Novel mRNA adjuvant ImmunER enhances prostate cancer tumor-associated antigen mRNA therapy via augmenting T cell activity.

Prostate cancer (PCa) is characterized as a "cold tumor" with limited immune responses, rendering the tumor resistant to immune checkpoint inhibitors (ICI). Therapeutic messenger RNA (mRNA) vaccines have emerged as a promising strategy to overcome this challenge by enhancing immune reactivity and significantly boosting anti-tumor efficacy. In our study, we synthesized Tetra, an mRNA vaccine mixed with multiple tumor-associated antigens, and ImmunER, an immune-enhancing adjuvant, aiming to induce potent anti-tumor immunity. ImmunER exhibited the capacity to promote dendritic cells (DCs) maturation, enhance DCs migration, and improve antigen presentation at both cellular and animal levels. Moreover, Tetra, in combination with ImmunER, induced a transformation of bone marrow-derived dendritic cells (BMDCs) to cDC1-CCL22 and up-regulated the JAK-STAT1 pathway, promoting the release of IL-12, TNF-α, and other cytokines. This cascade led to enhanced proliferation and activation of T cells, resulting in effective killing of tumor cells. In vivo experiments further revealed that Tetra + ImmunER increased CD8+T cell infiltration and activation in RM-1-PSMA tumor tissues. In summary, our findings underscore the promising potential of the integrated Tetra and ImmunER mRNA-LNP therapy for robust anti-tumor immunity in PCa.

Epigenetic editing of BRCA1 promoter increases cisplatin and olaparib sensitivity of ovarian cancer cells.

Drug resistance is the primary contributor to the high mortality rate of ovarian cancer (OC). The loss of BRCA1/2 function is linked to drug sensitivity in OC cells. The aim of this study is to enhance the drug sensitivity of OC cells by inducing BRCA1 dysfunction through promoter epigenetic editing. Epigenetic regulatory regions within the BRCA1 promoter, affecting gene expression, were initially discerned through analysis of clinical samples. Subsequently, we designed and rigorously validated epigenetic editing tools. Ultimately, we evaluated the cisplatin and olaparib sensitivity of the OC cells after editing. The BRCA1 promoter contains two CpG-rich regions, with methylation of the region covering the transcription start site (TSS) strongly correlating with transcription and influencing OC development, prognosis, and homologous recombination (HR) defects. Targeting this region in OC cells using our designed epigenetic editing tools led to substantial and persistent DNA methylation changes, accompanied by significant reductions in H3K27ac histone modifications. This resulted in a notable suppression of BRCA1 expression and a decrease in HR repair capacity. Consequently, edited OC cells exhibited heightened sensitivity to cisplatin and olaparib, leading to increased apoptosis rates. Epigenetic inactivation of the BRCA1 promoter can enhance cisplatin and olaparib sensitivity of OC cells through a reduction in HR repair capacity, indicating the potential utility of epigenetic editing technology in sensitization therapy for OC.

Theoretical Insights into Enhancing Catalytic Performance of Al-Cu Alloy for CO2 Electroreduction toward Ethene Production.

The understanding of the reaction mechanism of CO2 electroreduction (CO2RR) is essential for the precise design of catalysts for specific products with high selectivity. In this work, combined with the computational hydrogen electrode model and kinetic energy barrier calculations, CO2RR pathways on Cu(100) and Al1Cu3(100) are intensively investigated. The free energy barrier of the rate-determining step of ethylene formation is reduced from 1.08 eV for *CCOH formation on Cu(100) to 0.51 eV for *CH2OCHOH formation on Al1Cu3(100) and enhances the catalytic activity. The reaction free energy of *CO-*CO coupling is remarkably reduced from 0.86 eV on Cu(100) to -0.43 eV on Al1Cu3(100) and the coupling barrier is reduced from 0.97 to 0.37 eV, suppressing the production of gas phase CO and enhancing the production of C2 products. Furthermore, the selectivity toward C-O breaking of *CH2CHOH on Cu(100) and *CH2CH2OH on Al1Cu3(100) ensures high selectivity toward ethene rather than ethanol.

Modulating cell proliferation by asymmetric division: A conserved pattern in the early embryogenesis of nematode species.

In the early stage of the nematode Caenorhabditis elegans embryogenesis, the zygote divides asymmetrically into a symmetric fast lineage and an asymmetric slow lineage, producing 16 and 8 cells respectively almost at the same time, followed by the onset of gastrulation. It was recently reported that this cell division pattern is optimal for rapid cell proliferation. In this work, we compare the cell lineages of 9 nematode species, revealing that this pattern is conserved for >60 million years. It further suggests that such lineage design has an important functional role and it might speed up embryonic development in the nematode kingdom, not limited to C. elegans , and independent of the maternal-zygotic transition dynamics.

Clinical characteristics and prognostic factors of male breast cancer in China.

Purpose: This study aimed to explore the clinical characteristics of male breast cancer (MBC) patients and the factors influencing their prognosis. Methods: We conducted a retrospective case series analysis of 117 MBC cases who were treated at Zhejiang Cancer Hospital from 2009 to 2022. Cox proportional hazard model was used to identify prognostic factors of MBC. Nomogram was constructed based on these factors, which was further evaluated by C-index and calibration curves. Results: A total of 115 MBC cases were finally included in our analyses, with median diagnosis age of 59 years. Of these cases, 80.0% were estrogen receptor (ER) positive, 79.2% were progesterone receptor (PR) positive, 48.7% were human epidermal growth factor receptor 2 (HER2) negative, and 42.6% had Ki67 levels higher than 15%. 108 (93.9%) cases underwent radical mastectomy, while only 3 (2.6%) received breast-conserving surgery. The Logrank test suggested that lymphocyte-to-monocyte ratio (LMR) was negatively associated with both overall survival (OS) and disease-free survival (DFS) of MBC, while platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) were only positively associated with OS (all P-values < 0.05). Multivariate regression analysis showed that age (HR 1.08, 95% CI 1.03-1.13) was significant prognostic factors for OS. Meanwhile, age (HR 1.06, 95% CI 1.02-1.10), histological differentiation grade (poorly differentiated/undifferentiated vs. well-differentiated: HR 2.55, 95% CI 1.05-6.17), and TNM stage (IV vs. I: HR 31.59, 95% CI 6.01-165.93) were also significant prognostic factors for DFS. Nomograms were developed for DFS, with C-indexes of 0.782, indicating good predictive performance. Conclusion: Increased age, bigger tumor size, higher TNM stage, and lower histological differentiation grade were associated with poor MBC prognosis, and LMR, PLR, and NLR might be potential predictors for MBC prognosis.

Intelligent method to predict intensive care unit admission after drainage operation in patients with deep neck space abscess: A multicenter retrospective study.

BACKGROUNDS: A deep neck space abscess (DNSA) is a critical condition resulting from infection of deep neck fascia and soft issue, leading to high morbidity and mortality. Therefore, intensive care can be very significant for patients with DNSA. This study aimed to develop models to predict the need for postoperative intensive care in patients with DNSA. METHODS: We retrospectively analyzed the records of 332 patients with DNSA who received drainage operation between 2015 and 2020. Multivariate logistic regression analysis and the eXtrem Gradient Boosting (XGBoost) algorithm were used to develop predictive models. RESULTS: We developed two predictive models, the nomogram and the XGBoost model. The area under the curve (AUC) of the nomogram was 0.911 and of the XGBoost model was 0.935. CONCLUSION: We developed two predictive models for guiding clinical decision making for postoperative ICU admission for DNSA patients, which may help improve prognosis and optimize intensive care resource allocation.

Erratum: HOXC10 promotes carboplatin resistance of ovarian cancer by regulating ABCC3.

[This corrects the article on p. 4602 in vol. 12, PMID: 36381312.].

Theoretical Insights into Amido Group-Mediated Enhancement of CO2 Hydrogenation to Methanol on Cobalt Catalysts.

Catalytic reduction of carbon dioxide into high-value-added products, such as methanol, is an effective approach to mitigate the greenhouse effect, and improving Co-based catalysts is anticipated to yield potential catalysts with high performance and low cost. In this study, based on first-principles calculations, we elucidate the promotion effects of surface *NHx (x = 1, 2, and 3) on the carbon dioxide hydrogenation to methanol from both activity and selectivity perspectives on Co-based catalysts. The presence of *NHx reduced the energy barrier of each elementary step on Co(100) by regulating the electronic structure to alter the binding strength of intermediates or by forming a hydrogen bond between surface oxygen-containing species and *NHx to stabilize transition states. The best promotion effect for different steps corresponds to different *NHx. The energy barrier of the rate-determining step of CO2 hydrogenation to methanol is lowered from 1.55 to 0.88 eV, and the product selectivity shifts from methane to methanol with the assistance of *NHx on the Co(100) surface. A similar phenomenon is observed on the Co(111) surface. The promotion effect of *NHx on Co-based catalysts is superior to that of water, indicating that the introduction of *NHx on a Co-based catalyst is an effective strategy to enhance the catalytic performance of CO2 hydrogenation to methanol.

Erratum: Non-canonical signaling pathway of SNAI2 induces EMT in ovarian cancer cells by suppressing miR-222-3p transcription and upregulating PDCD10: Erratum.

[This corrects the article DOI: 10.7150/thno.43198.].

OsGA3ox genes regulate rice fertility and plant height by synthesizing diverse active GA.

Gibberellin (GA) is an important hormone, which is involved in regulating various growth and development. GA biosynthesis pathway and synthetase have been basically clarified. Gibberellin 3ß hydroxylase (GA3ox) is the key enzyme for the synthesis of various active GA. There are two GA3ox genes (OsGA3ox1 and OsGA3ox2) in rice, and their physiological functions have been preliminarily studied. However, it is not clear how they work together to synthesize active GA to regulate rice development. In this study, the knockout mutants ga3ox1 and ga3ox2 were obtained by CRISPR/Cas9 technology. The pollen fertility of ga3ox1 decreased significantly, while the plant height of ga3ox2 decreased significantly. It shows that OsGA3ox1 is necessary for normal pollen development, while OsGA3ox2 is necessary for stem and leaf elongation. Tissue expression analysis showed that OsGA3ox1 was mainly expressed in unopened flowers, while OsGA3ox2 was mainly expressed in unexpanded leaves. The GA in different tissues of wild type (WT), and two ga3ox mutants were detected. It was found that pollen fertility is most closely related to the content of GA7, and plant height is most closely related to the content of GA1. It was found that OsGA3ox1 catalyzes GA9 to GA7 in flowers, which is closely related to pollen fertility; OsGA3ox2 catalyzes the GA20 to GA1 in unexpanded leaves, thereby regulating plant height; OsGA3ox1 catalyzes the GA19 to GA20 in roots, regulating the generation of GA3. OsGA3ox1 and OsGA3ox2 respond to developmental and environmental signals, and cooperate to synthesize endogenous GA in different tissues to regulate rice development. This study provides a reference for clarifying its role in GA biosynthesis pathway and further understanding the function of OsGA3ox.

Glycolic acid-based deep eutectic solvents boosting co-production of xylo-oligomers and fermentable sugars from corncob and the related kinetic mechanism.

BACKGROUND: Xylo-oligomers are a kind of high value-added products in biomass fractionation. Although there are several chemical methods to obtain xylo-oligomers from biomass, the reports about the deep eutectic solvents (DESs)-mediated co-production of xylo-oligomers and fermentable sugars and the related kinetic mechanism are limited. RESULTS: In this work, glycolic acid-based DESs were used to obtain xylo-oligomers from corncob. The highest xylo-oligomers yield of 65.9% was achieved at 120 °C for 20 min, of which the functional xylo-oligosaccharides (XOSs, DP 2-5) accounted for up to 31.8%. Meanwhile, the enzymatic digestion of cellulose and xylan in residues reached 81.0% and 95.5%, respectively. Moreover, the addition of metal inorganic salts significantly accelerated the hydrolysis of xylan and even the degradation of xylo-oligomers in DES, thus resulting in higher selectivity of xylan removal. AlCl3 showed the strongest synergistic effect with DES on accelerating the processes, while FeCl2 is best one for xylo-oligomers accumulation, affording the highest xylo-oligomers yield of 66.1% for only 10 min. Furthermore, the kinetic study indicates that the 'potential hydrolysis degree' model could well describe the xylan hydrolysis processes and glycolic acid/lactic acid (3:1) is a promising solvent for xylo-oligomers production, in particular, it worked well with FeCl2 for the excellent accumulation of xylo-oligomers. CONCLUSIONS: Glycolic acid-based deep eutectic solvents can be successfully applied in corncob fractionation with excellent xylo-oligomers and fermentable sugars yields on mild conditions, and the large amount of xylo-oligosaccharides accumulation could be achieved by specific process controlling. The strategies established here can be useful for developing high-valued products from biomass.

Therapeutic silencing of lncRNA RMST alleviates cardiac fibrosis and improves heart function after myocardial infarction in mice and swine.

Rationale: Cardiac fibrosis is an adverse consequence of aberrant fibroblast activation and extracellular matrix (ECM) deposition following myocardial infarction (MI). Recently, long noncoding RNAs (lncRNAs) have been reported to participate in multiple cardiac diseases. However, the biological functions of lncRNA rhabdomyosarcoma 2-associated transcript (RMST) in cardiac fibrosis remain largely unknown. Methods: The role of RMST in regulating cardiac fibroblast (CF) proliferation, fibroblast-to-myofibroblast transition (FMT), and ECM production, which were induced by transforming growth factor-ß1, was evaluated through immunofluorescence staining, cell contraction assay, cell migration assay, qRT-PCR, and western blot. The therapeutic effect of RMST silencing was assessed in murine and porcine MI models. Results: The present study showed that RMST expression was upregulated and associated with cardiac fibrosis in murine and porcine MI models. Further loss-of-function studies demonstrated that RMST silencing in vitro significantly inhibited CF proliferation, FMT, and ECM production. Accordingly, RMST knockdown in vivo alleviated cardiac fibrosis and improved cardiac contractile function in MI mice. Moreover, RMST acted as a competitive endogenous RNA of miR-24-3p. miR-24-3p inhibition abolished, while miR-24-3p agomir reproduced, the RMST knockdown-mediated effects on CF fibrosis by regulating the lysyl oxidase signaling pathway. Finally, the therapeutic potential of RMST knockdown was evaluated in a porcine MI model, and local RMST knockdown significantly inhibited cardiac fibrosis and improved myocardial contractile function in pigs after MI. Conclusion: Our findings identified RMST as a crucial regulator of cardiac fibrosis, and targeting RMST may develop a novel and efficient therapeutic strategy for treating fibrosis-related cardiac diseases.

HOXC10 promotes carboplatin resistance of ovarian cancer by regulating ABCC3.

HOXC10 has been reported to be upregulated in ovarian cancer (OC) tissues, attributing to the metastasis of OC. However, the specific functions of HOXC10 in OC, especially its role in chemoresistance, remain to be determined. Therefore, in this study, we explored the function and the underlying mechanisms of HOXC10 in carboplatin resistance of OC. A variety of approaches were utilized to analyze the expression of HOXC10 and its related genes. The effect of HOXC10 in cell growth and chemoresistance was investigated in carboplatin-resistant OC subline TOV21G-R and the parental TOV21G-P cells. ROC curve and survival analysis were conducted to determine the predictive value of HOXC10 and ABCC3 combination in carboplatin resistance and the prognosis of OC. Luciferase reporter assay and Chromatin immunoprecipitation (ChIP) assay were used to explore the direct regulation of ß-catenin by HOXC10. Our results demonstrated that the expression of HOXC10 was upregulated both in the carboplatin-resistant OC tissues and TOV21G-R cells. Furthermore, the upregulation of HOXC10 could promote the expression of ABCC3 by transcriptionally upregulating ß-catenin. Moreover, overexpression of HOXC10 could decrease the sensitivity of cells to carboplatin, while knocking down HOXC10 had the opposite effect both in vitro and in vivo. Therefore, the expression of HOXC10/ABCC3 could be a novel biomarker for predicting the carboplatin resistance and the prognosis of OC patients.

Application of the ratio of the radiopaque calcified area to the dental follicle (RCA/DF) for dental age assessment on orthopantomograms.

OBJECTIVES: This study aimed at exploring a new tooth development evaluation method for age assessment and investigating the dynamic alteration and potential trend of tooth development by orthopantomograms (OPGs), in order to provide references for tooth development prediction and forensic purpose. MATERIALS AND METHODS: A total of 132 OPGs of children aged 3-8 years were collected. The developmental stages of the permanent mandibular second molar (M2)were evaluated by experienced examiners according to the Nolla method and Mimics software, respectively. Quantitative analysis of the ratio of the radiopaque calcified area to the dental follicle (RCA/DF) in different stages, ages, sexes and quadrants were evaluated and compared via descriptive statistics and Spearman's correlation coefficient analysis. RESULTS: There was a strong, positive correlation between the examiners' evaluation and mimics analysis results. With the age increased, the Nolla stage of M2 observed by OPGs increased, and the RCA/DF showed increased trends both in males and females. There were significant differences of the RCA/DF of the M2 at various ages. The tooth calcification development of female was 9.08% earlier than that of male between 3 and 8 years old. However, teeth of male seemed to develop faster than that of female during this period. There was no significant difference between left and right quadrant either according to the Nolla stage or RCA/DF. CONCLUSIONS: The RCA/DF value obtained from OPGs of the developmental mandibular second permanent molars could be used as a reliable indicator for tooth maturity and age estimation in children aged 3-8 years. CLINICAL RELEVANCE: Age assessment based on radiographs is considered as a reliable and efficient indicator for judging different types of malocclusion, making suitable orthodontic treatment plan, deciding the extraction time of retained deciduous teeth in clinic practice.

A novel design of in-line static mixer for permanganate/bisulfite process: Numerical simulations and pilot-scale testing.

An increasing number of chemical technologies to wipe out contaminants within an incredibly short period of time have been developed recently, while their application was always hindered by the inefficient or improper mixing of reactants. To address this issue, the present work proposed a new static mixer named Tai-Chi which consists of blade, fin, and spoiler elements. Tai-Chi mixer can slice and divert the solutions inside and generate high shear flow to promote mixing process. Numerical simulations helped to determine the optimal operating conditions for Tai-Chi mixer, including laying its components anterior to the injection nozzles and keeping the velocity rate ratio of main pipe to branch pipe within the range of 0.5 to 1. Numerical simulations further proved that Tai-Chi mixer could strike a great balance between mixing performance (coefficient of variation [CoV] reaches 0.1 within 5 to 7 pipe diameters downstream) and head loss (nearly a half of other high shear static mixer in the market). Data of pilot-scale testing by Tai-Chi mixer confirm that 80% sulfamethoxazole could be eliminated in permanganate/bisulfite process within 8 pipe diameters, as well as showed the superiority of Tai-Chi's mixing performance in early stage compared with other static mixers in the market. PRACTITIONER POINTS: A Tai-Chi static mixer with blade, fin, and spoiler elements is devised. The optimal condition of flow rate and installment of Tai-Chi mixer is determined. Ultra-fast mixing is achieved by Tai-Chi (CoV < 0.1 within 5-7 pipe diameters). Pilot-scale test verifies the mixing efficiency of Tai-Chi mixer.

Hotair promotes the migration and proliferation in ovarian cancer by miR-222-3p/CDK19 axis.

Previous studies in our laboratory have reported that miR-222-3p was a tumor-suppressive miRNA in OC. This study aims to further understand the regulatory role of miR-222-3p in OC and provide a new mechanism for its prevention and treatment. We first found that miR-222-3p inhibited the migration and proliferation of OC cells. Then, we observed CDK19 was highly expressed in OC and inversely correlated with miR-222-3p. Besides, we observed that miR-222-3p directly binds to the 3'-UTR of CDK19 and inhibits CDK19 translation, thus inhibiting OC cell migration and proliferation in vitro and repressed tumor growth in vivo. We also observed the inhibitory effect of Hotair on miR-222-3p in OC. In addition, Hotair could promote the proliferation and migration of OC cells in vitro and facilitate the growth and metastasis of tumors in vivo. Moreover, Hotair was positively correlated with CDK19 expression. These results suggest Hotair indirectly up-regulates CDK19 through sponging miR-222-3p, which enhances the malignant behavior of OC. This provides a further understanding of the mechanism of the occurrence and development of OC.

Protective immunity induced by oral vaccination with a recombinant Lactococcus lactis vaccine against H5Nx in chickens.

BACKGROUND: The development of an influenza vaccine for poultry that provides broadly protective immunity against influenza H5Nx viruses is a challenging goal. RESULTS: Lactococcus lactis (L. lactis)/pNZ8149-HA1-M2 expressing hemagglutinin-1 (HA1) of A/chicken/Vietnam/NCVD-15A59/2015 (H5N6) and the conserved M2 gene of A/Vietnam/1203/2004 (H5N1) was generated. L. lactis/pNZ8149-HA1-M2 could induce significant humoral, mucosal and cell-mediated immune responses, as well as neutralization antibodies. Importantly, L. lactis/pNZ8149-HA1-M2 could prevent disease symptoms without significant weight loss and confer protective immunity in a chicken model against lethal challenge with divergent influenza H5Nx viruses, including H5N6 and H5N1. CONCLUSIONS: L. lactis/pNZ8149-HA1-M2 can serve as a promising vaccine candidate in poultry industry for providing protection against H5Nx virus infection in the field application.

Highly sensitive and selective detection of butachlor based on the resonance light scattering of doped carbon quantum dots.

In this work, a new method of resonance light scattering was developed for the sensitive and selective detection of butachlor. Firstly, buckwheat was used as the main carbon source to prepare a new type of doped carbon quantum dot using the hydrothermal method. A new method for the determination of butachlor was then established by the change in resonance light scattering intensity after the addition of butachlor into the doped carbon quantum dot solution. The detection effect was successfully optimized by investigating the optimum reaction conditions. Under the optimum conditions, the resonance light scattering intensity of doped carbon quantum dots was greatly enhanced at 460 nm after the addition of butachlor, and the intensity changes were linearly correlated with the butachlor concentration in the range of 1-7 µg L-1. The detection limit was 0.136 µg L-1, and the recoveries ranged between 98.6% and 101.8%. This method was also used for butachlor detection in environmental water.

Six-month follow-up of functional status in discharged patients with coronavirus disease 2019.

BACKGROUND: The long-term functional outcome of discharged patients with coronavirus disease 2019 (COVID-19) remains unresolved. We aimed to describe a 6-month follow-up of functional status of COVID-19 survivors. METHODS: We reviewed the data of COVID-19 patients who had been consecutively admitted to the Tumor Center of Union Hospital (Wuhan, China) between 15 February and 14 March 2020. We quantified a 6-month functional outcome reflecting symptoms and disability in COVID-19 survivors using a post-COVID-19 functional status scale ranging from 0 to 4 (PCFS). We examined the risk factors for the incomplete functional status defined as a PCFS > 0 at a 6-month follow-up after discharge. RESULTS: We included a total of 95 COVID-19 survivors with a median age of 62 (IQR 53-69) who had a complete functional status (PCFS grade 0) at baseline in this retrospective observational study. At 6-month follow-up, 67 (70.5%) patients had a complete functional outcome (grade 0), 9 (9.5%) had a negligible limited function (grade 1), 12 (12.6%) had a mild limited function (grade 2), 7 (7.4%) had moderate limited function (grade 3). Univariable logistic regression analysis showed a significant association between the onset symptoms of muscle or joint pain and an increased risk of incomplete function (unadjusted OR 4.06, 95% CI 1.33-12.37). This association remained after adjustment for age and admission delay (adjusted OR 3.39, 95% CI 1.06-10.81, p = 0.039). CONCLUSIONS: A small proportion of discharged COVID-19 patients may have an incomplete functional outcome at a 6-month follow-up; intervention strategies are required.

Volume segregation programming in a nematode's early embryogenesis.

Nematode species are well-known for their invariant cell lineage pattern during development. Combining knowledge about the fate specification induced by asymmetric division and the anti-correlation between cell cycle length and cell volume in Caenorhabditis elegans, we propose a minimal model to simulate lineage initiation by altering cell volume segregation ratio in each division, and quantify the derived pattern's performance in proliferation speed, fate diversity, and space robustness. The stereotypic pattern in C. elegans embryo is found to be one of the most optimal solutions taking minimum time to achieve the cell number before gastrulation, by programming asymmetric divisions as a strategy.