LncRNA Osilr9 coordinates promoter DNA demethylation and the intrachromosomal loop structure required for maintaining stem cell pluripotency.

Nuclear reprogramming of somatic cells into a pluripotent status has the potential to create patient-specific induced pluripotent stem cells for regenerative medicine. Currently, however, the epigenetic mechanisms underlying this pluripotent reprogramming are poorly understood. To delineate this epigenetic regulatory network, we utilized a chromatin RNA in situ reverse transcription sequencing (CRIST-seq) approach to identify long noncoding RNAs (lncRNAs) embedded in the 3-dimensional intrachromosomal architecture of stem cell core factor genes. By combining CRIST-seq and RNA sequencing, we identified Oct4-Sox2 interacting lncRNA 9 (Osilr9) as a pluripotency-associated lncRNA. Osilr9 expression was associated with the status of stem cell pluripotency in reprogramming. Using short hairpin RNA (shRNA) knockdown, we showed that this lncRNA was required for the optimal maintenance of stem cell pluripotency. Overexpression of Osilr9 induced robust activation of endogenous stem cell core factor genes in fibroblasts. Osilr9 participated in the formation of the intrachromosomal looping required for the maintenance of pluripotency. After binding to the Oct4 promoter, Osilr9 recruited the DNA demethylase ten-eleven translocation 1, leading to promoter demethylation. These data demonstrate that Osilr9 is a critical chromatin epigenetic modulator that coordinates the promoter activity of core stem cell factor genes, highlighting the critical role of pluripotency-associated lncRNAs in stem cell pluripotency and reprogramming.

The nucleoporin NUP160 and NUP96 regulate nucleocytoplasmic export of mRNAs and participate in ethylene signaling and response in Arabidopsis.

KEY MESSAGE: Arabidopsis nucleoporin involved in the regulation of ethylene signaling via controlling of nucleocytoplasmic transport of mRNAs. The two-way transport of mRNAs between the nucleus and cytoplasm are controlled by the nuclear pore complex (NPC). In higher plants, the NPC contains at least 30 nucleoporins. The Arabidopsis nucleoporins are involved in various biological processes such as pathogen interaction, nodulation, cold response, flowering, and hormone signaling. However, little is known about the regulatory functions of the nucleoporin NUP160 and NUP96 in ethylene signaling pathway. In the present study, we provided data showing that the Arabidopsis nucleoporin NUP160 and NUP96 participate in ethylene signaling-related mRNAs nucleocytoplasmic transport. The Arabidopsis nucleoporin mutants (nup160, nup96-1, nup96-2) exhibited enhanced ethylene sensitivity. Nuclear qRT-PCR analysis and poly(A)-mRNA in situ hybridization showed that the nucleoporin mutants affected the nucleocytoplasmic transport of all the examined mRNAs, including the ethylene signaling-related mRNAs such as ETR2, ERS1, ERS2, EIN4, CTR1, EIN2, and EIN3. Transcriptome analysis of the nucleoporin mutants provided clues suggesting that the nucleoporin NUP160 and NUP96 may participate in ethylene signaling via various molecular mechanisms. These observations significantly advance our understanding of the regulatory mechanisms of nucleoporin proteins in ethylene signaling and ethylene response.

Photoactive 3D-Printed Hypertensile Metamaterials for Improving Dynamic Modeling of Stem Cells.

Current three-dimensional (3D) cell culture systems mainly rely on static cell culture and lack the ability to thoroughly manage cell intrinsic behaviors and biological characteristics, leading to unsatisfied cell activity. Herein, we have developed photoactive 3D-printed hypertensile metamaterials based dynamic cell culture system (MetaFold) for guiding cell fate. MetaFold exhibited high elasticity and photothermal conversion efficiency due to its metapattern architecture and micro/nanoscale polydopamine coating, allowing for responding to mechanical and light stimulation to construct dynamic culture conditions. In addition, MetaFold possessed excellent cell adhesion capability and could promote cell viability and function under dynamic stimulation, thereby maximizing cell activity. Importantly, MetaFold could improve the differentiation efficacy of stem cells into cardiomyocytes and even their maturation, offering high-quality precious candidates for cell therapy. Therefore, we present a dual stimuli-responsive dynamic culture system, which provides a physiologically realistic environment for cell culture and biological study.

Nanosized Phase-Changeable "Sonocyte" for Promoting Ultrasound Assessment.

Despite the ability of microbubble contrast agents to improve ultrasound diagnostic performance, their application potential is limited due to low stability, fast clearance, and poor tissue permeation. This study presents a promising nanosized phase-changeable erythrocyte (Sonocyte), composed of liposomal dodecafluoropentane coated with multilayered red blood cell membranes (RBCm), for improving ultrasound assessments. Sonocyte is the first RBCm-functionalized ultrasound contrast agent with uniform nanosized morphology, and exhibits good stability, systemic circulation, target-tissue accumulation, and even ultrasound-responsive phase transition, thereby satisfying the inherent requirement of ultrasound imaging. It is identified that Sonocyte displays similar sensitivity as microbubble SonoVue, a clinical ultrasound contrast agent, for effectively detecting normal parenchyma and hepatic necrosis. Importantly, compared with SonoVue lacking of ability to detect tumors, Sonocyte can identify tumors with high sensitivity and specificity due to superior tumor accumulation and penetration. Therefore, Sonocyte exhibits superior capabilities over SonoVue, endowing with a great clinical application potential.

Drought-induced changes in root biomass largely result from altered root morphological traits: Evidence from a synthesis of global field trials.

Extreme drought is likely to become more frequent and intense as a result of global climate change, which may significantly impact plant root traits and responses (i.e., morphology, production, turnover, and biomass). However, a comprehensive understanding of how drought affects root traits and responses remains elusive. Here, we synthesized data from 128 published studies under field conditions to examine the responses of 17 variables associated with root traits to drought. Our results showed that drought significantly decreased root length and root length density by 38.29% and 11.12%, respectively, but increased root diameter by 3.49%. However, drought significantly increased root:shoot mass ratio and root cortical aerenchyma by 13.54% and 90.7%, respectively. Our results suggest that drought significantly modified root morphological traits and increased root mortality, and the drought-induced decrease in root biomass was less than shoot biomass, causing higher root:shoot mass ratio. The cascading effects of drought on root traits and responses may need to be incorporated into terrestrial biosphere models to improve prediction of the climate-biosphere feedback.

Interactive effects of global change factors on soil respiration and its components: a meta-analysis.

As the second largest carbon (C) flux between the atmosphere and terrestrial ecosystems, soil respiration (Rs) plays vital roles in regulating atmospheric CO2 concentration ([CO2 ]) and climatic dynamics in the earth system. Although numerous manipulative studies and a few meta-analyses have been conducted to determine the responses of Rs and its two components [i.e., autotrophic (Ra) and heterotrophic (Rh) respiration] to single global change factors, the interactive effects of the multiple factors are still unclear. In this study, we performed a meta-analysis of 150 multiple-factor (≥2) studies to examine the main and interactive effects of global change factors on Rs and its two components. Our results showed that elevated [CO2 ] (E), nitrogen addition (N), irrigation (I), and warming (W) induced significant increases in Rs by 28.6%, 8.8%, 9.7%, and 7.1%, respectively. The combined effects of the multiple factors, EN, EW, DE, IE, IN, IW, IEW, and DEW, were also significantly positive on Rs to a greater extent than those of the single-factor ones. For all the individual studies, the additive interactions were predominant on Rs (90.6%) and its components (≈70.0%) relative to synergistic and antagonistic ones. However, the different combinations of global change factors (e.g., EN, NW, EW, IW) indicated that the three types of interactions were all important, with two combinations for synergistic effects, two for antagonistic, and five for additive when at least eight independent experiments were considered. In addition, the interactions of elevated [CO2 ] and warming had opposite effects on Ra and Rh, suggesting that different processes may influence their responses to the multifactor interactions. Our study highlights the crucial importance of the interactive effects among the multiple factors on Rs and its components, which could inform regional and global models to assess the climate-biosphere feedbacks and improve predictions of the future states of the ecological and climate systems.

Excessive free fatty acid sensing in pituitary lactotrophs elicits steatotic liver disease by decreasing prolactin levels.

The pituitary is the central endocrine gland with effects on metabolic dysfunction-associated steatotic liver disease (MASLD). However, it is not clear whether the pituitary responds to free fatty acid (FFA) toxicity, thus dysregulating hepatic lipid metabolism. Here, we demonstrate that decreased prolactin (PRL) levels are involved in the association between FFA and MASLD based on a liver biospecimen-based cohort. Moreover, overloaded FFAs decrease serum PRL levels, thus promoting liver steatosis in mice with both dynamic diet intervention and stereotactic pituitary FFA injection. Mechanistic studies show that excessive FFA sensing in pituitary lactotrophs inhibits the synthesis and secretion of PRL in a cell-autonomous manner. Notably, inhibiting excessive lipid uptake using pituitary stereotaxic virus injection or a specific drug delivery system effectively ameliorates hepatic lipid accumulation by improving PRL levels. Targeted inhibition of pituitary FFA sensing may be a potential therapeutic target for liver steatosis.

Impact of iron overload in hematopoietic stem cell transplantation.

Iron overload (IOL) is a common condition in patients with hematological malignancies(HMs) undergoing hematopoietic stem cell transplantation (HSCT). Pathophysiologically, IOL results in iron-induced toxicity in HSCT by producing reactive oxygen species (ROS), which leads to detrimental effects on hematopoiesis, clonal evolution, and immunosuppression. IOL, therefore, may have a negative impact on the clinical outcomes of HSCT. For patients at a higher risk of developing IOL before HSCT, it is necessary to monitor red blood cell transfusion units, serum ferritin (SF) levels and MRI image of organs, and initiate iron removal therapy as soon as possible. Iron chelating therapy (ICT) might be safe and efficient in the post-HSCT period. We provide an overview of results from experimental and clinical evidence on the current understanding of IOL in patients with HMs undergoing HSCT, involving the underlying pathophysiological and clinical impact of IOL, as well as the significance of iron reduction therapy.

Exogenous melatonin ameliorates heat damages by regulating growth, photosynthetic efficiency and leaf ultrastructure of carnation.

Carnation (Dianthus caryophyllus L.) is a floral crop that is highly valuable commercially. However, high temperatures adversely affect its growth and the quality of its cut flowers. Melatonin (MT) is a indole substance that can mitigate plant damage under heat stress. In this study, the leaves of carnation seedlings were sprayed with different concentrations of MT before exposure to high temperature. The indices of growth, physiological and chlorophyll fluorescence were measured and analyzed by the membership function method. The results showed that treatment with 100 µM MT was the most effective at ameliorating damage on carnation. We then analyzed the effects of 100 µM MT pretreatment on carnation at different time points of heat stress and found that this concentration of MT ameliorated the damage caused by heat stress, increased the content of photosynthetic pigments, enhanced the performance of photosystem II and improved photosynthesis. In addition, MT also reduced cell damage and lipid peroxidation, increased the activities of antioxidant enzymes and regulated the accumulation of osmotic substances in carnation. Moreover, MT increased the fresh/dry weight of stems and roots, promoted the opening of stomata, and protected the integrity of chloroplast structure of carnation. Compared with heat stress, pre-spraying with MT significantly down-regulated the transcription of a chlorophyll degradation gene and up-regulated the transcription of stress-related genes. Overall, this study provides a theoretical foundation for the mitigation of the adverse effects of exogenous MT under heat stress and proposes beneficial implications for the management of other plants subjected to global warming.

[Protective effect of salvianolic acid B on isolated heart ischemia/reperfusion injury in rats].

OBJECTIVE: To study the protective effect and mechanism of salvianolic acid B on isolated heart ischemia/reperfusion injury in rats. METHOD: Forty-eight SD rats were divided into 6 groups randomly(n = 8): the control group, the positive administration group (verapamil 150 microg x L(-1)), and high, middle and low-dose salvianolic acid B groups (10, 5, 2.5 mg x L(-1)). The myocardial ischemia/reperfusion injury model was established using the Langendorff method, re-perusing isolated working hearts for 30 min after ischemia for 25 min. A water-bag catheter was inserted in rat left atrium for recording the effect of salvianolic acid B on hemodynamics indexes-AST, LDH, SOD and MDA. RESULT: Various group with different doses showed that salvianolic acid B decreased AST, release of LDH and formation of MDA and increased SOD activity. CONCLUSION: Salvianolic acid B showed a protective effect on myocardial ischemia/reperfusion injury. Its mechanism may be related with improvement of cardiac contractility, cleaning of oxygen free radicals and reduction of lipid peroxidation.

Lentinan alleviates arsenic-induced hepatotoxicity in mice via downregulation of OX40/IL-17A and activation of Nrf2 signaling.

BACKGROUND: Arsenic, existing ubiquitously in soil, drinking water, or food, is well known to be an environmental pollutants concerned by European Food Safety Authority. Lentinan, a beta-1,6;1,3-glucan extracts from Lentinus edodes, which has the properties of antioxidant and immunomodulation, present study explored the pharmacological effects of Lentinan on arsenic induced hepatotoxicity in mice. METHODS: Mice experiments were performed by sodium arsenite (SA) treatment or Lentinan intervention, then histopathology, ELISA, Flow Cytometry, or Western-Blotting were applied to evaluate hepatic injury, oxidative stress, CD4+ type 17 helper T (Th17) cells, CD4+CD25+Foxp3+ regulatory T cells (Tregs), T cells receptor OX40/CD134, IL-17A, NLRP3, Nrf2, and NQO1. RESULTS: SA treatment showed hepatic pathological injury and the elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in serum, and induced the increases of malondialdehyde (MDA), Th17 cells, OX40 or IL-17A in liver tissues, which were consistently ameliorated by Lentinan intervention. Further, immunoblotting experiments showed that Lentinan intervention downregulated the levels of OX40, IL-17A, and NLRP3 signals, while elevated the levels of anti-oxidative Nrf2, NQO1 signals compared to arsenic treatment group. For Tregs, Lentinan intervention showed no significant difference from SA treatment group. CONCLUSION: Lentinan antagonizes SA-induced hepatotoxicity in mice, may be involved in the downregulations of pro-inflammatory OX40 or IL-17A and the activation of anti-oxidative Nrf2, NQO1 signals.

Impact of iron overload on poor graft function after allo-HSCT in a patient with transfusion-dependent low-risk MDS: A case report and literature review.

RATIONALE: Poor graft function (PGF) occurs in 5% to 27% of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with high life-threatening complications. The etiology of PGF is complex and multifactorial, and iron overload (IOL) is considered as a predictive factor. PATIENT CONCERN: A 45-years-old woman who was diagnosed as low-risk myelodysplastic syndrome in 2012 has been transfusion dependent and developed severe IOL. DIAGNOSES: Due to transfusion dependency and also ineffective erythropoiesis, this patient was diagnosed as IOL and developed PGF after allo-HSCT. INTERVENTIONS: Deferasirox (20mg/kg/d) was administered regularly after allo-HSCT for 2 years. OUTCOMES: Hematopoiesis was gradually recovered during iron chelation therapy treatment after allo-HSCT and PGF was reverted. LESSONS: IOL, as a prognostic factor for PGF, is a common problem in Transfusion dependent myelodysplastic syndrome patients undergoing HSCT. IOL issues should be considered at the time of diagnosis and throughout the treatment course for patients who are potential candidates for HSCT.

Intrinsically stretchable electronics with ultrahigh deformability to monitor dynamically moving organs.

Intrinsically stretchable electronics represent an attractive platform for next-generation implantable devices by reducing the mechanical mismatch and the immune responses with biological tissues. Despite extensive efforts, soft implantable electronic devices often exhibit an obvious trade-off between electronic performances and mechanical deformability because of limitations of commonly used compliant electronic materials. Here, we introduce a scalable approach to create intrinsically stretchable and implantable electronic devices featuring the deployment of liquid metal components for ultrahigh stretchability up to 400% tensile strain and excellent durability against repetitive deformations. The device architecture further shows long-term stability under physiological conditions, conformal attachments to internal organs, and low interfacial impedance. Successful electrophysiological mapping on rapidly beating hearts demonstrates the potential of intrinsically stretchable electronics for widespread applications in health monitoring, disease diagnosis, and medical therapies.

Pluripotency exit is guided by the Peln1-mediated disruption of intrachromosomal architecture.

The molecular circuitry that causes stem cells to exit from pluripotency remains largely uncharacterized. Using chromatin RNA in situ reverse transcription sequencing, we identified Peln1 as a novel chromatin RNA component in the promoter complex of Oct4, a stem cell master transcription factor gene. Peln1 was negatively associated with pluripotent status during somatic reprogramming. Peln1 overexpression caused E14 cells to exit from pluripotency, while Peln1 downregulation induced robust reprogramming. Mechanistically, we discovered that Peln1 interacted with the Oct4 promoter and recruited the DNA methyltransferase DNMT3A. By de novo altering the epigenotype in the Oct4 promoter, Peln1 dismantled the intrachromosomal loop that is required for the maintenance of pluripotency. Using RNA reverse transcription-associated trap sequencing, we showed that Peln1 targets multiple pathway genes that are associated with stem cell self-renewal. These findings demonstrate that Peln1 can act as a new epigenetic player and use a trans mechanism to induce an exit from the pluripotent state in stem cells.

Novel insights of acute myeloid leukemia with CEBPA deregulation: Heterogeneity dissection and re-stratification.

Acute myeloid leukemia with bi-allelic CEBPA mutation was categorized as an independent disease entity with favorable prognosis, however, recent researches have revealed huge heterogeneity within this disease group, and for some patients, relapse remained a major cause of treatment failure. Further risk stratification is essentially needed. Here by reviewing the latest literature, we summarized the characteristics of CEBPA mutation profiles and clinical features, with a special intention of dissecting the heterogeneity within the seemingly homogeneous AML with bi-allelic CEBPA mutations. Specifically, non-classical CEBPA mutation, miscellaneous companion genetic aberrations and the presence of germline CEBPA mutation are three major sources of heterogeneity. Identifying these factors can help us predict patients at a higher risk of relapse, for whom aggressive treatment may be recommended. Novel therapeutic approaches regarding manipulating potentially druggable targets as well as the debate over post remission consolidation regimens has also been discussed.

Multistage targeted "Photoactive neutrophil" for enhancing synergistic photo-chemotherapy.

Cell-based drug delivery system holds a great promise in anticancer treatment, due to its potential of maximizing therapeutic efficacy while minimizing adverse effects. However, current cell system can only deliver drugs in tumor lesions, but lack an ability to target subcellular locus of therapeutic actions, thereby compromising anticancer efficacy. Herein, we bioengineered living neutrophils as a novel type of "Photoactive neutrophil" (PAN) with capabilities of self-amplified multistage targeting and inflammation response for enhancing mitochondria-specific photo-chemotherapy. PAN encapsulated multifunctional nanocomplex (RA/Ce6) of RGD-apoptotic peptide conjugate (RA) decorated liposomal photosensitizer Ce6, and could overcome tumor barriers to selectively release RA/Ce6 within tumor. Consequently, RA/Ce6 actively entered cancer cells and accumulated in mitochondria to trigger combined photodynamic therapy (PDT) and RA-induced mitochondrial membrane disruption, resulting in enhanced therapeutic effects. Importantly, PAN exhibited inflammation amplified tumor targeting after PDT, and initiated combined photo-chemotherapy to suppress tumor growth without adverse effects, leading to prolonged mice survival. Therefore, PAN represents the first multistage targeted cell therapy, and brings new insights into cancer treatment.

Long non-coding RNA BACE1-AS is an independent unfavorable prognostic factor in liver cancer.

Liver cancer is one of the leading causes of cancer-associated deaths with incidence rates continuously on the rise. Biomarkers are urgently required for early diagnosis and better prognostic classification, which is essential for risk stratification and optimizing treatment strategies in clinical settings. By analyzing the data extracted from The Cancer Genome Atlas database using R, the long noncoding RNA (lncRNA) ß-site APP-cleaving enzyme 1 antisense (BACE1-AS) was discovered to have both high diagnostic and prognostic values in liver cancer, which could serve as a promising biomarker in clinical settings. Precisely, lncRNA BACE1-AS is significantly overexpressed in liver cancer and its levels vary within different subgroups, suggesting its tumorigenic role. Furthermore, higher BACE1-AS predicts poorer overall survival and relapse-free survival outcomes. Overall, the present study demonstrated that BACE1-AS may be involved in liver cancer progression and could serve as a promising biomarker for diagnosis and prognostic evaluation.

Genome-wide interaction target profiling reveals a novel Peblr20-eRNA activation pathway to control stem cell pluripotency.

Background: Long non-coding RNAs (lncRNAs) constitute an important component of the regulatory apparatus that controls stem cell pluripotency. However, the specific mechanisms utilized by these lncRNAs in the control of pluripotency are not fully characterized. Methods: We utilized a RNA reverse transcription-associated trap sequencing (RAT-seq) approach to profile the mouse genome-wide interaction targets for lncRNAs that are screened by RNA-seq. Results: We identified Peblr20 (Pou5F1 enhancer binding lncRNA 20) as a novel lncRNA that is associated with stem cell reprogramming. Peblr20 was differentially transcribed in fibroblasts compared to induced pluripotent stem cells (iPSCs). Notably, we found that Peblr20 utilized a trans mechanism to interact with the regulatory elements of multiple stemness genes. Using gain- and loss-of-function experiments, we showed that knockdown of Peblr20 caused iPSCs to exit from pluripotency, while overexpression of Peblr20 activated endogenous Pou5F1 expression. We further showed that Peblr20 promoted pluripotent reprogramming. Mechanistically, we demonstrated that Peblr20 activated endogenous Pou5F1 by binding to the Pou5F1 enhancer in trans, recruiting TET2 demethylase and activating the enhancer-transcribed RNAs. Conclusions: Our data reveal a novel epigenetic mechanism by which a lncRNA controls the fate of stem cells by trans-regulating the Pou5F1 enhancer RNA pathway. We demonstrate the potential for leveraging lncRNA biology to enhance the generation of stem cells for regenerative medicine.

Investigation of the Clinical Significance and Prognostic Value of the lncRNA ACVR2B-As1 in Liver Cancer.

A refined liver cancer staging system and effective prognostic prediction can help clinicians make optimized treatment decisions, which is essential in our fight against cancer and for improving the unsatisfying survival rate of liver cancer globally. The prognosis of liver cancer is not only related to tumor status, it is also affected by the patients' liver functions and the chosen treatment. Currently, several staging systems are being tested. Herein, we analyzed RNA-seq data from the TCGA database and identified a newly annotated lncRNA, ACVR2B-AS1, whose expression is upregulated in liver cancer. Higher ACVR2B-AS1 expression is an independent adverse prognostic factor for overall survival (OS) and relapse-free survival (RFS) in liver cancer patients. Our work suggests that the lncRNA ACVR2B-AS1 could be a candidate biomarker for liver cancer prognosis. Furthermore, ACVR2B-AS1 might serve as a potential therapeutic target, which is a possibility that is worthy of further study.