Hypoxia-induced ALKBH5 aggravates synovial aggression and inflammation in rheumatoid arthritis by regulating the m6A modification of CH25H.

Previous studies have shown that epigenetic factors are involved in the occurrence and development of rheumatoid arthritis (RA). However, the role of N6-methyladenosine (m6A) methylation in RA has not been determined. The aim of this study was to investigate the role and regulatory mechanisms of hypoxia-induced expression of the m6A demethylase alkB homolog 5 (ALKBH5) in RA fibroblast-like synoviocytes (FLSs). Synovial tissues were collected from RA and osteoarthritis (OA) patients, and RA FLSs were obtained. ALKBH5 expression in RA FLSs and collagen-induced arthritis (CIA) model rats was determined using quantitative reverse transcription-PCR (qRT-PCR), western blotting and immunohistochemistry (IHC). Using ALKBH5 overexpression and knockdown, we determined the role of ALKBH5 in RA FLS aggression and inflammation. The role of ALKBH5 in RA FLS regulation was explored using m6A-methylated RNA sequencing and methylated RNA immunoprecipitation coupled with quantitative real-time PCR. The expression of ALKBH5 was increased in RA synovial tissues, CIA model rats and RA FLSs, and a hypoxic environment increased the expression of ALKBH5 in FLSs. Increased expression of ALKBH5 promoted the proliferation and migration of RA-FLSs and inflammation. Conversely, decreased ALKBH5 expression inhibited the migration of RA-FLSs and inflammation. Mechanistically, hypoxia-induced ALKBH5 expression promoted FLS aggression and inflammation by regulating CH25H mRNA stability. Our study elucidated the functional roles of ALKBH5 and mRNA m6A methylation in RA and revealed that the HIF1α/2α-ALKBH5-CH25H pathway may be key for FLS aggression and inflammation. This study provides a novel approach for the treatment of RA by targeting the HIF1α/2α-ALKBH5-CH25H pathway.

A workflow for the enrichment, the identification, and the isolation of non-apoptotic single circulating tumor cells for RNA sequencing analysis.

Circulating tumor cells (CTCs) are constantly shed by tumor tissue and can serve as a valuable analyte for a gene expression analysis from a liquid biopsy. However, a high proportion of CTCs can be apoptotic leading to rapid mRNA decay and challenging the analysis of their transcriptome. We established a workflow to enrich, to identify, and to isolate single CTCs including the discrimination of apoptotic and non-apoptotic CTCs for further single CTC transcriptome analysis. Viable tumor cells-we first used cells from breast cancer cell lines followed by CTCs from metastatic breast cancer patients-were enriched with the CellSearch system from diagnostic leukapheresis products, identified by immunofluorescence analysis for neoplastic markers, and isolated by micromanipulation. Then, their cDNA was generated, amplified, and sequenced. In order to exclude early apoptotic tumor cells, staining with Annexin V coupled to a fluorescent dye was used. Annexin V staining intensity was associated with decreased RNA integrity as well as lower numbers of total reads, exon reads, and detected genes in cell line cells and CTCs. A comparative RNA analysis of single cells from MDA-MB-231 and MCF7 cell lines revealed the expected differential transcriptome profiles. Enrichment and staining procedures of cell line cells that were spiked into blood had only little effect on the obtained RNA sequencing data compared to processing of naïve cells. Further, the detection of transcripts of housekeeping genes such as GAPDH was associated with a significantly higher quality of expression data from CTCs. This workflow enables the enrichment, detection, and isolation of single CTCs for individual transcriptome analyses. The discrimination of apoptotic and non-apoptotic cells allows to focus on CTCs with a high RNA integrity to ensure a successful transcriptome analysis.

Rice and Arabidopsis homologs of yeast CHROMOSOME TRANSMISSION FIDELITY PROTEIN 4 commonly interact with Polycomb complexes but exert divergent regulatory functions.

Both genetic and epigenetic information must be transferred from mother to daughter cells during cell division. The mechanisms through which information about chromatin states and epigenetic marks like histone 3 lysine 27 trimethylation (H3K27me3) are transferred have been characterized in animals; these processes are less well understood in plants. Here, based on characterization of a dwarf rice (Oryza sativa) mutant (dwarf-related wd40 protein 1, drw1) deficient for yeast CTF4 (CHROMOSOME TRANSMISSION FIDELITY PROTEIN 4), we discovered that CTF4 orthologs in plants use common cellular machinery yet accomplish divergent functional outcomes. Specifically, drw1 exhibited no flowering-related phenotypes (as in the putatively orthologous Arabidopsis thaliana eol1 mutant), but displayed cell cycle arrest and DNA damage responses. Mechanistically, we demonstrate that DRW1 sustains normal cell cycle progression by modulating the expression of cell cycle inhibitors KIP-RELATED PROTEIN 1 (KRP1) and KRP5, and show that these effects are mediated by DRW1 binding their promoters and increasing H3K27me3 levels. Thus, although CTF4 orthologs ENHANCER OF LHP1 1 (EOL1) in Arabidopsis and DRW1 in rice are both expressed uniquely in dividing cells, commonly interact with several Polycomb complex subunits, and promote H3K27me3 deposition, we now know that their regulatory functions diverged substantially during plant evolution. Moreover, our work experimentally illustrates specific targets of CTF4/EOL1/DRW1, their protein-proteininteraction partners, and their chromatin/epigenetic effects in plants.

Preoperative multimodal ultrasonic imaging in a case of Peutz-Jeghers syndrome complicated by atypical lobular endocervical glandular hyperplasia: a case report and literature review.

BACKGROUND: Peutz-Jeghers syndrome (PJS), an autosomal dominant multiple cancerous disorder, is clinically characterized by mucocutaneous macules and multiple gastrointestinal hamartomatous polyps. Gastric-type endocervical adenocarcinoma (G-EAC), a special subtype of cervical adenocarcinoma with non-specific symptoms and signs, is known to occur in approximately 11% of female patients with PJS. CASE PRESENTATION: Here, we report a case of PJS in a 24-year-old female with multiple mucocutaneous black macules who complained of vaginal discharge and menorrhagia. Moreover, we first described the multimodal ultrasonographical manifestations of PJS-correlated G-EAC. The three-dimensional reconstructed view of G-EAC on 3D realisticVue exhibited a distinctive "cosmos pattern" resembling features on magnetic resonance imaging, and the contrast-enhanced ultrasound displayed a "quick-up and slow-down" pattern of the solid components inside the mixed cervical echoes. We reported the multimodal ultrasonographical characteristics of a case of PJS-related G-EAC, as well as reviewed PJS-related literature and medical imaging features and clinical characteristics of G-EAC to provide insight into the feasibility and potential of utilizing multimodal ultrasonography for the diagnosis of G-EAC. CONCLUSIONS: Multimodal ultrasound can visualize morphological features, solid components inside, and blood supplies of the G-EAC lesion and distinguish the G-EAC lesion from normal adjacent tissues. This facilitates preoperative diagnosis and staging of PJS-related G-EAC, thereby aiding subsequent health and reproductive management for patients with PJS.

SYNOPSIS: We reported multimodal ultrasonographical characteristics of a case of Peutz-Jeghers syndrome-related gastric-type endocervical adenocarcinoma (G-EAC), indicating the potential use of multimodal ultrasonography for G-EAC diagnosis.

Comparative analysis of EpCAM high-expressing and low-expressing circulating tumour cells with regard to their clonal relationship and clinical value.

BACKGROUND: Circulating tumour cells (CTCs) are mainly enriched based on the epithelial cell adhesion molecule (EpCAM). Although it was shown that an EpCAM low-expressing CTC fraction is not captured by such approaches, knowledge about its prognostic and predictive relevance and its relation to EpCAM-positive CTCs is lacking. METHODS: We developed an immunomagnetic assay to enrich CTCs from metastatic breast cancer patients EpCAM independently using antibodies against Trop-2 and CD-49f and characterised their EpCAM expression. DNA of single EpCAM high expressing and low expressing CTCs was analyzed regarding chromosomal aberrations and predictive mutations. Additionally, we compared CTC-enrichment on the CellSearch system using this antibody mix and the EpCAM based enrichment. RESULTS: Both antibodies acted synergistically in capturing CTCs. Patients with EpCAM high-expressing CTCs had a worse overall and progression-free survival. EpCAM high- and low-expressing CTCs presented similar chromosomal aberrations and mutations indicating a close evolutionary relationship. A sequential enrichment of CTCs from the EpCAM-depleted fraction yielded a population of CTCs not captured EpCAM dependently but harbouring predictive information. CONCLUSIONS: Our data indicate that EpCAM low-expressing CTCs could be used as a valuable tumour surrogate material-although they may be prognostically less relevant than EpCAM high-expressing CTCs-and have particular benefit if no CTCs are detected using EpCAM-dependent technologies.

Nitrate Radical Induced "Two in One" Interface Engineering toward High Reversibility of Zn Metal Anode.

Advanced interfacial engineering performs a forceful modulation effect on Zn2+ plating/stripping with simultaneous inhibition of hydrogen evolution reaction, chemical corrosion, and dendrite growth, which is responsible for high reversibility of Zn anode. Herein, a "two in one" interface engineering is developed to improve the reversibility of Zn anode, in which multi-functional Zn5 (NO3 )2 (OH)8 ·2H2 O layer and preferential Zn (002) texture are constructed simultaneously. Due to nucleophilicity to Zn2+ arising from electronegativity, the layer can accelerate the desolvation process of [Zn (H2 O)6 ]2+ and transfer kinetics of Zn2+ ions, leading to uniform nucleation and effective inhibition of water-induced side reactions. Meanwhile, the latter is beneficial to guiding   Zn (002)-preferred orientation deposition with compact structure. Consequently, the Zn electrodes with such complementary interface modulation exhibit prominent reversibility. With an area capacity of 1 mAh cm-2 at 1 mA cm-2 , the symmetric cell operates steadily for 4000 h. Highly reversible Zn anode is maintained even at 50 mA cm-2 . For full cells coupled with MnO2 cathode, impressive rate capability and cycling stability with a high capacity beyond 100 mAh g-1 at 1 A g-1 after 2000 cycles are achieved. The results provide new insights into Zn anodes with high reversibility for next-generation aqueous zinc ion batteries.

Multiscale Structural Engineering of Sulfur/Carbon Cathodes Enables High Performance All-Solid-State LiS Batteries.

Constructing all-solid-state lithium-sulfur batteries (ASSLSBs) cathodes with efficient charge transport and mechanical flexibility is challenging but critical for the practical applications of ASSLSBs. Herein, a multiscale structural engineering of sulfur/carbon composites is reported, where ultrasmall sulfur nanocrystals are homogeneously anchored on the two sides of graphene layers with strong SC bonds (denoted as S@EG) in chunky expanded graphite particles via vapor deposition method. After mixing with Li9.54 Si1.74 P1.44 S11.7 Cl0.3 (LSPSCL) solid electrolytes (SEs), the fabricated S@EG-LSPSCL cathode with interconnected "Bacon and cheese sandwich" feature can simultaneously enhance electrochemical reactivity, charge transport, and chemomechanical stability due to the synergistic atomic, nanoscopic and microscopic structural engineering. The assembled InLi/LSPSCL/S@EG-LSPSCL ASSLSBs demonstrate ultralong cycling stability over 2400 cycles with 100% capacity retention at 1 C, and a record-high areal capacity of 14.0 mAh cm-2 at a record-breaking sulfur loading of 8.9 mg cm-2 at room temperature as well as high capacities with capacity retentions of ≈100% after 600 cycles at 0 and 60 °C. Multiscale structural engineered sulfur/carbon cathode has great potential to enable high-performance ASSLSBs for energy storage applications.

Chromatin accessibility illuminates single-cell regulatory dynamics of rice root tips.

BACKGROUND: Root development and function have central roles in plant adaptation to the environment. The modification of root traits has additionally been a major driver of crop performance since the green revolution; however, the molecular underpinnings and the regulatory programmes defining root development and response to environmental stress remain largely unknown. Single-cell reconstruction of gene regulatory programmes provides an important tool to understand the cellular phenotypic variation in complex tissues and their response to endogenous and environmental stimuli. While single-cell transcriptomes of several plant organs have been elucidated, the underlying chromatin landscapes associated with cell type-specific gene expression remain largely unexplored. RESULTS: To comprehensively delineate chromatin accessibility during root development of an important crop, we applied single-cell ATAC-seq (scATAC-seq) to 46,758 cells from rice root tips under normal and heat stress conditions. Our data revealed cell type-specific accessibility variance across most of the major cell types and allowed us to identify sets of transcription factors which associate with accessible chromatin regions (ACRs). Using root hair differentiation as a model, we demonstrate that chromatin and gene expression dynamics during cell type differentiation correlate in pseudotime analyses. In addition to developmental trajectories, we describe chromatin responses to heat and identify cell type-specific accessibility changes to this key environmental stimulus. CONCLUSIONS: We report chromatin landscapes during rice root development at single-cell resolution. Our work provides a framework for the integrative analysis of regulatory dynamics in this important crop organ at single-cell resolution.

Restoration of bladder neck activity and levator hiatus dimensions in Asian primipara: a prospective study.

Pelvic floor muscle training (PFMT) reduces the symptoms in women with pelvic floor dysfunction (PFD); however, the optimal initial timing for secondary prevention of PFD by PFMT is not clear. To identify the optimal timing in Asian primiparas with vaginal delivery, bladder neck descent (BND), levator hiatus areas, and levator hiatus distensibility and contractility were assessed in 26 nulliparous women at 36 weeks of gestation and at 2, 4, 6, and 12 weeks postpartum. We found that BND increased significantly from 2 weeks onwards until 6 weeks postpartum (p = 0.004); the levator hiatus area at rest and contraction both showed the largest value at 2 weeks postpartum (p = 0.005 and p < 0.005 respectively), followed by a continuous decrease; the hiatus area during Valsalva manoeuvre, and the levator hiatus distensibility and contractility showed the lowest value at 2 weeks postpartum, followed by a continuous increase; the changes in BND showed no correlation with the changes in distensibility or hiatus area during Valsalva manoeuvre (p = 0.073 and 0.590 respectively). In Asian primiparas with vaginal delivery, the recovery of levator hiatus and bladder neck mobility begins at 2 and 6 weeks, respectively. This information could be useful in defining the best time to begin PFMT for secondary prevention of postpartum PFD in Asian primiparous women.IMPACT STATEMENTWhat is already known on this subject? Pelvic floor muscle training (PFMT) helps to reduce symptoms of pelvic floor dysfunction (PFD), however, there are no clear time strategies for the secondary prevention of PFD by PFMT in Asian primiparas with vaginal delivery.What do the results of this study add? This study was the first longitudinal study in Asian primipara to investigate the natural regeneration of pelvic floor functions in the early postpartum period by intensively monitoring the bladder neck mobility and levator hiatus dimensions at multiple time points. We found that bladder neck descent (BND) increased significantly from 2 weeks onwards until 6 weeks postpartum; the levator hiatus area at rest and contraction both showed the largest value at 2 weeks postpartum, followed by a continuous decrease; the hiatus area during Valsalva manoeuvre, and the levator hiatus distensibility and contractility showed the lowest value at 2 weeks postpartum, followed by a continuous increase; the changes in BND showed no correlation with the changes in distensibility or hiatus area during Valsalva manoeuvre.What are the implications of these findings for clinical practice and/or further research? Our study suggested that in Asian primipara, the recovery of bladder neck mobility after vaginal delivery begins at 6 weeks postpartum, while the levator hiatus muscle begins to recover within the first 2 weeks postpartum. Therefore, it could be useful in deciding the best time to start PFMT for secondary prevention of postpartum PFD in Asian primiparous women.

Water-Processable and Multiscale-Designed Vanadium Oxide Cathodes with Predominant Zn2+ Intercalation Pseudocapacitance toward High Gravimetric/Areal/Volumetric Capacity.

Layered vanadium oxides have great potential as cathode materials for recently surged aqueous zinc-ion batteries (AZIBs). However, achieving high energy/power densities simultaneously is challenging, and side reactions related to more frequently than disclosed Zn2+ /proton co-insertion mechanism aggravate stability concerns. Herein, an engineered binder-free cathode configuration based on water-processable and high packing-density sheet-shaped composites of carbon nanotubes network, surface poly(3,4-ethylenedioxythiophene) (PEDOT) bridging coating, and ultrasmall PEDOT-intercalated V2 O5 nanoflakes is developed, and therein, large pseudocapacitance via predominant (≈91%) Zn2+ intercalation is revealed. Besides competitive gravimetric/areal capacity, the binder-free cathodes exhibit high volumetric capacity of 1106.1 mAh cm-3 and high-rate capability of 180.0 mA g-1 at 30 A g-1 as well as long-cycling stability. Such combined level of performance and unwanted reaction mechanism are attributed to the contained multiscale material/electrode design formula from crystal structure modification to 3D architecture construction of whole electrode, which endows the binder-free cathodes with abundant accessible sites for Zn2+ storage, but the least hydroxyl terminated surface for H+ insertion, as well as highly conductive network for electron transfer and fast Zn2+ diffusion kinetics throughout the electrode. Combined with scalable fabrication protocols, this study opens up great opportunities for high-performance vanadium oxide cathodes practically applicable to AZIBs.

Implementing microwell slides for detection and isolation of single circulating tumor cells from complex cell suspensions.

Cell loss during detection and isolation of circulating tumor cells (CTCs) is a challenge especially when label-free pre-enrichment technologies are used without the aid of magnetic particles. Although microfluidic systems can remove the majority of "contaminating" white blood cells (WBCs), their remaining numbers are still impeding single CTC isolation, thus making additional separation steps needed. This study aimed to develop a workflow from blood-to-single CTC for complex cell suspensions by testing two microwell formats. In the first step, different cell lines were used to compare the performances of Sievewell™ 370 K (TOK, Japan) and CellCelector™ Nanowell U25 (ALS Automated Lab Solutions, Germany) slides for cell labelling and single-cell micromanipulation. Confounding levels of auto-fluorescence inherent to different plastic materials used to cast the microwells, staining recovery rates, and cell isolation rates were determined. In the second step, three different blood preservation tubes were tested for RNA analysis. Lastly, the established workflow was applied to isolate CTCs from peripheral blood samples obtained from metastasized breast cancer (mBC) patients for single-cell DNA and RNA analysis. The detection of CTCs in Sievewell slides profit from better signal-to-noise ratios in the fluorescence channels mainly used for CTC detection. In addition, due to its design, Sievewell supports direct in situ CTC labelling, which minimizes cell loss and leads to single-cell recovery rates after staining of approx. 94%. Detection of PIK3CA mutations in single CTCs verified the applicability of the workflow for the analysis of genomic DNA of CTCs. Furthermore, combined with blood preservation up to 48 h at room temperature in LBguard tubes, panel RT-PCR transcript analysis was successful for single cell line cells and CTCs, respectively. The combined use of Sievewell microwell slides and CellCelector™ automated micromanipulation system improves single CTC detection, labelling and isolation from complex cell suspensions. This approach is especially valuable when samples of high cellular content are processed.

FHY3 interacts with phytochrome B and regulates seed dormancy and germination.

Seed dormancy and germination are fundamental processes for plant propagation, both of which are tightly regulated by internal and external cues. Phytochrome B (phyB) is a major red/far-red-absorbing photoreceptor that senses light signals that modulate seed dormancy and germination. However, the components that directly transduce that signal downstream of phyB are mostly unknown. Here, we show that the transposase-derived transcription factor FAR-RED ELONGATED HYPOCOTYL3 (FHY3) inhibits seed dormancy and promotes phyB-mediated seed germination in Arabidopsis thaliana. FHY3 physically interacts with phyB in vitro and in vivo. RNA-sequencing and reverse transcription-quantitative polymerase chain reaction analyses showed that FHY3 regulates multiple downstream genes, including REVEILLE2 (RVE2), RVE7, and SPATULA (SPT). Yeast one-hybrid, electrophoresis mobility shift, and chromatin immunoprecipitation assays demonstrated that FHY3 directly binds these genes via a conserved FBS cis-element in their promoters. Furthermore, RVE2, RVE7, and GIBBERELLIN 3-OXIDASE 2 (GA3ox2) genetically act downstream of FHY3. Strikingly, light and phyB promote FHY3 protein accumulation. Our study reveals a transcriptional cascade consisting of phyB-FHY3-RVE2/RVE7/SPT-GA3ox2 that relays environmental light signals and thereby controls seed dormancy and germination.

Reorganization of the 3D chromatin architecture of rice genomes during heat stress.

BACKGROUND: The three-dimensional spatial organization of the genome plays important roles in chromatin accessibility and gene expression in multiple biological processes and has been reported to be altered in response to environmental stress. However, the functional changes in spatial genome organization during environmental changes in crop plants are poorly understood. RESULTS: Here we perform Hi-C, ATAC-seq, and RNA-seq in two agronomically important rice cultivars, Nipponbare (Nip; Japonica) and 93-11 (Indica), to report a comprehensive profile of nuclear dynamics during heat stress (HS). We show that heat stress affects different levels of chromosome organization, including A/B compartment transition, increase in the size of topologically associated domains, and loss of short-range interactions. The chromatin architectural changes were associated with chromatin accessibility and gene expression changes. Comparative analysis revealed that 93-11 exhibited more dynamic gene expression and chromatin accessibility changes, including HS-related genes, consistent with observed higher HS tolerance in this cultivar. CONCLUSIONS: Our data uncovered higher-order chromatin architecture as a new layer in understanding transcriptional regulation in response to heat stress in rice.

SiOx Anode: From Fundamental Mechanism toward Industrial Application.

Silicon monoxide (SiO) has been explored and confirmed as a promising anode material of lithium-ion batteries. Compared with pure silicon, SiO possesses a more stable microstructure which makes better comprehensive electrochemical properties. However, the lithiation mechanism remains in dispute, and problems such as poor cyclability, unsatisfactory electrical conductivity, and low initial Coulombic efficiency (ICE) need to be addressed. Additionally, more attention needs to be paid on the internal relationship between electrochemical performances and structures. In this review, the different preparation processes, the derived microstructure of the SiOx , the corresponding lithiation mechanism, and electrochemical properties are summarized. Researches about disproportionation reaction which is regarded as a key point and other modifications are systematically introduced. Closely linked with structure, the advantages and disadvantages of various SiOx anode materials are summarized and analyzed, and the possible directions toward the practical applications of SiOx anode material are presented. In a word, from the preparation and reaction mechanism of the material to the modifications and future development, a complete and systematical review on SiOx anode is presented.

MoO2@C modified separator as an interlayer for high performance lithium-sulfur batteries.

Lithium-sulfur batteries have attracted much attention as a promising next-generation energy storage system due to their high theoretical specific capacity and energy density. However, lithium-sulfur batteries are still facing some problems that hinder their large-scale commercial application. High conductivity molybdenum dioxide coated with carbon composite (MoO2@C) were introduced to coat the separator to study its application in lithium sulfur batteries. Molybdenum dioxide coated with carbon composite nanoparticles were synthesized by hydrothermal method and high-temperature calcination and then was coated on the separator with acetylene black. The coating layer can take advantage of the synergetic effect of physical barrier and chemical adsorption to reduce the loss of active substances. The electrochemical performance of the battery has been improved by applying MoO2@C in lithium-sulfur separator. The first discharge specific capacity is 917 mA h g-1 under the current density of 1.0 A g-1, after 300 cycles, the capacity is 618 mA h g-1; after 200 cycles under the current density of 2.0 A g-1, the reversible specific capacity can still maintain 551 mA h g-1.

Toward Building a Physical Proxy for Gas-Phase Sulfuric Acid Concentration Based on Its Budget Analysis in Polluted Yangtze River Delta, East China.

Gaseous sulfuric acid (H2SO4) is a crucial precursor for secondary aerosol formation, particularly for new particle formation (NPF) that plays an essential role in the global number budget of aerosol particles and cloud condensation nuclei. Due to technology challenges, global-wide and long-term measurements of gaseous H2SO4 are currently very challenging. Empirical proxies for H2SO4 have been derived mainly based on short-term intensive campaigns. In this work, we performed comprehensive measurements of H2SO4 and related parameters in the polluted Yangtze River Delta in East China during four seasons and developed a physical proxy based on the budget analysis of gaseous H2SO4. Besides the photo-oxidation of SO2, we found that primary emissions can contribute considerably, particularly at night. Dry deposition has the potential to be a non-negligible sink, in addition to condensation onto particle surfaces. Compared with the empirical proxies, the newly developed physical proxy demonstrates extraordinary stability in all the seasons and has the potential to be widely used to improve the understanding of global NPF fundamentally.

INPP4B exerts a dual function in the stemness of colorectal cancer stem-like cells through regulating Sox2 and Nanog expression.

Inositol polyphosphate 4-phosphatase type II (INPP4B), a lipid phosphatase, was identified as a negative regulator of phosphatidylinositol 3-kinase (PI3K)/Akt signaling in several cancers. The expression and biological function of INPP4B in human colorectal cancer (CRC) are controversial, while the role and molecular mechanism of INPP4B in colorectal cancer stem-like cells (CR-CSLCs) remains unclear. Here, we observed that INPP4B expression was markedly decreased in primary non-metastatic CR-CSLCs and increased in highly metastatic CR-CSLCs compared with corresponding control non-CSLCs. INPP4B overexpression inhibited self-renewal, and chemoresistance of primary non-metastatic CR-CSLCs, but exerted the opposite roles in highly metastatic CR-CSLCs in vitro. Similarly, INPP4B knockdown had dual functions in the self-renewal and chemoresistance of different CR-CSLCs. In addition, we demonstrated that INPP4B overexpression suppressed the tumorigenicity of primary non-metastatic CR-CSLCs while induced the tumorigenicity of highly metastatic CR-CSLCs in nude mice. Furthermore, INPP4B was found to modulate the stemness of CR-CSLCs by regulating Sox2 and Nanog expression, which was dependent on PI3K/PTEN/Akt signaling. In conclusion, our results highlight an important role of INPP4B in the stemness of CR-CSLCs for the first time and emphasize INPP4B as a dual therapeutic target for suppressing primary cancer cell proliferation and for preventing metastasis in CRC patients.

Interplay between REVEILLE1 and RGA-LIKE2 regulates seed dormancy and germination in Arabidopsis.

Environmental light signal and GAs synergistically regulate seed dormancy and germination. The phytochrome B (phyB) photoreceptor regulates expression of the REVEILLE1 (RVE1) transcription factor, which directly inhibits GIBBERELLIN 3-OXIDASE2 transcription, suppressing GA biosynthesis. However, whether phyB-RVE1 coordinates with GA signaling in controlling seed dormancy and germination remains unknown. Here, we demonstrate that RVE1 regulation of seed dormancy and germination requires a DELLA repressor, REPRESSOR OF GA-LIKE2 (RGL2), in Arabidopsis thaliana. RVE1 interacts with both RGL2 and its E3 ubiquitin ligase SLEEPY1 (SLY1) and promotes RGL2 stability by restraining the RGL2-SLY1 interaction. Furthermore, RVE1 and RGL2 synergistically regulate global transcriptome changes; RGL2 enhances the DNA-binding capacity and transcriptional activity of RVE1 in regulating downstream gene expression. Moreover, RGL2 expression is repressed by phyB. Our study reveals a novel regulatory mechanism in which the RVE1-RGL2 module coordinately controls seed dormancy and germination by integrating light perception, GA metabolism and GA signaling pathways.

Polychlorinated naphthalenes, polychlorinated dibenzo-p-dioxins and dibenzofurans, and polychlorinated biphenyls in soils in an industrial park in Northwestern China: Levels, source apportionment, and potential human health risks.

Seventeen soil samples collected in an industrial park located in Ningxia Province, Northwestern China were analyzed for polychlorinated naphthalenes (PCNs), polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), and polychlorinated biphenyls (PCBs). The PCN, PCDD/F, and PCB concentration ranges were 183-3340, 7.00-215, and 45.1-355 pg/g, respectively. Positive matrix factorization showed that secondary ferrous metal smelters and cement kilns contributed more than 70% of the total PCN concentration. Historical use of Halowax 1051 also affected the PCN concentrations in soil. Principal component analysis indicated that the PCDD/F concentrations in soil in the study area were mainly affected by thermal processes in secondary ferrous metal smelters. CB-209 was an important contributor to total PCBs in the study area, and likely originated from the phthalocyanine-type pigments used in a local recycled paper mill. Samples S10, S1, S17, and S6 had high ∑TEQ (PCDD/Fs + PCNs + PCBs) concentrations, and the carcinogenic risks of PCDD/Fs, PCNs, and PCBs for workers from these samples were 0.487 × 10-6, 0.234 × 10-6, 0.230 × 10-6, and 0.210 × 10-6, respectively. According to our results, the health risks of PCDD/Fs, PCNs, and PCBs for workers in this area should be given more attention.

The effects of CTX damage or inhibition of bone marrow hematopoiesis and GM-CSF stimulation of bone marrow hematopoiesis on the peripheral blood TCRß CDR3 repertoire of BALB/c mice.

Objective: This paper aims to investigate the dynamic changes of the T-cell receptor (TCR) ß complementarity-determining region 3 (CDR3) repertoire during cyclophosphamide or Cytoxan (CTX) damage or inhibition of bone marrow hematopoiesis caused by a reduction of peripheral blood white blood cells (WBCs) in BALB/c mice.Methods: We analyze TCR CDR3 repertoire of BALB/c mice including (1) NS control group (2) CTX damage group (3) CTX damage + GM-CSF recovery group (4) CTX damage + auto-recovery group.Results: The number of WBCs in the CTX group is significantly lower than that in the NS group and after GM-CSF injection, the GM-CSF group is higher than that in the NS group. The diversity of the CTX damage group is the highest and there is a significant difference in high-frequency clonal proliferation between the CTX damage group and CTX damage + GM-CSF recovery group compared with the NS control group. In addition, the numbers of unique productive CDR3 overlapping numbers in the four experimental groups are similar.Conclusions: These data reveal that CTX significantly reduced the number of WBCs and ratio of high-frequency TCR CDR3 sequences, and indirectly increased the diversity of the TCR CDR3 repertoire. GM-CSF quickly restored the number of WBCs, and partially restored changes in the TCR CDR3 repertoire induced by CTX. Results from monitoring the dynamic changes of the TCR CDR3 repertoire can be used to assess the effects of CTX and GM-CSF on the function of peripheral blood T cells and to explore the possible underlying mechanisms.