochemical composition, particularly phenolics and flavonoids. Clove exhibited slightly superior antimicrobial activity compared to black paper. These findings support the potential use of these spices as complementary antimicrobial agents. Further research should investigate their synergistic effects with conventional antibiotics and explore their applications in food preservation and alternative medicine.

A Se Nanoparticle/MgFe-LDH Composite Nanosheet as a Multifunctional Platform for Osteosarcoma Eradication, Antibacterial and Bone Reconstruction.

Despite advances in treating osteosarcoma, postoperative tumor recurrence, periprosthetic infection, and critical bone defects remain critical concerns. Herein, the growth of selenium nanoparticles (SeNPs) onto MgFe-LDH nanosheets (LDH) is reported to develop a multifunctional nanocomposite (LDH/Se) and further modification of the nanocomposite on a bioactive glass scaffold (BGS) to obtain a versatile platform (BGS@LDH/Se) for comprehensive postoperative osteosarcoma management. The uniform dispersion of negatively charged SeNPs on the LDH surface restrains toxicity-inducing aggregation and inactivation, thus enhancing superoxide dismutase (SOD) activation and superoxide anion radical (·O2 -)-H2O2 conversion. Meanwhile, Fe3+ within the LDH nanosheets can be reduced to Fe2+ by depleting glutathione (GSH) in the tumor microenvironments (TME), which can catalyze H2O2 into highly toxic reactive oxygen species. More importantly, incorporating SeNPs significantly promotes the anti-bacterial and osteogenic properties of BGS@LDH/Se. Thus, the developed BGS@LDH/Se platform can simultaneously inhibit tumor recurrence and periprosthetic infection as well as promote bone regeneration, thus holding great potential for postoperative "one-stop-shop" management of patients who need osteosarcoma resection and scaffold implantation.

The miR-641-STIM1 and SATB1 axes play important roles in the regulation of the Th17/Treg balance in ITP.

Immune thrombocytopenia (ITP) is an autoimmune disease caused by T-cell dysfunction. Recently, several studies have shown that a disturbed Th17/Treg balance contributes to the development of ITP. MicroRNAs (miRNAs) are small noncoding RNA moleculesthat posttranscriptionally regulate gene expression. Emerging evidences have demonstrated that miRNAs play an important role in regulating the Th17/Treg balance. In the present study, we found that miR-641 was upregulated in ITP patients. In primary T cells, overexpression of miR-641 could cause downregulation of its target genes STIM1 and SATB1, thus inducing a Th17 (upregulated)/Treg (downregulated) imbalance. Inhibition of miR-641 by a miR-641 sponge in primary T cells of ITP patients or by antagomiR-641 in an ITP murine model could cause upregulation of STIM1 and SATB1, thus restoring Th17/Treg homeostasis. These results suggested that the miR-641-STIM/SATB1 axis plays an important role in regulating the Th17/Treg balance in ITP.

Design, synthesis and biological evaluation of Thiazolo[3, 2-a]Pyrimidine derivatives as novel RNase H inhibitors.

Targeting Ribonuclease H (RNase H) has been considered a viable strategy for HIV therapy. In this study, a series of novel thiazolo[3, 2-a]pyrimidine derivatives were firstly designed and synthesized as potential inhibitors of HIV-1 RNase H. Among these compounds, A28 exhibited the most potent inhibition against HIV-1 RNase H with an IC50 value of 4.14 µM, which was about 5-fold increase in potency than the hit compound A1 (IC50 = 21.49 µM). To gain deeper insights into the structure-activity relationship (SAR), a CoMFA model was constructed to yield reasonable statistical results (q2 = 0.658 and R2 = 0.969). Results from magnesium ion chelation experiments and molecular docking studies revealed that these thiazolopyrimidine inhibitors may exert their inhibitory activity by binding to an allosteric site on RNase H at the interface between subunits p51 and p66. Furthermore, this analog demonstrated favorable physicochemical properties. Our findings provide valuable groundwork for further development of allosteric inhibitors targeting HIV-1 RNase H.

Efficacy of Random Forest Models in Predicting Multidrug-Resistant Gram-Negative Bacterial Nosocomial Infections Compared to Traditional Logistic Regression Models.

This study evaluates whether random forest (RF) models are as effective as traditional Logistic Regression (LR) models in predicting multidrug-resistant Gram-negative bacterial nosocomial infections. Data were collected from 541 patients with hospital-acquired Gram-negative bacterial infections at two tertiary-level hospitals in Urumqi, Xinjiang, China, from August 2022 to November 2023. Relevant literature informed the selection of significant predictors based on patients' pre-infection clinical information and medication history. The data were split into a training set of 379 cases and a validation set of 162 cases, adhering to a 7:3 ratio. Both RF and LR models were developed using the training set and subsequently evaluated on the validation set. The LR model achieved an accuracy of 84.57%, sensitivity of 82.89%, specificity of 80.10%, positive predictive value of 84%, negative predictive value of 85.06%, and a Yoden index of 0.69. In contrast, the RF model demonstrated superior performance with an accuracy of 89.51%, sensitivity of 90.79%, specificity of 88.37%, positive predictive value of 87.34%, negative predictive value of 91.57%, and a Yoden index of 0.79. Receiver operating characteristic curve analysis revealed an area under the curve of 0.91 for the LR model and 0.94 for the RF model. These findings indicate that the RF model surpasses the LR model in specificity, sensitivity, and accuracy in predicting hospital-acquired multidrug-resistant Gram-negative infections, showcasing its greater potential for clinical application.

Structure-guided design of novel biphenyl-quinazoline derivatives as potent non-nucleoside reverse transcriptase inhibitors featuring improved anti-resistance, selectivity, and solubility.

In pursuit of enhancing the anti-resistance efficacy and solubility of our previously identified NNRTI 1, a series of biphenyl-quinazoline derivatives were synthesized employing a structure-based drug design strategy. Noteworthy advancements in anti-resistance efficacy were discerned among some of these analogs, prominently exemplified by compound 7ag, which exhibited a remarkable 1.37 to 602.41-fold increase in potency against mutant strains (Y181C, L100I, Y188L, F227L + V106A, and K103N + Y181C) in comparison to compound 1. Compound 7ag also demonstrated comparable anti-HIV activity against both WT HIV and K103N, albeit with a marginal reduction in activity against E138K. Of significance, this analog showed augmented selectivity index (SI > 5368) relative to compound 1 (SI > 37764), Nevirapine (SI > 158), Efavirenz (SI > 269), and Etravirine (SI > 1519). Moreover, it displayed a significant enhancement in water solubility, surpassing that of compound 1, Etravirine, and Rilpivirine. To elucidate the underlying molecular mechanisms, molecular docking studies were undertaken to probe the critical interactions between 7ag and both WT and mutant strains of HIV-1 RT. These findings furnish invaluable insights driving further advancements in the development of DAPYs for HIV therapy.

Design and optimization of haze prediction model based on particle swarm optimization algorithm and graphics processor.

With the rapid expansion of industrialization and urbanization, fine Particulate Matter (PM2.5) pollution has escalated into a major global environmental crisis. This pollution severely affects human health and ecosystem stability. Accurately predicting PM2.5 levels is essential. However, air quality forecasting currently faces challenges in processing vast data and enhancing model accuracy. Deep learning models are widely applied for their superior learning and fitting abilities in haze prediction. Yet, they are limited by optimization challenges, long training periods, high data quality needs, and a tendency towards overfitting. Furthermore, the complex internal structures and mechanisms of these models complicate the understanding of haze formation. In contrast, traditional Support Vector Regression (SVR) methods perform well with complex non-linear data but struggle with increased data volumes. To address this, we developed CUDA-based code to optimize SVR algorithm efficiency. We also combined SVR with Genetic Algorithms (GA), Sparrow Search Algorithm (SSA), and Particle Swarm Optimization (PSO) to identify the optimal haze prediction model. Our results demonstrate that the model combining intelligent algorithms with Central Processing Unit-raphics Processing Unit (CPU-GPU) heterogeneous parallel computing significantly outpaces the PSO-SVR model in training speed. It achieves a computation time that is 6.21-35.34 times faster. Compared to other models, the Particle Swarm Optimization-Central Processing Unit-Graphics Processing Unit-Support Vector Regression (PSO-CPU-GPU-SVR) model stands out in haze prediction, offering substantial speed improvements and enhanced stability and reliability while maintaining high accuracy. This breakthrough not only advances the efficiency and accuracy of haze prediction but also provides valuable insights for real-time air quality monitoring and decision-making.

Subgenome-aware analyses reveal the genomic consequences of ancient allopolyploid hybridizations throughout the cotton family.

Malvaceae comprise some 4,225 species in 243 genera and nine subfamilies and include economically important species, such as cacao, cotton, durian, and jute, with cotton an important model system for studying the domestication of polyploids. Here, we use chromosome-level genome assemblies from representatives of five or six subfamilies (depending on the placement of Ochroma) to differentiate coexisting subgenomes and their evolution during the family's deep history. The results reveal that the allohexaploid Helicteroideae partially derive from an allotetraploid Sterculioideae and also form a component of the allodecaploid Bombacoideae and Malvoideae. The ancestral Malvaceae karyotype consists of 11 protochromosomes. Four subfamilies share a unique reciprocal chromosome translocation, and two other subfamilies share a chromosome fusion. DNA alignments of single-copy nuclear genes do not yield the same relationships as inferred from chromosome structural traits, probably because of genes originating from different ancestral subgenomes. These results illustrate how chromosome-structural data can unravel the evolutionary history of groups with ancient hybrid genomes.

Inhibitory Effect of Acetaminophen on Ocular Pigmentation and its Relationship with Thyroxine in Zebrafish Embryos.

Acetaminophen (N-acetyl-p-aminophenol; APAP) is one of the most widely used analgesics. To examine the toxicity of APAP, we used zebrafish embryos as model animals to detect the effect of APAP on the thyroid system of zebrafish embryos. The zebrafish embryos were exposed to APAP from 4 h post fertilization (4 hpf) until observation. The experimental results showed that APAP caused pericardial edema and decreased pigmentation in the zebrafish embryos or larvae. The APAP treatment caused a decrease in the expression of tpo and thrß in the zebrafish at 36 and 72 hpf. The transcriptomic analysis found that APAP affected retinol metabolism, the metabolism of xenobiotics by cytochrome P450, and the tyrosine metabolism pathway. The harmful effect of APAP on zebrafish embryos might be due to its disrupting effect on the functional regulation of the thyroid hormone system.

Ubiquitination and deubiquitination in the regulation of N6-methyladenosine functional molecules.

N6 methyladenosine (m6A) is the most prevalent RNA epigenetic modification, regulated by methyltransferases and demethyltransferases and recognized by methylation-related reading proteins to impact mRNA splicing, translocation, stability, and translation efficiency. It significantly affects a variety of activities, including stem cell maintenance and differentiation, tumor formation, immune regulation, and metabolic disorders. Ubiquitination refers to the specific modification of target proteins by ubiquitin molecule in response to a series of enzymes. E3 ligases connect ubiquitin to target proteins and usually lead to protein degradation. On the contrary, deubiquitination induced by deubiquitinating enzymes (DUBs) can separate ubiquitin and regulate the stability of protein. Recent studies have emphasized the potential importance of ubiquitination and deubiquitination in controlling the function of m6A modification. In this review, we discuss the impact of ubiquitination and deubiquitination on m6A functional molecules in diseases, such as metabolism, cellular stress, and tumor growth.

Ancient dormant virus remnant ERVW-1 drives ferroptosis via degradation of GPX4 and SLC3A2 in schizophrenia.

Human endogenous retroviruses (HERVs) are remnants of retroviral infections in human germline cells from millions of years ago. Among these, ERVW-1 (also known as HERV-W-ENV, ERVWE1, or ENVW) encodes the envelope protein of the HERV-W family, which contributes to the pathophysiology of schizophrenia. Additionally, neuropathological studies have revealed cell death and disruption of iron homeostasis in the brains of individuals with schizophrenia. Here, our bioinformatics analysis showed that differentially expressed genes in the human prefrontal cortex RNA microarray dataset (GSE53987) were mainly related to ferroptosis and its associated pathways. Clinical data demonstrated significantly lower expression levels of ferroptosis-related genes, particularly Glutathione peroxidase 4 (GPX4) and solute carrier family 3 member 2 (SLC3A2), in schizophrenia patients compared to normal controls. Further in-depth analyses revealed a significant negative correlation between ERVW-1 expression and the levels of GPX4/SLC3A2 in schizophrenia. Studies indicated that ERVW-1 increased iron levels, malondialdehyde (MDA), and transferrin receptor protein 1 (TFR1) expression while decreasing glutathione (GSH) levels and triggering the loss of mitochondrial membrane potential, suggesting that ERVW-1 can induce ferroptosis. Ongoing research has shown that ERVW-1 reduced the expression of GPX4 and SLC3A2 by inhibiting their promoter activities. Moreover, Ferrostatin-1 (Fer-1), the ferroptosis inhibitor, reversed the iron accumulation and mitochondrial membrane potential loss, as well as restored the expressions of ferroptosis markers GSH, MDA, and TFR1 induced by ERVW-1. In conclusion, ERVW-1 could promote ferroptosis by downregulating the expression of GPX4 and SLC3A2, revealing a novel mechanism by which ERVW-1 contributes to neuronal cell death in schizophrenia.

Captive ERVWE1 triggers impairment of 5-HT neuronal plasticity in the first-episode schizophrenia by post-transcriptional activation of HTR1B in ALKBH5-m6A dependent epigenetic mechanisms.

BACKGROUND: Abnormalities in the 5-HT system and synaptic plasticity are hallmark features of schizophrenia. Previous studies suggest that the human endogenous retrovirus W family envelope (ERVWE1) is an influential risk factor for schizophrenia and inversely correlates with 5-HT4 receptor in schizophrenia. To our knowledge, no data describes the effect of ERVWE1 on 5-HT neuronal plasticity. N6-methyladenosine (m6A) regulates gene expression and impacts synaptic plasticity. Our research aims to systematically investigate the effects of ERVWE1 on 5-HT neuronal plasticity through m6A modification in schizophrenia. RESULTS: HTR1B, ALKBH5, and Arc exhibited higher levels in individuals with first-episode schizophrenia compared to the controls and showed a strong positive correlation with ERVWE1. Interestingly, HTR1B was also correlated with ALKBH5 and Arc. Further analyses confirmed that ALKBH5 may be an independent risk factor for schizophrenia. In vitro studies, we discovered that ERVWE1 enhanced HTR1B expression, thereby activating the ERK-ELK1-Arc pathway and reducing the complexity and spine density of 5-HT neurons. Furthermore, ERVWE1 reduced m6A levels through ALKBH5 demethylation. ERVWE1 induced HTR1B upregulation by improving its mRNA stability in ALKBH5-m6A-dependent epigenetic mechanisms. Importantly, ALKBH5 mediated the observed alterations in 5-HT neuronal plasticity induced by ERVWE1. CONCLUSIONS: Overall, HTR1B, Arc, and ALKBH5 levels were increased in schizophrenia and positively associated with ERVWE1. Moreover, ALKBH5 was a novel risk gene for schizophrenia. ERVWE1 impaired 5-HT neuronal plasticity in ALKBH5-m6A dependent mechanism by the HTR1B-ERK-ELK1-Arc pathway, which may be an important contributor to aberrant synaptic plasticity in schizophrenia.

Limited energy migration and circumscribed multiphonon relaxation produced non-concentration quenching in a novel dazzling red-emitting phosphor.

White LED applications are still constrained by extremely efficient narrow band red emitting phosphors. Meanwhile, the concentration quenching induced by energy migration is the main reason that limits the emission intensity of a red emitting phosphor. Therefore, developing a novel red emitting material with energy migration limitations seems necessary. Here, we proposed and realized the non-concentration quenching doping of Eu3+ ions in a Sr9Y2-2xW4O24:xEu3+ (0 ≤ x ≤ 1.0) phosphor for the first time by means of host preferential selection. By clearly investigating the crystal structure and luminescence kinetics, the long-distance between the nearby Eu3+ ions and the low phonon energy are the main reasons that suppress the energy migration and the cross-relaxation among Eu3+ ions. These advantages result in a high internal (90.47%) and external quantum efficiency (42.1%) of Sr9Eu2W4O24. With the help of the Judd-Ofelt theory and the large value of oscillator strength Ω2, Eu3+ ions are verified to occupy the non-symmetric lattice site with high color purity (94.4%). In addition, only 5.2% emission intensity loss at 140 °C can guarantee its application in LED devices. Moreover, the SYWO:Eu3+ phosphor has high thermal tolerance, high color stability, excellent moisture resistance and superior physical/chemical stability, and thus has broad practical spectral application prospects. The prepared WLED shows superior performance, and the calculated NTSC values are as high as 101.8% and 104.7%, respectively. For comparison, the optical performances of the Sr9Y2W4O24:Eu3+ phosphor outperform those of the standard commercial red phosphors, Y2O3:Eu3+ and Y2O2S:Eu3+, and almost match that of K2MnF6. These results may pave the way for fresh approaches to the study of high-performance Eu3+-activated phosphors.

Safety and immunogenicity of the COVID-19 mRNA vaccine CS-2034: A randomized, double-blind, dose-exploration, placebo-controlled multicenter Phase I clinical trial in healthy Chinese adults.

BACKGROUND: The novel coronavirus pneumonia (COVID-19) is an infectious disease caused by the infection of a novel coronavirus known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which has resulted in millions of deaths. We aimed to evaluate the safety and immunogenicity of the COVID-19 mRNA vaccine (CS-2034, CanSino, Shanghai, China) in adults without COVID-19 infection from China. METHOD: This is a multicenter Phase I clinical trial with a randomized, double-blinded, dose-exploration, placebo-controlled design. The trial recruited 40 seronegative participants aged 18-59 years who had neither received any COVID-19 vaccine nor been infected before. They were divided into a low-dose group (administered with either the CS-2034 vaccine containing 30 µg of mRNA or a placebo of 0.3 ml type 5 adenovirus vector) and a high-dose group (administered with either the CS-2034 vaccine containing 50 µg of mRNA or a placebo of 0.5 ml type 5 adenovirus vector). Participants were randomly assigned in a 3:1 ratio to receive either the mRNA vaccine or a placebo on days 0 and 21 according to a two-dose immunization schedule. The first six participants in each dosage group were assigned as sentinel subjects. Participants were sequentially enrolled in a dose-escalation manner from low to high dose and from sentinel to non-sentinel subjects. Blood samples were collected from all participants on the day before the first dose (Day 0), the day before the second dose (day 21), 14 days after the second dose (day 35), and 28 days after the second dose (day 49) to evaluate the immunogenicity of the CS-2034 vaccine. Participants were monitored for safety throughout the 28-day follow-up period, including solicited adverse events, unsolicited adverse events, adverse events of special interest (AESI), and medically attended adverse events (MAE). This report focuses solely on the safety and immunogenicity analysis of adult participants aged 18-59 years, while the long-term phase of the study is still ongoing. This study is registered at ClinicalTrials.gov, NCT05373485. FINDINGS: During the period from May 17, 2022, to August 8, 2022, a total of 155 participants aged 18-59 years were screened for this study. Among them, 115 participants failed the screening process, and 40 participants were randomly enrolled (15 in the low-dose group, 15 in the high-dose group, and 10 in the placebo group). Throughout the 28-day follow-up period, the overall incidence of adverse reactions (related to vaccine administration) in the low-dose group, high-dose group, and placebo group was 93.33% (14/15), 100.00% (15/15), and 80.00% (8/10), respectively. There was a statistically significant difference in the incidence of local adverse reactions (soreness, pruritus, swelling at the injection site) among the low-dose group, high-dose group, and placebo group (P = 0.002). All adverse reactions were mainly of severity grade 1 (mild) or 2 (moderate), and no adverse events of severity grade 4 or higher occurred. Based on the analysis of Spike protein Receptor Binding Domain (S-RBD) IgG antibodies against the BA.1 strain, the seroconversion rates of antibodies at day 21 after the first dose were 86.67%, 93.33%, and 0.00% in the low-dose group, high-dose group, and placebo group, respectively. The geometric mean titer (GMT) of antibodies was 61.2(95%CI 35.3-106.2), 55.4(95%CI 36.3-84.4), and 15.0(95%CI 15.0-15.0), and the geometric mean fold increase (GMI) was 4.08(95%CI 2.35-7.08), 3.69(95%CI 2.42-5.63), and 1.00(95%CI 1.00-1.00) for each group. At day 28 after the full vaccination, the seroconversion rates of antibodies were 100.00%, 93.33%, and 0.00%, and the GMT of antibodies was 810.0(95%CI 511.4-1283.0), 832.2(95%CI 368.1-1881.6), and 15.0(95%CI 15.0-15.0), and the GMI was 54.00(95%CI 34.09-85.53), 55.48(95%CI 24.54-125.44), and 1.00(95%CI 1.00-1.00) for each group, respectively. Based on the analysis of CD3+/CD4+ cell cytokine response, the percentages of IL-2+, IL-4+, IFN-γ+, and TNF-α+ cells increased after 14 days and 28 days of full vaccination in both the low-dose group and high-dose group. The increase was most pronounced in the high-dose group. INTERPRETATION: At day 28 after the full vaccination, both the low-dose and the high-dose CS-2034 vaccine were able to induce the production of high titers of S-RBD IgG antibodies against the BA.1 strain. Adverse reactions in the low-dose and high-dose groups were mainly of severity grade 1 or 2, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine.

Targeting STING in cancer: Challenges and emerging opportunities.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a key pathway through which the host regulates immune responses by recognizing cytoplasmic double-stranded DNA of abnormal origin, and it plays an important role in tumor growth as well as metastasis, with relevant molecular details constantly being explored and updated. The significant immunomodulatory effects make STING an attractive target for cancer immunotherapy, and STING agonists have been receiving great attention for their development and clinical translation. Despite exciting results in preclinical work, the application of STING agonists to cancer therapy remains challenging due to their poor pharmacokinetic and physicochemical properties, as well as toxic side effects they produce. Here, we summarize the dichotomous role of cGAS-STING in cancer and discuss the limitations of cancer immunotherapy based on STING activation as well as feasible strategies to overcome them to achieve tumor regression.

Function of reactive oxygen species in myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous myeloid cell population and serve as a vital contributor to the tumor microenvironment. Reactive oxygen species (ROS) are byproducts of aerobic respiration and are involved in regulating normal biological activities and disease progression. MDSCs can produce ROS to fulfill their immunosuppressive activity and eliminate excessive ROS to survive comfily through the redox system. This review focuses on how MDSCs survive and function in high levels of ROS and summarizes immunotherapy targeting ROS in MDSCs. The distinctive role of ROS in MDSCs will inspire us to widely apply the blocked oxidative stress strategy in targeting MDSC therapy to future clinical therapeutics.