Promising preclinical models for lung cancer research-lung cancer organoids: a narrative review.

Background and Objective: Traditional cell line models are the commonly used preclinical models for lung cancer research. However, cell lines cannot recapitulate the complex tumor heterogeneity and cannot mimic the microenvironment of human cancer. Recently, 3D multicellular in vitro self-assembled models called "organoids" have been developed at a fast pace in the field of research, which can mimic the actual primary tumor. At present, several studies have reported on protocols of lung cancer organoids (LCOs) generation, and using LCOs can provide novel insight into the basic and translational research of lung cancer. However, the establishment of the LCO models remains challenging due to the complexity of lung cancer and the immaturity of organoid technology, so it is necessary to understand the influences of different methodologies on LCO generation and review the applications and limitations of LCO models. Methods: In this review, we searched the literature in the recent ten years in the field of LCOs. Key Content and Findings: We summarized the methodology, the problems, and the solutions in the LCOs generation, its application and limitations, as well as proposing future challenges and perspectives. Conclusions: Currently, LCOs are successfully generated via exploring the methodology by the researchers. Though there are still challenges in clinical application, LCOs are applied in some cancer studies including investigation of anti-cancer treatment response in vitro, modeling tumor immune microenvironment, and construction of organ chips, which are forging a promising path towards precision medicine.

Analysis of the Predictive Efficacy of Serum suPAR Combined with APN and IgE Test and the Relationship of Patients with CHF and Cardiac Function.

Background: Chronic heart failure (CHF) is a complex cardiovascular disorder resulting from prolonged heart disease, leading to structural and functional damage, weakened myocardial contraction, and inadequate cardiac output for daily metabolism. The purpose of study is accurate evaluation and early identification of cardiac function and ventricular remodeling through effective biochemical indicators. Methods: This study, conducted from April 2020 to March 2021, included 100 CHF patients meeting the Chinese Guidelines for the Diagnosis and Treatment of Heart Failure 2020 from First People's Hospital of Linping District, ascertaining a confirmed diagnosis based on these established guidelines. The objective of detecting these biomarkers is not for early diagnosis, given that the subjects are already diagnosed according to the guidelines. Instead, our focus is on using these biomarkers to assess disease severity, prognosis, or treatment response in the context of diagnosed CHF patients. Classification comprised 42 ischemic and 58 non-ischemic CHF cases, with NYHA cardiac function grading (I, II, III-IV) and left ventricular ejection fraction (LVEF) categorization (≤ 40%, >40%). A control group of 100 healthy volunteers was selected for comparison. SuPAR, APN, and IgE expressions were analyzed among different groups and LVEF categories. Diagnostic efficacy was assessed through ROC curves, and correlations with cardiac function and LVEF were explored. Results: SuPAR, APN, and IgE expressions were significantly higher in CHF patients compared to the control group. Increasing cardiac function grades in CHF patients correlated with a gradual elevation in suPAR, APN, and IgE expressions. Comparing LVEF groups, CHF patients with LVEF ≤ 40% exhibited significantly higher suPAR, APN, and IgE expressions. Combined detection of suPAR, APN, and IgE demonstrated superior diagnostic accuracy (AUC of 0.899) compared to individual markers. Positive correlations were observed between suPAR, APN, IgE, and cardiac function grades, while LVEF showed a significant negative correlation with these biomarkers. Conclusions: SuPAR, APN, and IgE expressions are elevated in CHF patients, and their combined detection serves as a highly efficient auxiliary diagnostic method. The findings offer valuable insights into the diagnosis and treatment of CHF patients.

MiR-449b-5p Ameliorates Hypoxia-induced Cardiomyocyte Injury through Activating PI3K/AKT Pathway by Targeting BCL2L13.

Recent reports show miR-449b-5p reduces liver and renal ischemia/reperfusion (I/R) injury, but its effects on hypoxia-induced cardiomyocyte injury in ischemic heart disease are still unknown. In this study, AC16 human cardiomyocytes underwent hypoxic conditions for durations of 24, 48, and 72 h. We observed that miR-449b-5p expression was significantly downregulated in hypoxic AC16 cardiomyocytes. Elevating the levels of miR-449b-5p in these cells resulted in enhanced cell survival, diminished release of LDH, and a reduction in cell apoptosis and oxidative stress using CCK-8, LDH assays, flow cytometry, TUNEL staining, and various commercial kits. Conversely, reducing miR-449b-5p levels resulted in the opposite effects. Through bioinformatics analysis and luciferase reporter assays, BCL2-like 13 (BCL2L13) was determined to be a direct target of miR-449b-5p. Inhibiting BCL2L13 greatly inhibited hypoxia-induced cell viability loss, LDH release, cell apoptosis, and excessive production of oxidative stress, whereas increasing BCL2L13 negated miR-449b-5p's protective impact in hypoxic AC16 cardiomyocytes. Additionally, miR-449b-5p elevated the levels of the proteins p-PI3K, p-AKT, and Bcl-2, while decreasing Bax expression in hypoxic AC16 cardiomyocytes by targeting BCL2L13. In summary, the research indicates that the protective effects of miR-449b-5p are facilitated through the activation of the PI3K/AKT pathway, which promotes cell survival, and by targeting BCL2L13, which inhibits apoptosis, offering a potential therapeutic strategy for ischemic heart disease by mitigating hypoxia-induced cardiomyocyte injury.

Comparison of laser guidance and freehand hook-wire for CT-guided preoperative localization of pulmonary nodules.

PURPOSE: In VATS surgery, precise preoperative localization is particularly crucial when dealing with small-diameter pulmonary nodules located deep within the lung parenchyma. The purpose of this study was to compare the efficacy and safety of laser guidance and freehand hook-wire for CT-guided preoperative localization of pulmonary nodules. METHODS: This retrospective study was conducted on 164 patients who received either laser guidance or freehand hook-wire localization prior to Uni-port VATS from September 1st, 2022 to September 30th, 2023 at The First Affiliated Hospital of Soochow University. Patients were divided into laser guidance group and freehand group based on which technology was used. Preoperative localization data from all patients were compiled. The localization success and complication rates associated with the two groups were compared. The risk factors for common complications were analyzed. RESULTS: The average time of the localization duration in the laser guidance group was shorter than the freehand group (p<0.001), and the average CT scan times in the laser guidance group was less than that in the freehand group (p<0.001). The hook-wire was closer to the nodule in the laser guidance group (p<0.001). After the localization of pulmonary nodules, a CT scan showed 14 cases of minor pneumothorax (22.58%) in the laser guidance group and 21 cases (20.59%) in the freehand group, indicating no statistical difference between the two groups (p=0.763). CT scans in the laser guidance group showed pulmonary minor hemorrhage in 8 cases (12.90%) and 6 cases (5.88%) in the freehand group, indicating no statistically significant difference between the two groups (p=0.119). Three patients (4.84%) in the laser guidance group and six patients (5.88%) in the freehand group had hook-wire dislodgement, showing no statistical difference between the two groups (p=0.776). CONCLUSION: The laser guidance localization method possessed a greater precision and less localization duration and CT scan times compared to the freehand method. However, laser guidance group and freehand group do not differ in the appearance of complications such as pulmonary hemorrhage, pneumothorax and hook-wire dislodgement.

RIPK3 deficiency blocks R-2-hydroxyglutarate-induced necroptosis in IDH-mutated AML cells.

Mutant isocitrate dehydrogenases (IDHs) produce R-2-hydroxyglutarate (R-2HG), which inhibits the growth of most acute myeloid leukemia (AML) cells. Here, we showed that necroptosis, a form of programmed cell death, contributed to the antileukemia activity of R-2HG. Mechanistically, R-2HG competitively inhibited the activity of lysine demethylase 2B (KDM2B), an α-ketoglutarate-dependent dioxygenase. KDM2B inhibition increased histone 3 lysine 4 trimethylation levels and promoted the expression of receptor-interacting protein kinase 1 (RIPK1), which consequently caused necroptosis in AML cells. The expression of RIPK3 was silenced because of DNA methylation in IDH-mutant (mIDH) AML cells, resulting in R-2HG resistance. Decitabine up-regulated RIPK3 expression and repaired endogenous R-2HG-induced necroptosis pathway in mIDH AML cells. Together, R-2HG induced RIPK1-dependent necroptosis via KDM2B inhibition in AML cells. The loss of RIPK3 protected mIDH AML cells from necroptosis. Restoring RIPK3 expression to exert R-2HG's intrinsic antileukemia effect will be a potential therapeutic strategy in patients with AML.

Deep learning assists detection of esophageal cancer and precursor lesions in a prospective, randomized controlled study.

Endoscopy is the primary modality for detecting asymptomatic esophageal squamous cell carcinoma (ESCC) and precancerous lesions. Improving detection rate remains challenging. We developed a system based on deep convolutional neural networks (CNNs) for detecting esophageal cancer and precancerous lesions [high-risk esophageal lesions (HrELs)] and validated its efficacy in improving HrEL detection rate in clinical practice (trial registration ChiCTR2100044126 at www.chictr.org.cn). Between April 2021 and March 2022, 3117 patients ≥50 years old were consecutively recruited from Taizhou Hospital, Zhejiang Province, and randomly assigned 1:1 to an experimental group (CNN-assisted endoscopy) or a control group (unassisted endoscopy) based on block randomization. The primary endpoint was the HrEL detection rate. In the intention-to-treat population, the HrEL detection rate [28 of 1556 (1.8%)] was significantly higher in the experimental group than in the control group [14 of 1561 (0.9%), P = 0.029], and the experimental group detection rate was twice that of the control group. Similar findings were observed between the experimental and control groups [28 of 1524 (1.9%) versus 13 of 1534 (0.9%), respectively; P = 0.021]. The system's sensitivity, specificity, and accuracy for detecting HrELs were 89.7, 98.5, and 98.2%, respectively. No adverse events occurred. The proposed system thus improved HrEL detection rate during endoscopy and was safe. Deep learning assistance may enhance early diagnosis and treatment of esophageal cancer and may become a useful tool for esophageal cancer screening.

Incorporation of Shewanella oneidensis MR-1 and goethite stimulates anaerobic Sb(III) oxidation by the generation of labile Fe(III) intermediate.

Dissimilatory iron-reducing bacteria (DIRB) affect the geochemical cycling of redox-sensitive pollutants in anaerobic environments by controlling the transformation of Fe morphology. The anaerobic oxidation of antimonite (Sb(III)) driven by DIRB and Fe(III) oxyhydroxides interactions has been previously reported. However, the oxidative species and mechanisms involved remain unclear. In this study, both biotic phenomenon and abiotic verification experiments were conducted to explore the formed oxidative intermediates and related processes that lead to anaerobic Sb(III) oxidation accompanied during dissimilatory iron reduction. Sb(V) up to 2.59 µmol L-1 combined with total Fe(II) increased to 188.79 µmol L-1 when both Shewanella oneidensis MR-1 and goethite were present. In contrast, no Sb(III) oxidation or Fe(III) reduction occurred in the presence of MR-1 or goethite alone. Negative open circuit potential (OCP) shifts further demonstrated the generation of interfacial electron transfer (ET) between biogenic Fe(II) and goethite. Based on spectrophotometry, electron spin resonance (ESR) test and quenching experiments, the active ET production labile Fe(III) was confirmed to oxidize 94.12% of the Sb(III), while the contribution of other radicals was elucidated. Accordingly, we proposed that labile Fe(III) was the main oxidative species during anaerobic Sb(III) oxidation in the presence of DIRB and that the toxicity of antimony (Sb) in the environment was reduced. Considering the prevalence of DIRB and Fe(III) oxyhydroxides in natural environments, our findings provide a new perspective on the transformation of redox sensitive substances and build an eco-friendly bioremediation strategy for treating toxic metalloid pollution.

Preventive and Therapeutic Benefits of Natural Ingredients in Photo-Induced Epidermal Dysfunction.

BACKGROUND: The skin, particularly the epidermis, is subjected to various external stresses, including ultraviolet [UV] irradiation. UV irradiation, mainly UVB at wavelength of 280-315 nm, can alter several epidermal functions, including cutaneous inflammation, epidermal hyperproliferation, DNA damage, disruption of epidermal permeability barrier and reduction in stratum corneum hydration levels. Because of the negative impacts of UVB irradiation on epidermal functions, great efforts have been made to develop regimens for the protection of alterations in epidermal function induced by UV irradiation. SUMMARY: While sunscreen can provide physical barrier to UV light, some natural ingredients can also effectively protect the skin from UVB irradiation-induced damages. Studies have demonstrated that either topical or oral administrations of some natural ingredients attenuate UVB irradiation-induced alterations in the epidermal function. The underlying mechanisms by which natural ingredients improve epidermal functions are attributable to antioxidation, stimulation of keratinocyte differentiation, increases in the content of epidermal natural moisturizers and inhibition of inflammation. KEY MESSAGE: Some natural ingredients exhibit protective and therapeutical benefits in photo-induced epidermal dysfunctions via divergent mechanisms.

Effectiveness of human immunodeficiency virus prevention strategies by mapping the geographic dispersion pattern of human immunodeficiency virus prevalence in Nanning, China.

BACKGROUND: The Guangxi government initiated two rounds of the Guangxi AIDS Conquering Project (GACP) in 2010 (Phase I) and 2015 (Phase II) to control human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) epidemics. However, the effectiveness of GACP in HIV prevention and treatment has rarely been reported. This study aimed to assess the effectiveness of the GACP implemented in Guangxi, China and provide data for strategy and praxis improvements to achieve Joint United Nations Programme on HIV/AIDS (UNAIDS) 95-95 targets. METHODS: We used spatial approaches to trace the spatiotemporal distribution properties, epidemic trends, and correlation between macroscopic factors and HIV incidence using data from the Chinese HIV/AIDS case reporting system to explore the effects of the GACP. RESULTS: During the GACP era, the HIV epidemic stabilized in urban centers, showing a downward trend in the Hengzhou and Binyang Counties in the eastern region, whereas it continued to increase in rural areas of the northwest region, such as the Long'an, Mashan, Shanglin, and Wuming Districts. The linear directional mean (LDM) of HIV infection reported cases displayed a southeast-northwest direction, with an LDM value of 12.52°. Compared with that in Phase I, Hengzhou withdrew from the high-high clustering area, and the west-north suburban counties pulled out the low-low clustering area during Phase II. Significant HIV clusters were identified in the eastern region during Phase I, whereas these clusters emerged in the northwestern areas during Phase II. Regarding HIV, socioeconomic status, population mobility, and medical care levels were the key social drivers of heterogeneous spatial distribution. CONCLUSIONS: The GACP assisted in effectively managing the HIV epidemic in urban and eastern areas of Nanning City. However, prevention and control efforts in rural regions, particularly those located in the northwest, may not have yielded comparable outcomes. To address this disparity, allocating additional resources and implementing tailored intervention measures for these rural areas are imperative.

Identification of the shared hub gene signatures and molecular mechanisms between HIV-1 and pulmonary arterial hypertension.

The close link between HIV-1 infection and the occurrence of pulmonary arterial hypertension (PAH). However, the underlying molecular mechanisms of their interrelation remain unclear. The microarray data of HIV-1 and PAH were downloaded from GEO database. We utilized WGCNA to identify shared genes between HIV-1 and PAH, followed by conducting GO and pathway enrichment analyses. Subsequently, differentially genes analysis was performed using external validation datasets to further filter hub genes. Immunoinfiltration analysis was performed using CIBERSORT. Finally, hub gene expression was validated using scRNA-seq data. We identified 109 shared genes through WGCNA, primarily enriched in type I interferon (IFN) pathways. By taking the intersection of WGCNA important module genes and DEGs, ISG15 and IFI27 were identified as pivotal hub genes. Immunoinfiltration analysis and scRNA-seq results indicated the significant role of monocytes in the shared molecular mechanisms of HIV-1 and PAH. In summary, our study illustrated the possible mechanism of PAH secondary to HIV-1 and showed that the heightened IFN response in HIV-1 might be a crucial susceptibility factor for PAH, with monocytes being pivotal cells involved in the type I IFN response pathway. This provides potential new insights for further investigating the molecular mechanisms connecting HIV-1 and PAH.

Evidence linking COVID-19 and the health/well-being of children and adolescents: an umbrella review.

BACKGROUND: Experiences during childhood and adolescence have enduring impacts on physical and mental well-being, overall quality of life, and socioeconomic status throughout one's lifetime. This underscores the importance of prioritizing the health of children and adolescents to establish an impactful healthcare system that benefits both individuals and society. It is crucial for healthcare providers and policymakers to examine the relationship between COVID-19 and the health of children and adolescents, as this understanding will guide the creation of interventions and policies for the long-term management of the virus. METHODS: In this umbrella review (PROSPERO ID: CRD42023401106), systematic reviews were identified from the Cochrane Database of Systematic Reviews; EMBASE (OvidSP); and MEDLINE (OvidSP) from December 2019 to February 2023. Pairwise and single-arm meta-analyses were extracted from the included systematic reviews. The methodological quality appraisal was completed using the AMSTAR-2 tool. Single-arm meta-analyses were re-presented under six domains associated with COVID-19 condition. Pairwise meta-analyses were classified into five domains according to the evidence classification criteria. Rosenberg's FSN was calculated for both binary and continuous measures. RESULTS: We identified 1551 single-arm and 301 pairwise meta-analyses from 124 systematic reviews that met our predefined criteria for inclusion. The focus of the meta-analytical evidence was predominantly on the physical outcomes of COVID-19, encompassing both single-arm and pairwise study designs. However, the quality of evidence and methodological rigor were suboptimal. Based on the evidence gathered from single-arm meta-analyses, we constructed an illustrative representation of the disease severity, clinical manifestations, laboratory and radiological findings, treatments, and outcomes from 2020 to 2022. Additionally, we discovered 17 instances of strong or highly suggestive pairwise meta-analytical evidence concerning long-COVID, pediatric comorbidity, COVID-19 vaccines, mental health, and depression. CONCLUSIONS: The findings of our study advocate for the implementation of surveillance systems to track health consequences associated with COVID-19 and the establishment of multidisciplinary collaborative rehabilitation programs for affected younger populations. In future research endeavors, it is important to prioritize the investigation of non-physical outcomes to bridge the gap between research findings and clinical application in this field.

Effect of Spironolactone and dbcAMP-Ca Combination Therapy on Clinical Outcomes and Left Ventricular Function in Chronic Heart Failure Patients Post Percutaneous Coronary Intervention.

Background: Improving treatment outcomes in chronic heart failure (CHF) patients post percutaneous coronary intervention (PCI) is of significant importance. CHF is a prevalent and severe chronic condition that negatively impacts patients' quality of life and increases the risks of hospitalization and mortality. Therefore, evaluating effective treatment strategies is crucial in improving the prognosis of CHF patients after PCI. Objective: The main objective of this study was to evaluate the clinical efficacy of combining spironolactone with dbcAMP-Ca in CHF patients following PCI. The study aimed to assess the impact of this combination therapy on both clinical outcomes and left ventricular function. Methodology: The study design involved the random assignment of 110 CHF subjects post-PCI into two groups: a combination group receiving spironolactone with dbcAMP-Ca and a spironolactone-only group. The subjects' clinical efficacy, left ventricular function, plasma brain natriuretic peptide (BNP), serum uric acid (UA), serum high-sensitivity C-reactive protein (hs-CRP) levels, autonomic nerve function, and postoperative adverse reactions were assessed. Results: The results demonstrated that the combination group, receiving spironolactone with dbcAMP-Ca, showed superior clinical efficacy, improved left ventricular function, and enhanced autonomic nerve function compared to the spironolactone-only group. Additionally, the combination group exhibited a lower incidence of adverse reactions and reduced levels of plasma BNP, UA, and hs-CRP. These findings indicate that spironolactone combined with dbcAMP-Ca has a favorable clinical effect in CHF patients post-PCI, effectively improving left ventricular and autonomic nerve function while maintaining high safety. Conclusions: The combination therapy of spironolactone and dbcAMP-Ca holds potential as an effective treatment strategy for CHF patients following PCI. This combination therapy demonstrated superior clinical efficacy, improved left ventricular function, and enhanced autonomic nerve function, with reduced adverse reactions and biomarker levels. Spironolactone combined with dbcAMP-Ca can be considered as a beneficial treatment strategy for CHF patients post-PCI. The demonstrated clinical efficacy, improvement in left ventricular function, and enhanced autonomic nerve function support the wider application of this combination therapy in the management of CHF patients in clinical settings.

SPRY1 Deficiency in Keratinocytes Induces Follicular Melanocyte Stem Cell Migration to the Epidermis through p53/Stem Cell Factor/C-KIT Signaling.

The function and survival of melanocytes is regulated by an elaborate network of paracrine factors synthesized mainly by epidermal keratinocytes (KCs). KCs and melanocytes respond to UV exposure by eliciting a tanning response. However, how KCs and melanocytes interact in the absence of UV exposure is unknown. In this study, we demonstrate that after SPRY1 knockout in epidermal KCs, melanocyte stem cells in the hair follicle exit the niche without depleting the pool of these cells. We also found that melanocyte stem cells migrate to the epidermis in a p53/stem cell factor/C-KIT-dependent manner induced by a tanning-like response resulting from SPRY1 loss in epidermal KCs. Once there, these cells differentiate into functional melanocytes. These findings provide an example in which the migration of melanocyte stem cells to the epidermis is due to loss of SPRY1 in epidermal KCs and show the potential for developing therapies for skin pigmentation disorders by manipulating melanocyte stem cells.

Two Undescribed Germacrane-Type Sesquiterpenoids from Salvia cavaleriei var. simplicifolia Stib. and Their Anti-Alzheimer's Disease Activity.

Two undescribed germacrane-type sesquiterpenoids, salcasins A (1) and B (2), together with three known compounds (3-5) were isolated and identified from the whole plant of Salvia cavaleriei var. simplicifolia Stib. The structures of the undescribed compounds were elucidated on the basis of spectroscopic methods, such as HR-ESI-MS, 1D and 2D NMR data. The relative configurations of 1 and 2 were established by analyzing their NOESY spectra as well as by 13C NMR calculations with DP4+ probability analyses. The absolute configurations of 1 and 2 were determined by comparing experimental and calculated ECD spectra. Furthermore, the in vivo anti-Alzheimer's disease activities of 1-5 were evaluated using Caenorhabditis elegans AD pathological model. Among all isolated compounds, salcasin A (1) significantly delayed AD-like symptoms of worm paralysis, which may be a potential anti-AD candidate agent.

An Assessment of Trends in HIV-1 Prevalence and Incidence and Spatio-Temporal Analyses of HIV-1 Recent Infection Among MSM During the Surveillance Period Between 2018 and 2022 in Sichuan, China.

Background: Men who have sex with men (MSM) is one main type of high-risk activities facilitating HIV-1 transmission in Sichuan province. Previous works on HIV-1 incidence and prevalence among MSM only concentrated before 2018, the situation after that is unknown. In addition, the distribution of hot-spots related to current HIV-1 epidemic is also rarely known among MSM in Sichuan. Objective: To update trends of HIV-1 prevalence and incidence and to visualize hot-spots of ongoing transmission in Sichuan province during surveillance period among MSM between 2018 and 2022. Methods: Limiting Antigen Avidity assay was performed to detect recent infection within new HIV-1 diagnoses founded during surveillance period among MSM. The HIV-1 prevalence and incidence were calculated according to an extrapolation method proposed by publications and guidelines. Trend tests were performed using χ2 tests with linear-by-linear association. The spatial analysis was conducted with ArcGIS 10.7 to figure hot-spots of HIV-1 recent infections among MSM. Results: Between 2018 and 2022, 16,697 individuals participated in HIV-1 MSM sentinel surveillance program, of which 449 samples (98.25%) were tested with LAg-Avidity EIA, and 230 samples were classified as recent infection. Respectively, the overall prevalence and incidence were 2.74% and 3.69% (95% CI: 3.21, 4.16) and both had significant declining trends (p < 0.001). Luzhou city had a highest HIV-1 incidence (10.74%, 95% CI: 8.39, 13.10) over the study period and was recognized as a hot-spot for recent HIV-1 infection among MSM. Conclusion: During the surveillance period, both HIV-1 prevalence and incidence were declining. However, Luzhou city had an unusually high HIV-1 incidence and became an emerging hot-spot of recent HIV-1 infection among MSM. This finding suggested focused attention, cross-regional intervention strategies, and prevention programs are urgently required to curb the spread of ongoing transmission.

Ectopic expression of the transcription factor ONECUT3 drives a complex karyotype in myelodysplastic syndromes.

Chromosomal instability is a prominent biological feature of myelodysplastic syndromes (MDS), with over 50% of patients with MDS harboring chromosomal abnormalities or a complex karyotype (CK). Despite this observation, the mechanisms underlying mitotic and chromosomal defects in MDS remain elusive. In this study, we identified ectopic expression of the transcription factor ONECUT3, which is associated with CKs and poorer survival outcomes in MDS. ONECUT3-overexpressing cell models exhibited enrichment of several notable pathways, including signatures of sister chromosome exchange separation and mitotic nuclear division with the upregulation of INCENP and CDCA8 genes. Notably, dysregulation of chromosome passenger complex (CPC) accumulation, besides the cell equator and midbody, during mitotic phases consequently caused cytokinesis failure and defective chromosome segregation. Mechanistically, the homeobox (HOX) domain of ONECUT3, serving as the DNA binding domain, occupied the unique genomic regions of INCENP and CDCA8 and transcriptionally activated these 2 genes. We identified a lead compound, C5484617, that functionally targeted the HOX domain of ONECUT3, inhibiting its transcriptional activity on downstream genes, and synergistically resensitized MDS cells to hypomethylating agents. This study revealed that ONECUT3 promoted chromosomal instability by transcriptional activation of INCENP and CDCA8, suggesting potential prognostic and therapeutic roles for targeting high-risk MDS patients with a CK.

Possible contributions of fibrogenesis to recurrent miscarriages - A transcriptome analysis.

Recurrent miscarriages (RM) generally refer to two or more consecutive pregnancy losses. The risk of miscarriages grows with its frequency of occurrences, so as the future obstetric complications or longer-term health problems for patients. Most previous researches sought to discover the etiology of RM by making comparisons between patients with RM and fertile women. Our study collected decidua tissues from patients with RM and single miscarriage (SM) for transcriptome sequencing analysis and aimed at identifying vital factors contributing to additional miscarriages after previous miscarriage. Between the RM and SM group, a total of 122 differentially expressed genes (DEGs) were detected and pathways associated with cell adhesion and ECM remodeling were particularly enriched in the RM group, which indicated abnormally activated fibrogenesis process. Particularly, the enhancement of ITGB6, EGFLAM and COL3A1 in the RM group were validated by RT-qPCR. Our study discovered that fibrogenesis, which might be caused by intrauterine manipulation, could lead to recurrent miscarriages after a previous miscarriage. Therefore, we encourage higher attention to thorough prevention and prompt remedies towards fibrotic disorders related diseases.

Dynamic m6 A profiles reveal the role of YTHDC2-TLR2 signaling axis in Talaromyces marneffei infection.

Talaromyces marneffei (TM) immune evasion is an important factor leading to the high mortality rate of Penicilliosis marneffei. N6 -methyladenosine (m6 A) plays important roles in host immune response to various pathogen infections, yet its role in TM and HIV/TM coinfection remains largely unexplored. Here we reported genome-wide transcriptional m6 A profiles of TM mono-infection and HIV/TM coinfection. Our finding revealed dynamic alterations in global m6 A levels and upregulation of the m6 A reader YTH N6 -methyladenosine RNA binding protein C2 (YTHDC2) in TM-infected macrophages. Knockdown of YTHDC2 in TM-infected cells showed an elevated expression of TLR2 through m6 A-dependence, along with upregulation of TNF-α and IL1-ß. Overall, we characterized the m6 A profiles of the host and fungus before and after TM infection, and demonstrated that YTHDC2 mediates the key m6 A site of TLR2 to exert its function. These findings provide new insights into the underlying mechanisms and novel therapeutic approaches for TM diseases.

Transcription Factor Pdr3p Promotes Carotenoid Biosynthesis by Activating GAL Promoters in Saccharomyces cerevisiae.

Pleiotropic drug resistance (PDR) family proteins have been extensively studied for their roles in transporting hydrophobic substances, including carotenoids. Overexpression of the PDR family regulator Pdr3p was recently found to boost the biosynthesis of carotenoids, which could not be explained by enhanced product secretion due to the meager extracellular proportions. To provide insights into the possible mechanism, comparative transcriptomics, reverse metabolic engineering, and electrophoretic mobility shift assay (EMSA) were conducted. Transcriptomic data suggested an unexpected correlation between Pdr3p overexpression and the transcriptional levels of GAL promoter-driven genes. This assumption was verified using mCherry and the lycopene synthetic pathway as the reporters. qRT-PCR and EMSA provided further evidence for the activation of GAL promoters by Pdr3p binding to their upstream activation sequences (UASs). This work gives insight into the mechanism of Pdr3p-promoted carotenoid production and highlights the complicated metabolic networking between transcriptional factors and promoters in yeast.