Computationally designed mRNA-launched protein nanoparticle vaccines.

Both protein nanoparticle and mRNA vaccines were clinically de-risked during the COVID-19 pandemic1-6. These vaccine modalities have complementary strengths: antigen display on protein nanoparticles can enhance the magnitude, quality, and durability of antibody responses7-10, while mRNA vaccines can be rapidly manufactured11 and elicit antigen-specific CD4 and CD8 T cells12,13. Here we leverage a computationally designed icosahedral protein nanoparticle that was redesigned for optimal secretion from eukaryotic cells14 to develop an mRNA-launched nanoparticle vaccine for SARS-CoV-2. The nanoparticle, which displays 60 copies of a stabilized variant of the Wuhan-Hu-1 Spike receptor binding domain (RBD)15, formed monodisperse, antigenically intact assemblies upon secretion from transfected cells. An mRNA vaccine encoding the secreted RBD nanoparticle elicited 5- to 28-fold higher levels of neutralizing antibodies than an mRNA vaccine encoding membrane-anchored Spike, induced higher levels of CD8 T cells than the same immunogen when delivered as an adjuvanted protein nanoparticle, and protected mice from vaccine-matched and -mismatched SARS-CoV-2 challenge. Our data establish that delivering protein nanoparticle immunogens via mRNA vaccines can combine the benefits of each modality and, more broadly, highlight the utility of computational protein design in genetic immunization strategies.

A tumour-associated macrophage-based signature for deciphering prognosis and immunotherapy response in prostate cancer.

For the multistage progression of prostate cancer (PCa) and resistance to immunotherapy, tumour-associated macrophage is an essential contributor. Although immunotherapy is an important and promising treatment modality for cancer, most patients with PCa are not responsive towards it. In addition to exploring new therapeutic targets, it is imperative to identify highly immunotherapy-sensitive individuals. This research aimed to establish a signature risk model, which derived from the macrophage, to assess immunotherapeutic responses and predict prognosis. Data from the UCSC-XENA, GEO and TISCH databases were extracted for analysis. Based on both single-cell datasets and bulk transcriptome profiles, a macrophage-related score (MRS) consisting of the 10-gene panel was constructed using the gene set variation analysis. MRS was highly correlated with hypoxia, angiogenesis, and epithelial-mesenchymal transition, suggesting its potential as a risk indicator. Moreover, poor immunotherapy responses and worse prognostic performance were observed in the high-MRS group of various immunotherapy cohorts. Additionally, APOE, one of the constituent genes of the MRS, affected the polarisation of macrophages. In particular, the reduced level of M2 macrophage and tumour progression suppression were observed in PCa xenografts which implanted in Apolipoprotein E-knockout mice. The constructed MRS has the potential as a robust prognostic prediction tool, and can aid in the treatment selection of PCa, especially immunotherapy options.

Partial Substitution of Nitrogen Fertilizer with Biogas Slurry Increases Rice Yield and Fertilizer Utilization Efficiency, Enhancing Soil Fertility in the Chaohu Lake Basin.

To investigate the effects of biogas slurry substitution for fertilizer on rice yield, fertilizer utilization efficiency, and soil fertility, a field experiment was conducted on rice-wheat rotation soil in the Chaohu Lake Basin for two consecutive years, with the following six treatments: no fertilization (CK), conventional fertilization (CF), optimized fertilization (OF), biogas slurry replacing 15% of fertilizer (15% OFB), biogas slurry replacing 30% of fertilizer (30% OFB), and biogas slurry replacing 50% of fertilizer (50% OFB). The field experiment results showed that, compared with CF treatment, OF treatment in 2022 and 2023 significantly increased (p < 0.05) rice yield, promoted the uptake of nitrogen (N), phosphorus (P), and potassium (K) by grains and straws, improved fertilizer utilization efficiency, and increased the contents of soil organic C (SOC), NH4+-N, NO3--N, hydrolysable N, and available P. The 15% OFB and 30% OFB treatments significantly increased (p < 0.05) rice grain and straw yields compared with CF treatment, and rice grain and straw yields were the highest in the 30% OFB treatment. Compared with CF and OF treatments, 30% OFB treatment significantly increased (p < 0.05) the N, P, and K uptake of grains and straws and increased the fertilizer utilization efficiency. Compared with CF treatment, the grain yield of 50% OFB treatment was significantly decreased (p < 0.05) in 2022, and there was no significant difference in 2023, which may be because the biogas slurry was applied before planting in 2023 to provide more nutrients for early rice growth. Compared with CF treatment, 30% OFB treatment significantly increased (p < 0.05) the contents of SOC, NH4+-N, available K, and hydrolysable N. In summary, optimizing N and K topdressing methods can increase rice yield and improve the fertilizer utilization efficiency and soil fertility. The 30% OFB treatment resulted in the highest rice yield, fertilizer utilization efficiency, and improved soil fertility, indicating that biogas slurry replacing 30% of fertilizer was the best application mode for rice in this region.

[Clinical and genetic features of children with 3-methylcrotonyl-coenzyme A carboxylase deficiency: an analysis of six cases]. / 3-ç”²åŸºå·´è±†é °è¾ é ¶Aç¾§åŒ–é ¶ç¼ºä¹ç—‡6ä¾‹æ‚£å„¿çš„ä¸´åºŠç‰¹å¾åŠé—ä¼ å­¦åˆ†æž.

OBJECTIVES: To investigate the clinical and genetic features of children with 3-methylcrotonyl-coenzyme A carboxylase deficiency (MCCD). METHODS: A retrospective analysis was conducted on the clinical manifestations and genetic testing results of six children with MCCD who attended Children's Hospital Affiliated to Zhengzhou University from January 2018 to October 2023. RESULTS: Among the six children with MCCD, there were 4 boys and 2 girls, with a mean age of 7 days at the time of attending the hospital and 45 days at the time of confirmed diagnosis. Of all children, one had abnormal urine odor and five had no clinical symptoms. All six children had increases in blood 3-hydroxyisovaleryl carnitine and urinary 3-hydroxyisovaleric acid and 3-methylcrotonoylglycine, and five of them had a reduction in free carnitine. A total of six mutations were identified in the MCCC1 gene, i.e., c.1630del(p.R544Dfs*2), c.269A>G(p.D90G), c.1609T>A(p.F537I), c.639+2T>A, c.761+1G>T, and c.1331G>A(p.R444H), and three mutations were identified in the MCCC2 gene, i.e., c.838G>T(p.D280Y), c.592C>T(p.Q198*,366), and c.1342G>A(p.G448A). Among these mutations, c.269A>G(p.D90G) and c.1609T>A(p.F537I) had not been previously reported in the literature. There was one case of maternal MCCD, and the child carried a heterozygous mutation from her mother. Five children with a reduction in free carnitine were given supplementation of L-carnitine, and free carnitine was restored to the normal level at the last follow-up visit. CONCLUSIONS: This study identifies two new mutations, c.269A>G(p.D90G) and c.1609T>A(p.F537I), thereby expanding the mutation spectrum of the MCCC1 gene. A combination of blood amino acid and acylcarnitine profiles, urine organic acid analysis, and genetic testing can facilitate early diagnosis and treatment of MCCD, and provide essential data for genetic counseling.

BACE1 inhibitors from the fruits of Alpinia oxyphylla have efficacy to treat T2DM-related cognitive disorder.

The fruits of Alpinia oxyphylla (Alpiniae Oxyphyllae Fructus, AOF) are one of the "Four Famous South Medicines" in China. In this study, beta-site amyloid protein precursor cleaving enzyme 1 (BACE1) was applied to explore the active components in AOF responsible for type 2 diabetes mellitus (T2DM)-related cognitive disorder. As a result, 24 compounds including three unreported ones (1, 3, 4) were isolated from AOF. Compound 1 is an unusual carbon­carbon linked diarylheptanoid dimer, and compound 4 is the first case of 3,4-seco-eudesmane sesquiterpenoid with a 5/6-bicyclic skeleton. Four diarylheptanoids (3, 5-7), one flavonoid (9) and two sesquiterpenoids (14 and 20) showed BACE1 inhibitory activity, of which the most active 6 was revealed to be a non-competitive and anti-competitive mixed inhibitor. Docking simulation suggested that OH-4' of 6 played important roles in maintaining activity by forming hydrogen bonds with Ser36 and Ile126 residues. Compounds 3, 5, 9 and 20 displayed neuroprotective effects against amyloid ß (Aß)-induced damage in BV2 cells. Mechanism study revealed that compounds 5 and 20 downregulated the expression of BACE1 and upregulated the expression of Lamp2 to exert effects. Thus, the characteristic diarylheptanoids and sesquiterpenoids in AOF had the efficacy to alleviate T2DM-related cognitive disorder by inhibiting BACE1 activity and reversing Aß-induced neuronal damage.

Protective Effect of Hibifolin on Lipopolysaccharide-Induced Acute Lung Injury Through Akt Phosphorylation and NFκB Pathway.

Acute lung injury (ALI) is a difficult condition to manage, especially when it is complicated by bacterial sepsis. Hibifolin, a flavonoid glycoside, has anti-inflammatory properties that make it a potential treatment for ALI. However, more research is needed to determine its effectiveness in LPS-induced ALI. In this study, male ICR mice were treated with hibifolin before LPS-induced ALI. Protein content and neutrophil count in bronchoalveolar lavage (BAL) fluid were measured by BCA assay and Giemsa staining method, respectively. The levels of proinflammatory cytokines and adhesive molecules were detected by ELISA assay. The expression of NFκB p65 phosphorylation, IκB degradation, and Akt phosphorylation was assessed by western blot assay. Hibifolin pre-treatment significantly reduced pulmonary vascular barrier dysfunction and neutrophil infiltration into the BAL fluid in LPS-induced ALI mice. In addition, LPS-induced expression of proinflammatory cytokines (IL-1ß, IL-6, TNF-α) and adhesive molecules (ICAM-1, VCAM-1) within the BAL fluid were markedly reduced by hibifolin in LPS-induced ALI mice. More, hibifolin inhibited LPS-induced phosphorylation of NFκB p65, degradation of IκB, and phosphorylation of Akt in lungs with ALI mice. In conclusion, hibifolin shows promise in improving the pathophysiological features and proinflammatory responses of LPS-induced ALI in mice through the NFκB pathway and its upstream factor, Akt phosphorylation.

PV and SST neurons in the anterior cingulate cortex regulate social disorders in adulthood induced by sensory abnormalities in childhood.

OBJECTIVE: Childhood sensory abnormalities experience has a crucial influence on the structure and function of the adult brain. The underlying mechanism of neurological function induced by childhood sensory abnormalities experience is still unclear. Our study was to investigate whether the GABAergic neurons in the anterior cingulate cortex (ACC) regulate social disorders caused by childhood sensory abnormalities experience. METHODS: We used two mouse models, complete Freund's adjuvant (CFA) injection mice and bilateral whisker trimming (BWT) mice in childhood. We applied immunofluorescence, chemogenetic and optogenetic to study the mechanism of parvalbumin (PV) neurons and somatostatin (SST) neurons in ACC in regulating social disorders induced by sensory abnormalities in childhood. RESULTS: Inflammatory pain in childhood leads to social preference disorders, while BWT in childhood leads to social novelty disorders in adult mice. Inflammatory pain and BWT in childhood caused an increase in the number of PV and SST neurons, respectively, in adult mice ACC. Inhibiting PV neurons in ACC improved social preference disorders in adult mice that experienced inflammatory pain during childhood. Inhibiting SST neurons in ACC improved social novelty disorders in adult mice that experienced BWT in childhood. CONCLUSIONS: Our study reveals that PV and SST neurons of the ACC may play a critical role in regulating social disorders induced by sensory abnormalities in childhood.

Stress perception and associated factors among patients with Parkinson's disease: a cross-sectional study after the COVID-19 pandemic.

BACKGROUND: Parkinson's disease (PD) is a serious neurodegenerative disease that brings great stress to the physical and mental health of patients. At the same time, long-term treatment will also bring great economic losses and social burden to the family and society, especially after COVID-19 pandemic. The aim of this study is to analyze the current status of stress perception and anxiety in patients with PD and explore the influencing factors after the COVID-19 pandemic. METHODS: This study used the convenient sampling method to select the research objects of patients with PD who were outpatients or inpatients in a general public hospital in Hangzhou, Zhejiang Province, and the survey time was from February 2023 to March 2023. The measurements included the General information questionnaire, The Perceived Stress Scale (PSS) and The Self Rating Anxiety Scale (SAS). SPSS 21.0 software was used for data statistical analysis. RESULT: 394 out of 420 patients with PD completed the questionnaire. The stress perception score of PD was (16.41 ± 6.435) and the anxiety score was (54.77 ± 10.477). The stress perception scores of patients with PD were significantly different in gender, age, educational, occupation, nature of costs, time of sleep, quality of sleep, duration of disease, way of medical treatment and anxiety level (p < 0.05). Among them, age, duration of disease, public expenses, online remote therapy and anxiety level were the main influencing factors of stress perception in patients with PD (p < 0.05). Besides, there were significant differences in gender, educational, nature of costs, time of sleep, quality of sleep and duration of disease in anxiety among patients with PD (p < 0.05). CONCLUSION: After the COVID-19 pandemic, the level of stress perception and anxiety in patients with PD is high, and the influencing factors are complex.

Glutathione determines chronic myeloid leukemia vulnerability to an inhibitor of CMPK and TMPK.

Bcr-Abl transformation leads to chronic myeloid leukemia (CML). The acquirement of T315I mutation causes tyrosine kinase inhibitors (TKI) resistance. This study develops a compound, JMF4073, inhibiting thymidylate (TMP) and cytidylate (CMP) kinases, aiming for a new therapy against TKI-resistant CML. In vitro and in vivo treatment of JMF4073 eliminates WT-Bcr-Abl-32D CML cells. However, T315I-Bcr-Abl-32D cells are less vulnerable to JMF4073. Evidence is presented that ATF4-mediated upregulation of GSH causes T315I-Bcr-Abl-32D cells to be less sensitive to JMF4073. Reducing GSH biosynthesis generates replication stress in T315I-Bcr-Abl-32D cells that require dTTP/dCTP synthesis for survival, thus enabling JMF4073 susceptibility. It further shows that the levels of ATF4 and GSH in several human CML blast-crisis cell lines are inversely correlated with JMF4073 sensitivity, and the combinatory treatment of JMF4073 with GSH reducing agent leads to synthetic lethality in these CML blast-crisis lines. Altogether, the investigation indicates an alternative option in CML therapy.

Utilizing Esophageal Motility Tests in Diagnosing and Evaluating Gastroesophageal Reflux Disease.

Gastroesophageal reflux disease (GERD), a prevalent clinical condition, is often attributed to aberrant esophageal motility, leading to gastric content reflux and associated symptoms or complications. The rising incidence of GERD presents an escalating healthcare challenge. Endoscopic and esophageal reflux monitoring can provide a basis for the diagnosis of patients with gastroesophageal reflux disease, but when the diagnostic basis is at an inconclusive value, some additional supportive evidence will be needed. Advanced technology is the key to improving patient diagnosis, accurate assessment, and the development of effective treatment strategies. High-resolution esophageal manometry (HREM) and endoscopic functional lumen imaging probe (EndoFLIP) represent the forefront of esophageal motility assessment. HREM, an evolution of traditional esophageal manometry, is considered the benchmark for identifying esophageal motility disorders. Its widespread application in esophageal dynamics research highlights its diagnostic significance. Concurrently, EndoFLIP's emerging clinical relevance is evident in diagnosing and guiding the treatment of coexisting esophageal motility issues. This review integrates contemporary research to delineate the contributions of HREM, EndoFLIP, and novel technologies in GERD. It examines their efficacy in facilitating an accurate diagnosis, differentiating similar gastrointestinal disorders, quantifying the extent of reflux, assessing the severity of the disease, forecasting patient responsiveness to proton pump inhibitor therapy, and guiding decisions for surgical interventions. The overarching aim is to deepen the understanding of GERD's underlying mechanisms and advance the formulation of holistic, efficacious treatment approaches.

Comprehensive investigation in oncogenic functions and immunological roles of NCBP2 and its validation in prostate cancer.

BACKGROUND: Nuclear cap-binding protein 2 (NCBP2), as the component of the cap-binding complex, participates in a number of biological processes, including pre-mRNA splicing, transcript export, translation regulation and other gene expression steps. However, the role of NCBP2 on the tumor cells and immune microenvironment remains unclear. To systematically analyze and validate functions of NCBP2, we performed a pan-cancer analysis using multiple approaches. METHODS: The data in this study were derived from sequencing, mutation, and methylation data in the TCGA cohort, normal sample sequencing data in the GTEx project, and cell line expression profile data in the CCLE database. RESULTS: Survival analyses including the Cox proportional-hazards model and log-rank test revealed the poor prognostic role of NCBP2 in multiple tumors. We further validated the oncogenic ability of NCBP2 in prostate cancer cell lines, organoids and tumor-bearing mice. A negative correlation was observed between NCBP2 expression and immune score by the ESTIMATE algorithm. Simultaneously, the NCBP2-induced immunosuppressive microenvironment might be related to the decline in CD8+T cells and the increase in regulatory T cells and neutrophils, examined by flow cytometry experiments for NCBP2 overexpressed tumor-bearing mice. CONCLUSION: This research offered strong proof supporting NCBP2 as the prognostic marker and the therapeutic target in the future.

New labdane diterpenoids from Alpinia galanga: A new type of GLP-1 secretagogues targeting the PKA-CREB and PI3K-Akt signaling axes.

Glucagon-like peptide-1 (GLP-1) secretagogues are fascinating pharmacotherapies to overcome the defects of GLP-1 analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors in treating diabetes and obesity. To discover new GLP-1 secretagogues from natural sources, alpigalangols A-Q (1-17), 17 new labdane diterpenoids including four unusual nor-labdane and N-containing ones, were isolated from the fruits of Alpinia galanga. Most of the isolates showed GLP-1 promotive effects in NCl-H716 cells, of which compounds 3, 4, 12, and 14-17 were revealed with high promoting rates of 246.0%-413.8% at 50 µM. A mechanistic study manifested that the most effective compound 12 upregulated the mRNA expression of Gcg and Pcsk1, and the protein phosphorylation of PKA, CREB, and GSK3ß, but was inactive on GPBAR and GPR119 receptors. Network pharmacology analysis indicated that the PI3K-Akt pathway was involved in the GLP-1 stimulation of 12, which was highly associated with AKT1, CASP3, PPARG, and ICAM1 proteins. This study suggests that A. galanga is rich in diverse labdane diterpenoids with GLP-1 promoting effects, representing a new type of antidiabetic candidates from natural sources.

Increased ONECUT2 induced by Helicobacter pylori promotes gastric cancer cell stemness via an AKT-related pathway.

Helicobacter pylori (HP) infection initiates and promotes gastric carcinogenesis. ONECUT2 shows promise for tumor diagnosis, prognosis, and treatment. This study explored ONECUT2's role and the specific mechanism underlying HP infection-associated gastric carcinogenesis to suggest a basis for targeting ONECUT2 as a therapeutic strategy for gastric cancer (GC). Multidimensional data supported an association between ONECUT2, HP infection, and GC pathogenesis. HP infection upregulated ONECUT2 transcriptional activity via NFκB. In vitro and in vivo experiments demonstrated that ONECUT2 increased the stemness of GC cells. ONECUT2 was also shown to inhibit PPP2R4 transcription, resulting in reduced PP2A activity, which in turn increased AKT/ß-catenin phosphorylation. AKT/ß-catenin phosphorylation facilitates ß-catenin translocation to the nucleus, initiating transcription of downstream stemness-associated genes in GC cells. HP infection upregulated the reduction of AKT and ß-catenin phosphorylation triggered by ONECUT2 downregulation via ONECUT2 induction. Clinical survival analysis indicated that high ONECUT2 expression may indicate poor prognosis in GC. This study highlights a critical role played by ONECUT2 in promoting HP infection-associated GC by enhancing cell stemness through the PPP2R4/AKT/ß-catenin signaling pathway. These findings suggest promising therapeutic strategies and potential targets for GC treatment.

Design of Mn-based nanozymes with multiple enzyme-like activities for identification/quantification of glyphosate and green transformation of organophosphorus.

A Mn-based nanozyme, Mn-uNF/Si, with excellent alkali phosphatase-like activity was designed by in-situ growth of ultrathin Mn-MOF on the surface of silicon spheres, and implemented as an effective solid Lewis-Brønsted acid catalyst for broad-spectrum dephosphorylation. H218O-mediated GC-MS studies confirmed the cleavage sites and the involvement of H2O in the new bonds. DRIFT NH3-IR and in-situ ATR-FTIR confirmed the coexistence of Lewis-Brønsted acid sites and the adjustment of adsorption configurations at the interfacial sites. In addition, a green transformation route of "turning waste into treasure" was proposed for the first time ("OPs→PO43-→P food additive") using edible C. reinhardtii as a transfer station. By alkali etching of Mn-uNF/Si, a nanozyme Mn-uNF with laccase-like activity was obtained. Intriguingly, glyphosate exhibits a laccase-like fingerprint-like response (+,-) of Mn-uNF, and a non-enzyme amplified sensor was thus designed, which shows a good linear relationship with Glyp in a wide range of 0.49-750 µM, with a low LOD of 0.61 µM, as well as high selectivity and anti-interference ability under the co-application of phosphate fertilizers and multiple pesticides. This work provides a controllable methodology for the design of bifunctional nanozymes, which sheds light on the highly efficient green transformation of OPs, and paves the way for the selective recognition and quantification of glyphosate. Mechanistically, we also provided deeper insights into the structure-activity relationship at the atomic scale.

Isospongian Diterpenoids from the Leaves of Amomum tsao-ko Promote GLP-1 Secretion via Ca2+/CaMKII and PKA Pathways and Inhibit DPP-4 Enzyme.

Three uncommon isospongian diterpenoids including a new one, 3-epi-kravanhin A (2), were isolated from the leaves of Amomum tsao-ko. Compounds 2 and 3 dose-dependently promoted GLP-1 secretion on STC-1 cells with promotion ratios of 109.7% and 186.1% (60 µM). Mechanism study demonstrated that the GLP-1 stimulative effects of 2 and 3 were closely related with Ca2+/CaMKII and PKA pathways, but irrelevant to GPBAR1 and GPR119 receptors. Moreover, compound 1 showed moderate DPP-4 inhibitory activity with an IC50 value of 311.0 µM. Molecular docking verified the binding affinity of 1 with DPP-4 by hydrogen bonds between the γ-lactone carbonyl (C-15) and Arg61 residue. Bioinformatics study indicated that compound 1 exerted antidiabetic effects by improving inflammation, oxidative stress and insulin resistance. This study first disclosed the presence of isospongian diterpenoids in A. tsao-ko, which showed antidiabetic potency by promoting GLP-1 secretion and inhibiting DPP-4 activity.

DMLS: an automated pipeline to extract the Drosophila modular transcription regulators and targets from massive literature articles.

Transcription regulation in multicellular species is mediated by modular transcription factor (TF) binding site combinations termed cis-regulatory modules (CRMs). Such CRM-mediated transcription regulation determines the gene expression patterns during development. Biologists frequently investigate CRM transcription regulation on gene expressions. However, the knowledge of the target genes and regulatory TFs participating in the CRMs under study is mostly fragmentary throughout the literature. Researchers need to afford tremendous human resources to fully surf through the articles deposited in biomedical literature databases in order to obtain the information. Although several novel text-mining systems are now available for literature triaging, these tools do not specifically focus on CRM-related literature prescreening, failing to correctly extract the information of the CRM target genes and regulatory TFs from the literature. For this reason, we constructed a supportive auto-literature prescreener called Drosophila Modular transcription-regulation Literature Screener (DMLS) that achieves the following: (i) prescreens articles describing experiments on modular transcription regulation, (ii) identifies the described target genes and TFs of the CRMs under study for each modular transcription-regulation-describing article and (iii) features an automated and extendable pipeline to perform the task. We demonstrated that the final performance of DMLS in extracting the described target gene and regulatory TF lists of CRMs under study for given articles achieved test macro area under the ROC curve (auROC) = 89.7% and area under the precision-recall curve (auPRC) = 77.6%, outperforming the intuitive gene name-occurrence-counting method by at least 19.9% in auROC and 30.5% in auPRC. The web service and the command line versions of DMLS are available at https://cobis.bme.ncku.edu.tw/DMLS/  and  https://github.com/cobisLab/DMLS/, respectively. Database Tool URL: https://cobis.bme.ncku.edu.tw/DMLS/.

Power-Doppler-based NH002 microbubble sonoporation with chemotherapy relieves hypoxia and enhances the efficacy of chemotherapy and immunotherapy for pancreatic tumors.

Pancreatic ductal adenocarcinoma (PDAC) poses challenges due to late-stage diagnosis and limited treatment response, often attributed to the hypoxic tumor microenvironment (TME). Sonoporation, combining ultrasound and microbubbles, holds promise for enhancing therapy. However, additional preclinical research utilizing commercially available ultrasound equipment for PDAC treatment while delving into the TME's intricacies is necessary. This study investigated the potential of using a clinically available ultrasound system and phase 2-proven microbubbles to relieve tumor hypoxia and enhance the efficacy of chemotherapy and immunotherapy in a murine PDAC model. This approach enables early PDAC detection and blood-flow-sensitive Power-Doppler sonoporation in combination with chemotherapy. It significantly extended treated mice's median survival compared to chemotherapy alone. Mechanistically, this combination therapy enhanced tumor perfusion and substantially reduced tumor hypoxia (77% and 67%, 1- and 3-days post-treatment). Additionally, cluster of differentiation 8 (CD8) T-cell infiltration increased four-fold afterward. The combined treatment demonstrated a strengthening of the anti-programmed death-ligand 1(αPDL1) therapy against PDAC. Our study illustrates the feasibility of using a clinically available ultrasound system with NH-002 microbubbles for early tumor detection, alleviating hypoxic TME, and improving chemotherapy and immunotherapy. It suggests the development of an adjuvant theragnostic protocol incorporating Power-Doppler sonoporation for pancreatic tumor treatment.

ι-Carrageenan catabolism is initiated by key sulfatases in the marine bacterium Pseudoalteromonas haloplanktis LL1.

Marine bacteria contribute substantially to cycle macroalgae polysaccharides in marine environments. Carrageenans are the primary cell wall polysaccharides of red macroalgae. The carrageenan catabolism mechanism and pathways are still largely unclear. Pseudoalteromonas is a representative bacterial genus that can utilize carrageenan. We previously isolated the strain Pseudoalteromonas haloplanktis LL1 that could grow on ι-carrageenan but produce no ι-carrageenase. Here, through a combination of bioinformatic, biochemical, and genetic analyses, we determined that P. haloplanktis LL1 processed a desulfurization-depolymerization sequential pathway for ι-carrageenan utilization, which was initiated by key sulfatases PhSulf1 and PhSulf2. PhSulf2 acted as an endo/exo-G4S (4-O-sulfation-ß-D-galactopyranose) sulfatase, while PhSulf1 was identified as a novel endo-DA2S sulfatase that could function extracellularly. Because of the unique activity of PhSulf1 toward ι-carrageenan rather than oligosaccharides, P. haloplanktis LL1 was considered to have a distinct ι-carrageenan catabolic pathway compared to other known ι-carrageenan-degrading bacteria, which mainly employ multifunctional G4S sulfatases and exo-DA2S (2-O-sulfation-3,6-anhydro-α-D-galactopyranose) sulfatase for sulfate removal. Furthermore, we detected widespread occurrence of PhSulf1-encoding gene homologs in the global ocean, indicating the prevalence of such endo-acting DA2S sulfatases as well as the related ι-carrageenan catabolism pathway. This research provides valuable insights into the enzymatic processes involved in carrageenan catabolism within marine ecological systems.IMPORTANCECarrageenan is a type of linear sulfated polysaccharide that plays a significant role in forming cell walls of marine algae and is found extensively distributed throughout the world's oceans. To the best of our current knowledge, the ι-carrageenan catabolism in marine bacteria either follows the depolymerization-desulfurization sequential process initiated by ι-carrageenase or starts from the desulfurization step catalyzed by exo-acting sulfatases. In this study, we found that the marine bacterium Pseudoalteromonas haloplanktis LL1 processes a distinct pathway for ι-carrageenan catabolism employing a specific endo-acting DA2S-sulfatase PhSulf1 and a multifunctional G4S sulfatase PhSulf2. The unique PhSulf1 homologs appear to be widely present on a global scale, indicating the indispensable contribution of the marine bacteria containing the distinct ι-carrageenan catabolism pathway. Therefore, this study would significantly enrich our understanding of the molecular mechanisms underlying carrageenan utilization, providing valuable insights into the intricate roles of marine bacteria in polysaccharide cycling in marine environments.

Visible-to-Near-Infrared Mechanoluminescence in Bi-Activated Spinel Compounds for Multiple Information Anticounterfeiting.

Mechanoluminescence (ML) is the nonthermal luminescence generated in the process of force-to-light conversion, which has broad prospects in stress sensing, wearable devices, biomechanics, and multiple information anticounterfeiting. Multivalence emitter ions utilize their own self-reduction process to realize multiband ML without introducing another dopant, such as Eu3+/Eu2+, Sm3+/Sm2+, and Mn4+/Mn2+. However, self-reduction-induced ML in bismuth-activated materials has rarely been reported so far. In this work, a novel visible-to-near-infrared (vis-NIR) ML induced by the self-reduction of Bi3+ to Bi2+ in the spinel-type compound (MgGa2O4) is reported. The photoluminescence (PL) spectra, PL excitation (PLE) spectra, and PL lifetime curves demonstrate that Bi3+/Bi2+ ions are the main luminescence centers. Notably, the possible self-reduction model is proposed, where a magnesium vacancy (VMg″) is considered as the driving force for the self-reduction of Bi3+ to Bi2+. Furthermore, an oxygen vacancy (VO••) is confirmed by electron paramagnetic resonance (EPR) spectroscopy. Combined with thermoluminescence (TL) glow curves and ML spectra, a plausible trap-controlled ML mechanism is illustrated, where electron-hole (VO••/VMg″) pairs play a significant role in capturing electrons and holes. It is worth noting that the proof-of-concept dual-mode electronic signature application is implemented based on the flexible ML film, which improves the capabilities of signature anticounterfeiting for high-level security applications. Besides, multistimulus-responsive luminescence behaviors of the ML film are realized under the excitation of a 254 nm UV lamp, thermal disturbance, 980 nm laser, and mechanical stimuli. In general, this study provides new insights into designing vis-NIR ML materials toward wider application possibilities.