Design, synthesis and biological evaluation of 4-(indolin-1-yl)-6-substituted-pyrido[3,2-d]pyrimidine derivatives as Mnk1/2 inhibitors.

The Mnk-eIF4E axis plays a crucial role in tumor development, and inhibiting Mnk kinases is a promising approach for cancer therapy. Starting with fragment WS23, a series of 4-(indolin-1-yl)-6-substituted-pyrido[3,2-d]pyrimidine derivatives were designed and synthesized. Among these derivatives, compound 15b showed the highest potency with IC50 values of 0.8 and 1.5 nM against Mnk1 and Mnk2, respectively. Additionally, it demonstrated good selectivity among 30 selected kinases. 15b significantly suppressed MOLM-13 and K562 cell lines growth and caused cell cycle arrest. Furthermore, the Western blot assay revealed that 15b effectively downregulated the downstream proteins p-eIF4E, Mcl-1, and c-myc. Additionally, 15b exhibited remarkable stability in rat plasma and rat and human microsomes. In vivo anti-tumor activity study suggested that treatment with 15b suppressed tumor growth in LL/2 syngeneic models. These findings highlight the potential of 15b as a novel and potent Mnks inhibitor, which deserves further investigation.

The Receptor Kinases DRUS1 and DRUS2 Behave Distinctly in Osmotic Stress Tolerance by Modulating the Root System Architecture via Auxin Signaling.

Receptor kinases DRUS1 (Dwarf and Runtish Spikelet1) and DRUS2 are orthologues of the renowned Arabidopsis thaliana gene FERONIA, which play redundant roles in rice growth and development. Whether the two duplicated genes perform distinct functions in response to environmental stress is largely unknown. Here, we found that osmotic stress (OS) and ABA increased DRUS1 expression while decreasing DRUS2. When subjected to osmotic stress, the increased DRUS1 in drus2 mutants suppresses the OsIAA repressors, resulting in a robust root system with an increased number of adventitious and lateral roots as well as elongated primary, adventitious, and lateral roots, conferring OS tolerance. In contrast, the decreased DRUS2 in drus1-1 mutants are not sufficient to suppress OsIAA repressors, leading to a feeble root system with fewer adventitious and lateral roots and hindering seminal root growth, rendering OS intolerance. All these findings offer valuable insights into the biological significance of the duplication of two homologous genes in rice, wherein, if one is impaired, the other one is able to continue auxin-signaling-mediated root growth and development to favor resilience to environmental stress, such as water shortage.

Clinical efficacy of acupuncture in treating postoperative gastrointestinal dysfunction of colorectal cancer, a systematic review and Meta analysis. / é’ˆåˆºæ²»ç–—ç»“ç›´è‚ ç™Œæœ¯åŽèƒƒè‚ åŠŸèƒ½éšœç¢ç–—æ•ˆçš„ 系统评价和Meta分析.

OBJECTIVES: To evaluate the efficacy of acupuncture in the treatment of postoperative gastrointestinal dysfunction(POGD) of colorectal cancer. METHODS: Randomized controlled trials of acupuncture in the treatment of POGD were retrieved from 7 databases including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, VIP Chinese Journal Service Platform, WanFang Data Knowledge Service Platform, and China Biology Medicine disc. The search period ranged from the inception of the databases to November 10th, 2022. The quality of the included literature was assessed using the Cochrane bias risk assessment tool and the modified Jadad scale. Meta analysis was conducted using RevMan 5.4. Regression analysis and bias risk analysis were performed using Stata 16.0. Trial sequential analysis was conducted using TSA 0.9 software. RESULTS: A total of 27 randomized controlled trials involving 2 629 patients were included. Intervention measures included manual acupuncture, electroacupuncture, transcutaneous acupoint electrical stimulation, warm acupuncture, and thumb-tack needle. The results showed that acupuncture treatment significantly reduced time to tolerance of liquid diet after surgery (MD=-13.70, 95% CI=ï¼»-17.94, -9.46ï¼½, P<0.000 01), time to first defecation (MD=-18.20, 95% CI=ï¼»-22.62, -13.78ï¼½, P<0.000 01), time to first flatus (MD=-16.31, 95% CI=ï¼»-20.32, -12.31ï¼½, P<0.000 01), time to bowel sounds recovery (MD=-11.91, 95% CI=ï¼»-14.01, -9.81ï¼½, P<0.000 01), and length of hospital stay (MD=-1.49, 95% CI=ï¼»-2.27, -0.70ï¼½, P=0.000 2). Regression analysis indicated that cancer type, study quality and number of acupuncture were the main sources of heterogeneity. Bias analysis suggested potential publication bias risks. Trial sequential analysis indicated that the required number of cases had been met and the conclusion was reliable. CONCLUSIONS: Acupuncture is an effective intervention for promoting gastrointestinal recovery in patients undergoing colorectal cancer surgery. Further large-sample and well-designed clinical trials are still needed to compare different acupuncture techniques.

How do the main components influence the VOCs emission characteristics and formation pathways during moso bamboo heat treatment?

Bamboo heat treatment will cause plenty of release of volatile organic compounds (VOCs) into the atmosphere which are important precursors for ozone (O3) formation. In this study, dewaxed bamboo was heat-treated at 180 °C for 2 h to investigate the emission characteristics and the formation pathways of VOCs during heat treatment by removing different main components. The results showed that aldehydes (22.61%-57.54%) and esters (14.64%-38.88%) are the primary VOCs released during heat treatment. These compounds mainly originate from the degradation of hemicellulose, lignin, cellulose, and the linkage bonds between them in bamboo. During the bamboo heat treatment, the degradation of CO, CH, and CO bonds in hemicellulose results in the release of 5-hydroxymethylfurfural, 3-furfural, and 1-(+)-ascorbic acid 2,6-dihexadecanoate. The breakage of benzene ring group and the CO and CH bonds of lignin leading to the emission of VOCs including m-Formylphenol, Vanillin, and Syringaldehyde. The degradation of aliphatic CH, CC, and CO bonds in the amorphous region of cellulose contributes to an enhanced release of alcohols, olefins, and alkanes. It is calculated that acids (28.92%-59.47%), esters (10.10%-22.03%) and aldehydes (17.88%-39.91%) released during heat treatment contributed more to Ozone Formation Potential (OFP).

Clinical effects of a combination of phenylbutazone and omeprazole on chronic lameness in Mongolian horses.

BACKGROUND: Phenylbutazone (PBZ) is the most commonly used drug to treat symptoms of lameness in horses; however, it is associated with adverse effects such as gastric ulcer syndrome (EGUS). Interestingly, many practitioners prescribe omeprazole (OME) concurrently with PBZ to prevent the development of EGUS. However, the efficacy and safety of this practice in Mongolian horses with chronic lameness remain unknown. OBJECTIVES: To evaluate the clinical effects of a combination of PBZ and OME on chronic lameness in Mongolian horses. STUDY DESIGN: Randomised block experimental design. METHODS: Eighteen Mongolian horses with lameness score was ≥3 points, were divided into three treatment groups, with six horses in each group: placebo (CON), PBZ (4.4 mg/kg PO q. 24 h), or PBZ plus OME (4 mg/kg PO q. 24 h; PBZ + OME) in a randomised block design based on the initial lameness score. The horses were treated for 15 days. During this period, weekly gastroscopy, and physiological and biochemical tests were performed. RESULTS: Both PBZ (median 1.0, interquartile range [IQR]: 0.8-1.3; p = 0.01) and PBZ + OME (median 1.0, IQR: 1.0-1.0; p = 0.01) significantly decreased the lameness score compared with before administration. In addition, PBZ significantly increased the equine glandular gastric disease (EGGD) score (3.0 ± 0.6, p < 0.001), GT-17 content (293.4 ± 21.8 pg/mL, p < 0.001), and pepsinogen-1 (PG1) content (295.3 ± 38.3 ng/mL, p < 0.001) compared with CON or PBZ + OME. However, it significantly reduced the total protein (53.6 ± 1.5 g/L, p < 0.05) and albumin (25.5 ± 1.8 g/L, p < 0.05) contents. Nevertheless, compared with PBZ, PBZ + OME significantly decreased the EGGD score (0.3 ± 0.5, p < 0.001) and significantly increased the gastric fluid pH (7.3 ± 0.5, p < 0.001), total protein content (62.5 ± 4.6 g/L, p = 0.009), and albumin content (29.4 ± 1.1 g/L, p = 0.004). Meanwhile, they significantly diminished the gastrin 17 (GT-17) (162.0 ± 21.0 pg/mL, p < 0.001) and PG1 (182.4 ± 22.5 ng/mL, p < 0.001) contents. MAIN LIMITATIONS: Individual differences in horses were larger, but the sample size was small. There was larger interval between observations for each index. CONCLUSIONS: Compared with PBZ alone, PBZ + OME had no therapeutic effect on chronic lameness; however, it reduced the occurrence of EGGD in Mongolian horses. Horses may be protected against chronic lameness and PBZ-induced EGGD by increasing the pH value, decreasing serum PG1 and GT-17 content, and preventing the reduction of myeloperoxidase content.

miR-155-5p/Bmal1 Modulates the Senescence and Osteogenic Differentiation of Mouse BMSCs through the Hippo Signaling Pathway.

BACKGROUND: The core clock gene brain and muscle ARNT like-1 (Bmal1) is involved in the regulation of bone tissue aging. However, current studies are mostly limited to the establishment of the association between Bmal1 and bone senescence, without in-depth exploration of its main upstream and downstream regulatory mechanisms. METHODS: The luciferase reporter assay, RT-qPCR and Western blotting were performed to detect the interaction between miR-155-5p and Bmal1. The effects of miR-155-5p and Bmal1 on the aging and osteogenic differentiation ability of mouse bone marrow mesenchymal stem cells (BMSCs) were investigated by cell counting kit-8 (CCK-8) assay, flow cytometry, ß-gal staining, alkaline phosphatase quantitative assay and alizarin red staining in vitro. The potential molecular mechanism was identified by ChIP-Seq, RNA-seq database analysis and immunofluorescence staining. RESULTS: The expression of Bmal1 declined with age, while the miR-155-5p was increased. miR-155-5p and Bmal1 repressed each other's expression, and miR-155-5p targeted the Bmal1. Besides, miR-155-5p inhibited the proliferation and osteogenic differentiation of BMSCs, promoted cell apoptosis and senescence, inhibited the expression and nuclear translocation of YAP and TAZ. However, Bmal1 facilitated the osteogenic differentiation and suppressed the aging of BMSCs, meanwhile inactivated the Hippo pathway. Moreover, YAP inhibitors abrogated the positive regulation of aging and osteogenic differentiation in BMSCs by miR-155-5p and Bmal1. CONCLUSION: In mouse BMSCs, miR-155-5p and Bmal1 regulated the aging and osteogenic differentiation ability of BMSCs mainly through the Hippo signaling pathway. Our findings provide new insights for the interventions in bone aging.

Comprehensive review of solid tumor bone marrow metastasis.

Bone marrow metastasis (BMM) of solid tumors refers to a group of diseases that originate from non-hematopoietic malignant tumor cells invading the bone marrow (BM) through complex metastatic patterns. If BMM identification is delayed, the disease will rapidly develop into disseminated carcinogenesis of the BM, which manifests as a series of hematological disorders and microangiopathic hemolytic anemia, leading to serious life-threatening conditions. Although the study of solid tumor BMM is receiving increasing attention, study remains limited, and most descriptions are derived from case reports. Currently, clinicians have insufficient understanding of BMM, and BMM occurrence is often not recognized early or treated effectively, resulting in high mortality rates. In this article, we review the epidemiology, molecular mechanisms, clinical diagnosis, treatment, and prognosis of solid tumor BMM.

Extraction, functionality, and applications of Chlorella pyrenoidosa protein/peptide.

Chlorella pyrenoidosa (C. pyrenoidosa) has been widely used in commercial food and feed production for numerous years. Its high protein content and cost-effectiveness make it an attractive source of novel protein. With a focus on sustainable development and the search for green natural products, current research is dedicated to maximizing the utilization of C. pyrenoidosa protein (CPP) and peptide. Various techniques, such as the use of ionic liquids, freeze-thawing, ultrasonication, enzyme digest, microwaving are employed in the extraction of CPP. The extracted CPP has demonstrated antioxidant, anti-inflammatory, and bacteriostatic properties. It can also stimulate immune regulation, prevent cardiovascular disease, protect red blood cells, and even be used in wastewater treatment. Furthermore, CPP has shown some potential in combating obesity. Additionally, CPP is being explored in three-dimensional (3D) printing applications, particularly for the creation of biological scaffolds. It is also anticipated to play a role in 3D food printing. This review aimed to supply a comprehensive summary of CPP and C. pyrenoidosa peptide extraction methods, their functions, and practical applications in various industries. By doing so, it seeks to underpin subsequent research efforts, highlight current research limitations, and identify future research directions in this field.

Model-based predictions of protective HIV pre-exposure prophylaxis adherence levels in cisgender women.

Most human immunodeficiency virus (HIV) infections occur in cisgender women in resource-limited settings. In women, self-protection with emtricitabine/tenofovir disoproxil fumarate pre-exposure prophylaxis (FTC/TDF-PrEP) constitutes a major pillar of HIV prevention. However, clinical trials in women had inconsistent outcomes, sparking uncertainty about adherence requirements and reluctance in evaluating on-demand regimens. We analyzed data from published FTC/TDF-PrEP trials to establish efficacy ranges in cisgender women. In a 'bottom-up' approach, we modeled hypotheses in the context of risk-group-specific, adherence-efficacy profiles and challenged those hypotheses with clinical data. We found that different clinical outcomes were related to the proportion of women taking the product, allowing coherent interpretation of the data. Our analysis showed that 90% protection was achieved when women took some product. We found that hypotheses of putative male/female differences were either not impactful or statistically inconsistent with clinical data. We propose that differing clinical outcomes could arise from pill-taking behavior rather than biological factors driving specific adherence requirements in cisgender women.

Development and validation of a clinical prediction model for detecting coronary heart disease in middle-aged and elderly people: a diagnostic study.

OBJECTIVE: To develop and validate a multivariate prediction model to estimate the risk of coronary heart disease (CHD) in middle-aged and elderly people and to provide a feasible method for early screening and diagnosis in middle-aged and elderly CHD patients. METHODS: This study was a single-center, retrospective, case-control study. Admission data of 932 consecutive patients with suspected CHD were retrospectively assessed from September 1, 2020 to December 31, 2021 in the Department of Integrative Cardiology at China-Japan Friendship Hospital. A total of 839 eligible patients were included in this study, and 588 patients were assigned to the derivation set and 251 as the validation set at a 7:3 ratio. Clinical characteristics of included patients were compared between derivation set and validation set by univariate analysis. The least absolute shrinkage and selection operator (Lasso) regression analysis method was performed to avoid collinearity and identify key potential predictors. Multivariate logistic regression analysis was used to construct a clinical prediction model with identified predictors for clinical practice. Bootstrap validation was used to test performance and eventually we obtained the actual model. And the Hosmer-Lemeshow test was carried out to evaluate the goodness-fit of the constructed model. The area under curve (AUC) of receiver operating characteristic (ROC), calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) were plotted and utilized with validation set to comprehensively evaluate the predictive accuracy and clinical value of the model. RESULTS: A total of eight indicators were identified as risk factors for the development of CHD in middle-aged and elderly people by univariate analysis. Of these candidate predictors, four key parameters were defined to be significantly related to CHD by Lasso regression analysis, including age (OR 1.034, 95% CI 1.002 ~ 1.067, P = 0.040), hemoglobin A1c (OR 1.380, 95% CI 1.078 ~ 1.768, P = 0.011), ankle-brachial index (OR 0.078, 95% CI 0.012 ~ 0.522, P = 0.009), and brachial artery flow-mediated vasodilatation (OR 0.848, 95% CI 0.726 ~ 0.990, P = 0.037). The Hosmer-Lemeshow test showed a good calibration performance of the clinical prediction model (derivation set, χ2 = 7.865, P = 0.447; validation set, χ2 = 11.132, P = 0.194). The ROCs of the nomogram in the derivation set and validation set were 0.722 and 0.783, respectively, suggesting excellent predictive power and suitable performance. The clinical prediction model presented a greater net benefit and clinical impact based on DCA and CIC analysis. CONCLUSION: Overall, the development and validation of the multivariate model combined the laboratory and clinical parameters of patients with CHD, which could be beneficial to the individualized prediction of middle-aged and elderly people, and helped to facilitate clinical assessments and decisions during treatment and management of CHD.

Prognosis of coronary heart disease after percutaneous coronary intervention: a bibliometric analysis over the period 2004-2022.

BACKGROUND: As the complexity and diversity of the percutaneous coronary intervention (PCI) are being explored and reported, burgeoning research has progressed in this field. However, there is no comprehensive analysis available on PCI-related studies published in the literature. This study aimed to analyze and visualize the changes of scientific output regarding prognosis of coronary heart disease (CHD) after PCI over the past 20 years and to reveal the knowledge domain and development trends in this field by using CiteSpace software. METHODS: Relevant articles published over the period 2004-2022 were retrieved from the Web of Science Core Collection database. After manual selection, qualified documents were included and recorded with the information of their title, abstract, keyword, author, descriptor, citation, identifier, publishing year and publishing organization. We transferred the data to CiteSpace V5.8.R2 (Version 5.8.R2) to draw knowledge maps and to conduct co-occurrence analysis, cluster analysis, timeline analysis, burst term detection and citation analysis. RESULTS: A total of 14,699 literature records were found relating prognosis of CHD after PCI in the past 20 years (2004-2022), including 14,212 original articles and reviews, and they were published in 153 different journals. Publication production has increased annually and a total of 1182 authors, 796 institutes and 147 countries have contributed to these publications. Moreover, the most representative author was Gregg W Stone from the CardioVascular Research Foundation (CVRF) with 368 publications, whose team mainly focused on exploring the efficacy and safety of revascularization and the characteristics of susceptible population. The global productivity ranking was led by the USA with 3326 published papers, followed by Italy (n = 1355), Japan (n = 1080), China (n = 1075) and Germany (n = 937). And the keywords of these publications were "percutaneous coronary intervention" (n = 2271), "outcome" (n = 1756), "mortality" (n = 1730) and "impact" (n = 1334). Other commonly-used words were "predictor" (n = 1324), "intervention" (n = 1310), "angioplasty" (n = 1299), "risk" (n = 1144), "acute myocardial infarction" (n = 1136) and "artery disease" (n = 1098). Cluster analysis showed that 15 high connected clusters were generated with a modularity Q of 0.831 and a weighted mean silhouette of 0.9388 by applying the log-likelihood ratio algorithm, and the top 5 clusters were #0 optical coherence tomography, #1 dual antiplatelet therapy, #2 bleeding, #3 clopidogrel and #4 thrombus aspiration. Furthermore, the frontiers in the field of prognosis of CHD after PCI mainly involved "decision making", "reperfusion", "angioplasty", "balloon", "unstable angina", "dual antiplatelet therapy", "cardiac surgical score", "restenosis", "reperfusion", "thrombolytic therapy", etc. CONCLUSIONS: To sum up, efficacy and safety of different types of stents, the risk factors of restenosis and thrombotic events after PCI, early risk assessment, and secondary prevention and complications of patients with CHD after PCI were research hotspots and frontier topics in the area by bibliometric analysis. The results could provide a comprehensive overview of the research hotspots and frontier topics relating prognosis of CHD after PCI, promoting a better understanding of the knowledge domain and development trends in this field during the past 20 years.

Identifying STRN3-RARA as a new fusion gene for acute promyelocytic leukemia.

Here we report a new fusion gene, STRN3-RARA, in acute promyelocytic leukemia (APL). It cooperates with UTX deficiency to drive full-blown APL in mice. Although STRN3-RARA leukemia quickly relapses after all-trans retinoic acid treatment, it can be restrained by cepharanthine.

Gas Phase Experimental and Computational Studies of AlkB Substrates: Intrinsic Properties and Biological Implications.

The gas phase acidity and proton affinity of nucleobases that are substrates for the DNA repair enzyme AlkB have been examined using both computational and experimental methods. These thermochemical values have not heretofore been measured and provide experimental data that help benchmark the theoretical results. We also use our gas phase results to lend insight into the AlkB mechanism, particularly in terms of the role AlkB plays in DNA repair, versus its complementary enzyme AlkA.

IGH rod-like tracer: An AlphaFold2 structural similarity extraction-based predictive biomarker for MRD monitoring in pre-B-ALL.

Sequence variation resulting from the evolution of IGH clones and immunophenotypic drift makes it difficult to track abnormal B cells in children with precursor B cell acute lymphoblastic leukemia (pre-B-ALL) by flow cytometry, qPCR, or next-generation sequencing (NGS). The V-(D)-J regions of immunoglobulin and T cell receptor of 47 pre-B-ALL samples were sequenced using the Illumina NovaSeq platform. The IGH rod-like tracer consensus sequence was extracted based on its rod-like alpha-helices structural similarity predicted by AlphaFold2. Additional data from published 203 pre-B-ALL samples were applied for validation. NGS-IGH (+) patients with pre-B-ALL had a poor prognosis. Consistent CDR3-coded protein structures in NGS-IGH (+) samples could be extracted as a potential follow-up marker for pre-B-ALL children during treatment. IGH rod-like tracer from quantitative immune repertoire sequencing may serve as a class of biomarker with significant predictive values for the dynamic monitoring of MRD in pre-B-ALL children.

Rapid and Sensitive Detection of Polycyclic Aromatic Hydrocarbons in Tea Leaves Using Magnetic Approach.

A rapid and efficient method using an alkyl-functionalized magnetic nanoparticles-based extraction technique combined with Ultra-High Performance Liquid Chromatography was developed for the detection of trace amounts of polycyclic aromatic hydrocarbons in tea leaves. As a popular coating for chromatographic column packing materials, C18-alkyl has been demonstrated to be effective in separating polycyclic aromatic hydrocarbons. Additionally, the magnetism of the nanomaterials accelerates the extraction process while their high surface ratio enables desirable dispersity in the sample matrix. Meanwhile, the adsorbents can be washed and reused 30 times without compromising recovery, which greatly reduces the budget. The effects of various parameters were investigated and optimized, and the recoveries for five analytes were in the range of 84.8-105.4%. The RSD of intra-day and inter-day were below 11.9% and 6.8%, respectively. The limits of detection and limits of quantification ranged from 1.69-9.97 ng g-1 and 5.12-30.21 ng g-1, indicating satisfactory sensitivity. Thus, the proposed methodology is rapid, highly efficient, and economical, and it expands the application of magnetic cleanup approaches in complex food matrices.

Hydrocarbon Accumulation Periods in the Upper Paleozoic Strata of the Western Ordos Basin, China, Based on Fluid Inclusions and Basin Modeling.

The upper Paleozoic strata in the western part of the Ordos Basin have rich oil and gas resources but low exploration levels. These strata were subjected to multiple tectonic events, such as the Caledonian, Hercynian, Indosinian, and Himalayan movements, which led to a relatively complex process of hydrocarbon accumulation in the study area. These strata also have obvious structural segmentation in the north-south direction. However, the accumulation periods of the upper Paleozoic strata in different structural sections of the western Ordos Basin and their differences are poorly understood. A total of 65 sandstone samples from the upper Paleozoic reservoirs in 16 representative wells were selected for fluid inclusion analyses. The results of fluid inclusion analyses, combined with the burial-thermal histories of representative wells, were used to determine the hydrocarbon accumulation periods of the main layers and summarize their patterns in different structural regions and layers. The results show that the formation of fluid inclusions in the main upper Paleozoic strata can be divided into two stages. The first-stage inclusions mainly occur in secondary quartz edges, and the second-stage inclusions mainly occur in healed microcracks. The inclusion types are dominantly hydrocarbon-bearing, brine, and minor nonhydrocarbon gas inclusions. The hydrocarbon components are mostly CH4 and minor asphaltene, and the nonhydrocarbon gases are dominantly CO2 and minor SO2. The homogenization temperatures of the brine inclusions associated with hydrocarbon inclusions in major layers in the study area have a wide distribution and multiple peaks; the main peaks in the central part of a given tectonic area are slightly lower than those in the eastern part, and the main peaks in a given location tend to increase with decreasing burial depth. Hydrocarbon accumulation in the upper Paleozoic strata in the study area mainly occurred in the Early and Middle Jurassic and Early Cretaceous. The Early and Middle Jurassic were the mature oil and gas accumulation periods, and the Early Cretaceous was the high-maturity natural gas accumulation period and the most critical accumulation period. The accumulation period in the central part of a given structural region occurred earlier than that in the eastern part, and the accumulation period in different layers in a given location gradually shifted at a later time from deep to shallow.

Impact of Nystatin Oral Rinse on Salivary and Supragingival Microbial Community among Adults with Oral Candidiasis.

This study aimed to evaluate the impact of Nystatin oral rinse on salivary and supragingival microbiota in adults with oral candidiasis and identify predictive factors related to individuals' responses to Nystatin. The trial involved twenty participants who used 600,000 International Units/application of Nystatin oral rinse for seven days, four times a day, and were followed up at one week and three months after the rinse. The salivary and plaque microbiome of the participants were assessed via 16S rDNA amplicon sequencing. Overall, salivary and plaque microbiomes remained stable. However, among the participants (53 percent) who responded to Nystatin rinse (defined as free of oral Candida albicans post treatment), Veillonella emerged as a core genus alongside Streptococcus and Actinomyces in supragingival plaque at the 3-month follow-up. Furthermore, statistical models were fit to identify predictive factors of Nystatin rinse success (elimination of C. albicans) or failure (remaining C. albicans). The results revealed that an increased level of salivary Interferon (IFN)-γ-inducible protein (IP-10), also known as C-X-C motif chemokine ligand 10 (CXCL10), was an indicator of a failure of responding to Nystatin rinse. Future clinical trials are warranted to comprehensively assess the impact of antifungal treatment on the oral flora.

A precise and efficient circular RNA synthesis system based on a ribozyme derived from Tetrahymena thermophila.

Classic strategies for circular RNA (circRNA) preparation always introduce large numbers of linear transcripts or extra nucleotides to the circularized product. In this study, we aimed to develop an efficient system for circRNA preparation based on a self-splicing ribozyme derived from an optimized Tetrahymena thermophila group Ⅰ intron. The target RNA sequence was inserted downstream of the ribozyme and a complementary antisense region was added upstream of the ribozyme to assist cyclization. Then, we compared the circularization efficiency of ribozyme or flanking intronic complementary sequence (ICS)-mediated methods through the DNMT1, CDR1as, FOXO3, and HIPK3 genes and found that the efficiency of our system was remarkably higher than that of flanking ICS-mediated method. Consequently, the circularized products mediated by ribozyme are not introduced with additional nucleotides. Meanwhile, the overexpressed circFOXO3 maintained its biological functions in regulating cell proliferation, migration, and apoptosis. Finally, a ribozyme-based circular mRNA expression system was demonstrated with a split green fluorescent protein (GFP) using an optimized Coxsackievirus B3 (CVB3) internal ribosome entry site (IRES) sequence, and this system achieved successful translation of circularized mRNA. Therefore, this novel, convenient, and rapid engineering RNA circularization system can be applied for the functional study and large-scale preparation of circular RNA in the future.

Synthesis of protective oral PrEP adherence levels in cisgender women using convergent clinical- and bottom-up modeling.

Globally, most HIV infections occur in heterosexual women in resource-limited settings. In these settings, female self-protection with generic emtricitabine/tenofovir disoproxil fumarate pre-exposure prophylaxis (FTC/TDF-PrEP) may constitute a major pillar of the HIV prevention portfolio. However, clinical trials in women had inconsistent outcomes, sparking uncertainty regarding risk-group specific adherence requirements and causing reluctance in testing and recommending on-demand regimen in women. We analyzed all FTC/TDF-PrEP trials to establish PrEP efficacy ranges in women. In a 'bottom-up' approach, we modeled hypotheses corroborating risk-group specific adherence-efficacy profiles. Finally, we used the clinical efficacy ranges to (in-)validate hypotheses. We found that different clinical outcomes could solely be explained by the proportion of enrolled participants not taking the product, allowing, for the first time, to unify clinical observations. This analysis showed that 90% protection was achieved, when women took some of the product. Using 'bottom-up' modelling, we found that hypotheses of putative male/female differences were either irrelevant, or statistically inconsistent with clinical data. Furthermore, our multiscale modelling indicated that 90% protection was achieved if oral FTC/TDF was taken at least twice weekly.

KMT2D Deficiency Promotes Myeloid Leukemias which Is Vulnerable to Ribosome Biogenesis Inhibition.

KMT2C and KMT2D are the most frequently mutated epigenetic genes in human cancers. While KMT2C is identified as a tumor suppressor in acute myeloid leukemia (AML), the role of KMT2D remains unclear in this disease, though its loss promotes B cell lymphoma and various solid cancers. Here, it is reported that KMT2D is downregulated or mutated in AML and its deficiency, through shRNA knockdown or CRISPR/Cas9 editing, accelerates leukemogenesis in mice. Hematopoietic stem and progenitor cells and AML cells with Kmt2d loss have significantly enhanced ribosome biogenesis and consistently, enlarged nucleolus, increased rRNA and protein synthesis rates. Mechanistically, it is found that KMT2D deficiency leads to the activation of the mTOR pathway in both mouse and human AML cells. Kmt2d directly regulates the expression of Ddit4, a negative regulator of the mTOR pathway. Consistent with the abnormal ribosome biogenesis, it is shown that CX-5461, an inhibitor of RNA polymerase I, significantly restrains the growth of AML with Kmt2d loss in vivo and extends the survival of leukemic mice. These studies validate KMT2D as a de facto tumor suppressor in AML and reveal an unprecedented vulnerability to ribosome biogenesis inhibition.