ALBERT

Beschreibung: Background The results of a previous study verified that umbilical cord mesenchymal stem cells (UCMSCs) have good therapeutic effects for the treatment of HBV-related acute-on-chronic liver failure (ACLF) and liver cirrhosis (LC). Nevertheless, it is still unknown whether the effects of UCMSCs are affected by recipient age. Methods Patients treated with UCMSCs who met the criteria of HBV-related ACLF and liver cirrhosis were identified in this retrospective observational study. Patients were divided into subgroups according to the World Health Organization (WHO) age criteria (

Beschreibung: Objectives To investigate the safety for clinic use and therapeutic effects of basic fibroblast growth factor (bFGF)-overexpressing human umbilical cord-derived mesenchymal stem cells (HUCMSCs) in mice with completely transected spinal cord injury (SCI). Methods Stable bFGF-overexpressing HUCMSCs clones were established by electrotransfection and then subjected to systematic safety evaluations. Then, bFGF-overexpressing and control HUCMSCs were used to treat mice with completely transected SCI by tail intravenous injection. Therapeutic outcomes were then investigated, including functional recovery of locomotion, histological structures, nerve regeneration, and recovery mechanisms. Results Stable bFGF-overexpressing HUCMSCs met the standards and safety of MSCs for clinic use. In the mouse SCI model, stable bFGF-overexpressing HUCMSCs markedly improved therapeutic outcomes such as reducing glial scar formation, improving nerve regeneration and proliferation of endogenous neural stem cells (NSCs), and increasing locomotion functional recovery of posterior limbs compared with the control HUCMSCs group. Furthermore, bFGF-overexpressing HUCMSCs promoted the proliferation and neuronal differentiation of NSCs in vitro through the PI3K-Akt-GSK-3β pathway. Conclusion bFGF-overexpressing HUCMSCs meet the requirements of clinical MSCs and improve evident therapeutic outcomes of mouse SCI treatment, which firmly supports the safety and efficacy of gene-modified MSCs for clinical application.

Beschreibung: Hepatocellular carcinoma (HCC) is the most common visceral neoplasms with its heterogeneity and high rate of recurrence. HCC is characterized to be delayed diagnosis and the development of resistant disease. However, the molecular mechanism for HCC pathogenesis and progression remains largely unknown. Here, we demonstrated that ubiquitin-specific protease14 (USP14) is highly expressed in HCC samples, and the higher expression of USP14 is positively correlated with poor prognosis. Interestingly, USP14 is involved in the maintenance of HIF1-α stability to activate HIF1-α-induced transactivation via its deubiquitinase activity. USP14 depletion or its specific inhibitor IU1 treatment decreased cell proliferation, invasion, migration, and Vascular Mimicry (VM) formation even under hypoxia conditions in HCC cell lines. Moreover, we provided the evidence to show that knockdown of USP14 or USP14 inhibitor (IU1) treatment inhibited tumor growth in tumor-bearing nude mice. Our findings suggest that USP14 maintains HIF1-α stability through its deubiquitination activity, providing a potential biomarker for the early diagnosis and therapy of HCC.

Beschreibung: Background Coronary artery disease (CAD) is considered as a multi-faceted chronic inflammatory disease involving reduced blood supply to the myocardium as a result of accumulating lipids in the atrial walls. Visceral adiposity with disrupted release of adipokines play a key role in its pathogenesis. Asprosin is a newly identified fasting-induced glucogenic adipokine that has been related with metabolic disorders such as type II diabetes mellitus and polycystic ovary syndrome. The preset study sought to assess circulating asprosin in context of CAD. Methods In this study, serum levels of asprosin were determined in 88 CAD patients and 88 non-CAD healthy controls. Serum IL-6, TNF-α, asprosin and adiponectin were assessed using ELISA kits. Results: Serum asprosin was found to be higher in CAD patients when compared to non-CAD subjects (7.84 ± 2.08 versus 5.02 ± 1.29 μg/mL, p 

Beschreibung: Identification of causal variants and genes underlying genome-wide association study (GWAS) loci is essential to understand the biology of alcohol use disorder (AUD) and drinks per week (DPW). Multi-omics integration approaches have shown potential for fine mapping complex loci to obtain biological insights to disease mechanisms. In this study, we use multi-omics approaches, to fine-map AUD and DPW associations at single SNP resolution to demonstrate that rs56030824 on chromosome 11 significantly reduces SPI1 mRNA expression in myeloid cells and lowers risk for AUD and DPW. Our analysis also identifies MAPT as a candidate causal gene specifically associated with DPW. Genes prioritized in this study show overlap with causal genes associated with neurodegenerative disorders. Multi-omics integration analyses highlight, genetic similarities and differences between alcohol intake and disordered drinking, suggesting molecular heterogeneity that might inform future targeted functional and cross-species studies.

Beschreibung: As a critical evolutionary pivot between invertebrates and vertebrates, lampreys provide rich genetic information. Lamprey immune protein (LIP) is a key immune regulator. MicroRNAs, well-conserved in the response to immunological stress, remain understudied in lamprey immunity. We generated a lamprey microRNA expression atlas, using deep sequencing, upon Vibrio anguillarum infection. Using comparative methods, we found that miR-4561 potentially regulates innate immunity via interaction with lip. We found a sequence in the 3′-UTR region of LIP mRNA complementary to the miR-4561 seed region; miR-4561 expression was negatively correlated with LIP. During V. anguillarum infection, miR-4561 inhibited LIP expression and bacterial clearance. Notably, LIP expression in supraneural body cells was necessary for the Gram-negative immune response. Additionally, we observed that overexpression of miR-4561 induced apoptosis in embryonic cells, suggesting a role in embryonic development. Collectively, we show lamprey microRNAs may significantly affect gene regulation and provide new insights on LIP-mediated immune regulation.

Beschreibung: Background Metabolic stress, as negative energy balance on one hand or obesity on the other hand can lead to increased levels of free fatty acids in the plasma and follicular fluid of animals and humans. In an earlier study, we showed that increased oleic acid (OA) concentrations affected the function of cultured bovine granulosa cells (GCs). Here, we focus on genome wide effects of increased OA concentrations. Results Our data showed that 413 genes were affected, of which 197 were down- and 216 up-regulated. Specifically, the expression of FSH-regulated functional key genes, CCND2, LHCGR, INHA and CYP19A1 and 17-β-estradiol (E2) production were reduced by OA treatment, whereas the expression of the fatty acid transporter CD36 was increased and the morphology of the cells was changed due to lipid droplet accumulation. Bioinformatic analysis revealed that associated pathways of the putative upstream regulators “FSH” and “Cg (choriogonadotropin)” were inhibited and activated, respectively. Down-regulated genes are over-represented in GO terms “reproductive structure/system development”, “ovulation cycle process”, and “(positive) regulation of gonadotropin secretion”, whereas up-regulated genes are involved in “circulatory system development”, “vasculature development”, “angiogenesis” or “extracellular matrix/structure organization”. Conclusions From these data we conclude that besides inhibiting GC functionality, increased OA levels seemingly promote angiogenesis and tissue remodelling, thus suggestively initiating a premature fulliculo-luteal transition. In vivo this may lead to impeded folliculogenesis and ovulation, and cause sub-fertility.

Beschreibung: Graphene-based photodetectors have attracted significant attention for high-speed optical communication due to their large bandwidth, compact footprint, and compatibility with silicon-based photonics platform. Large-bandwidth silicon-based optical coherent receivers are crucial elements for large-capacity optical communication networks with advanced modulation formats. Here, we propose and experimentally demonstrate an integrated optical coherent receiver based on a 90-degree optical hybrid and graphene-on-plasmonic slot waveguide photodetectors, featuring a compact footprint and a large bandwidth far exceeding 67 GHz. Combined with the balanced detection, 90 Gbit/s binary phase-shift keying signal is received with a promoted signal-to-noise ratio. Moreover, receptions of 200 Gbit/s quadrature phase-shift keying and 240 Gbit/s 16 quadrature amplitude modulation signals on a single-polarization carrier are realized with a low additional power consumption below 14 fJ/bit. This graphene-based optical coherent receiver will promise potential applications in 400-Gigabit Ethernet and 800-Gigabit Ethernet technology, paving another route for future high-speed coherent optical communication networks.

Beschreibung: An overarching challenge of the electrochemical carbon dioxide reduction reaction (eCO2RR) is finding an earth-abundant, highly active catalyst that selectively produces hydrocarbons at relatively low overpotentials. Here, we report the eCO2RR performance of two-dimensional transition metal carbide class of materials. Our results indicate a maximum methane (CH4) current density of −421.63 mA/cm2 and a CH4 faradic efficiency of 82.7% ± 2% for di-tungsten carbide (W2C) nanoflakes in a hybrid electrolyte of 3 M potassium hydroxide and 2 M choline-chloride. Powered by a triple junction photovoltaic cell, we demonstrate a flow electrolyzer that uses humidified CO2 to produce CH4 in a 700-h process under one sun illumination with a CO2RR energy efficiency of about 62.3% and a solar-to-fuel efficiency of 20.7%. Density functional theory calculations reveal that dissociation of water, chemisorption of CO2 and cleavage of the C-O bond—the most energy consuming elementary steps in other catalysts such as copper—become nearly spontaneous at the W2C surface. This results in instantaneous formation of adsorbed CO—an important reaction intermediate—and an unlimited source of protons near the tungsten surface sites that are the main reasons for the observed superior activity, selectivity, and small potential.

Beschreibung: The contents of numerous membrane lipids change upon ageing. However, it is unknown whether and how any of these changes are causally linked to lifespan regulation. Acyl chains contribute to the functional specificity of membrane lipids. In this study, working with C. elegans, we identified an acyl chain-specific sphingolipid, C22 glucosylceramide, as a longevity metabolite. Germline deficiency, a conserved lifespan-extending paradigm, induces somatic expression of the fatty acid elongase ELO-3, and behenic acid (22:0) generated by ELO-3 is incorporated into glucosylceramide for lifespan regulation. Mechanistically, C22 glucosylceramide is required for the membrane localization of clathrin, a protein that regulates membrane budding. The reduction in C22 glucosylceramide impairs the clathrin-dependent autophagic lysosome reformation, which subsequently leads to TOR activation and longevity suppression. These findings reveal a mechanistic link between membrane lipids and ageing and suggest a model of lifespan regulation by fatty acid-mediated membrane configuration.

Beschreibung: Background Left-right (LR) asymmetry is an essential feature of bilateral animals. Studies in vertebrates show that LR asymmetry formation comprises three major steps: symmetry breaking, asymmetric gene expression, and LR morphogenesis. Although much progress has been made in the first two events, mechanisms underlying asymmetric morphogenesis remain largely unknown due to the complex developmental processes deployed by vertebrate organs. Results We here addressed this question by studying Pitx gene function in the basal chordate amphioxus whose asymmetric organogenesis, unlike that in vertebrates, occurs essentially in situ and does not rely on cell migration. Pitx null mutation in amphioxus causes loss of all left-sided organs and incomplete ectopic formation of all right-sided organs on the left side, whereas Pitx partial loss-of-function leads to milder phenotypes with only some LR organs lost or ectopically formed. At the N1 to N3 stages, Pitx expression is gradually expanded from the dorsal anterior domain to surrounding regions. This leads to activation of genes like Lhx3 and/or Prop1 and Pit, which are essential for left-side organs, and downregulation of genes like Hex and/or Nkx2.1 and FoxE4, which are required for right-side organs to form ectopically on the left side. In Pitx mutants, the left-side expressed genes are not activated, while the right-side genes fail to decrease expression on the left side. In contrast, in embryos overexpressing Pitx genes, the left-side genes are induced ectopically on the right side, and the right-side genes are inhibited. Several Pitx binding sites are identified in the upstream sequences of the left-side and right-side genes which are essential for activation of the former and repression of the latter by Pitx. Conclusions Our results demonstrate that (1) Pitx is a major (although not the only) determinant of asymmetric morphogenesis in amphioxus, (2) the development of different LR organs have distinct requirements for Pitx activity, and (3) Pitx controls amphioxus LR morphogenesis probably through inducing left-side organs and inhibiting right-side organs directly. These findings show much more dependence of LR organogenesis on Pitx in amphioxus than in vertebrates. They also provide insight into the molecular developmental mechanism of some vertebrate LR organs like the lungs and atria, since they show a right-isomerism phenotype in Pitx2 knockout mice like right-sided organs in Pitx mutant amphioxus. Our results also explain why some organs like the adenohypophysis are asymmetrically located in amphioxus but symmetrically positioned in vertebrates.

Beschreibung: Reactive oxygen species (ROS) oxidize cellular nucleotide pools and cause double strand breaks (DSBs). Non-homologous end-joining (NHEJ) attaches broken chromosomal ends together in mammalian cells. Ribonucleotide insertion by DNA polymerase (pol) μ prepares breaks for end-joining and this is required for successful NHEJ in vivo. We previously showed that pol μ lacks discrimination against oxidized dGTP (8-oxo-dGTP), that can lead to mutagenesis, cancer, aging and human disease. Here we reveal the structural basis for proficient oxidized ribonucleotide (8-oxo-rGTP) incorporation during DSB repair by pol μ. Time-lapse crystallography snapshots of structural intermediates during nucleotide insertion along with computational simulations reveal substrate, metal and side chain dynamics, that allow oxidized ribonucleotides to escape polymerase discrimination checkpoints. Abundant nucleotide pools, combined with inefficient sanitization and repair, implicate pol μ mediated oxidized ribonucleotide insertion as an emerging source of widespread persistent mutagenesis and genomic instability.

Beschreibung: Previous studies have suggested that PTEN loss is associated with p110β signaling dependency, leading to the clinical development of p110β-selective inhibitors. Here we use a panel pre-clinical models to reveal that PI3K isoform dependency is not governed by loss of PTEN and is impacted by feedback inhibition and concurrent PIK3CA/PIK3CB alterations. Furthermore, while pan-PI3K inhibition in PTEN-deficient tumors is efficacious, upregulation of Insulin Like Growth Factor 1 Receptor (IGF1R) promotes resistance. Importantly, we show that this resistance can be overcome through targeting AKT and we find that AKT inhibitors are superior to pan-PI3K inhibition in the context of PTEN loss. However, in the presence of wild-type PTEN and PIK3CA-activating mutations, p110α-dependent signaling is dominant and selectively inhibiting p110α is therapeutically superior to AKT inhibition. These discoveries reveal a more nuanced understanding of PI3K isoform dependency and unveil novel strategies to selectively target PI3K signaling nodes in a context-specific manner.

Beschreibung: Background After repairing double-strand breaks (DSBs) caused by CRISPR-Cas9 cleavage, genomic damage, such as large deletions, may have pathogenic consequences. Results We show that large deletions are ubiquitous but are dependent on editing sites and cell types. Human primary T cells display more significant deletions than hematopoietic stem and progenitor cells (HSPCs), whereas we observe low levels in induced pluripotent stem cells (iPSCs). We find that the homology-directed repair (HDR) with single-stranded oligodeoxynucleotides (ssODNs) carrying short homology reduces the deletion damage by almost half, while adeno-associated virus (AAV) donors with long homology reduce large deletions by approximately 80%. In the absence of HDR, the insertion of a short double-stranded ODN by NHEJ reduces deletion indexes by about 60%. Conclusions Timely bridging of broken ends by HDR and NHEJ vastly decreases the unintended consequences of dsDNA cleavage. These strategies can be harnessed in gene editing applications to attenuate unintended outcomes.

Beschreibung: Non-invasive approaches for cell-free DNA (cfDNA) assessment provide an opportunity for cancer detection and intervention. Here, we use a machine learning model for detecting tumor-derived cfDNA through genome-wide analyses of cfDNA fragmentation in a prospective study of 365 individuals at risk for lung cancer. We validate the cancer detection model using an independent cohort of 385 non-cancer individuals and 46 lung cancer patients. Combining fragmentation features, clinical risk factors, and CEA levels, followed by CT imaging, detected 94% of patients with cancer across stages and subtypes, including 91% of stage I/II and 96% of stage III/IV, at 80% specificity. Genome-wide fragmentation profiles across ~13,000 ASCL1 transcription factor binding sites distinguished individuals with small cell lung cancer from those with non-small cell lung cancer with high accuracy (AUC = 0.98). A higher fragmentation score represented an independent prognostic indicator of survival. This approach provides a facile avenue for non-invasive detection of lung cancer.

Beschreibung: Background C. sinensis is an important economic crop with fluoride over-accumulation in its leaves, which poses a serious threat to human health due to its leaf consumption as tea. Recently, our study has indicated that cell wall proteins (CWPs) probably play a vital role in fluoride accumulation/detoxification in C. sinensis. However, there has been a lack in CWP identification and characterization up to now. This study is aimed to characterize cell wall proteome of C. sinensis leaves and to develop more CWPs related to stress response. A strategy of combined cell wall proteomics and N-glycoproteomics was employed to investigate CWPs. CWPs were extracted by sequential salt buffers, while N-glycoproteins were enriched by hydrophilic interaction chromatography method using C. sinensis leaves as a material. Afterwards all the proteins were subjected to UPLC-MS/MS analysis. Results A total of 501 CWPs and 195 CWPs were identified respectively by cell wall proteomics and N-glycoproteomics profiling with 118 CWPs in common. Notably, N-glycoproteomics is a feasible method for CWP identification, and it can enhance CWP coverage. Among identified CWPs, proteins acting on cell wall polysaccharides constitute the largest functional class, most of which might be involved in cell wall structure remodeling. The second largest functional class mainly encompass various proteases related to CWP turnover and maturation. Oxidoreductases represent the third largest functional class, most of which (especially Class III peroxidases) participate in defense response. As expected, identified CWPs are mainly related to plant cell wall formation and defense response. Conclusion This was the first large-scale investigation of CWPs in C. sinensis through cell wall proteomics and N-glycoproteomics. Our results not only provide a database for further research on CWPs, but also an insight into cell wall formation and defense response in C. sinensis.

Beschreibung: The discovery of moiré superlattices (MSLs) opened an era in the research of ‘twistronics’. Engineering MSLs and realizing unique emergent properties are key challenges. Herein, we demonstrate an effective synthetic strategy to fabricate MSLs based on mechanical flexibility of WS2 nanobelts by a facile one-step hydrothermal method. Unlike previous MSLs typically created through stacking monolayers together with complicated method, WS2 MSLs reported here could be obtained directly during synthesis of nanobelts driven by the mechanical instability. Emergent properties are found including superior conductivity, special superaerophobicity and superhydrophilicity, and strongly enhanced electro-catalytic activity when we apply ‘twistronics’ to the field of catalytic hydrogen production. Theoretical calculations show that such excellent catalytic performance could be attributed to a closer to thermoneutral hydrogen adsorption free energy value of twisted bilayers active sites. Our findings provide an exciting opportunity to design advanced WS2 catalysts through moiré superlattice engineering based on mechanical flexibility.

Beschreibung: DNA methylation (DNAm) alterations have been heavily implicated in carcinogenesis and the pathophysiology of diseases through upstream regulation of gene expression. DNAm deep-learning approaches are able to capture features associated with aging, cell type, and disease progression, but lack incorporation of prior biological knowledge. Here, we present modular, user-friendly deep-learning methodology and software, MethylCapsNet and MethylSPWNet, that group CpGs into biologically relevant capsules—such as gene promoter context, CpG island relationship, or user-defined groupings—and relate them to diagnostic and prognostic outcomes. We demonstrate these models’ utility on 3,897 individuals in the classification of central nervous system (CNS) tumors. MethylCapsNet and MethylSPWNet provide an opportunity to increase DNAm deep-learning analyses’ interpretability by enabling a flexible organization of DNAm data into biologically relevant capsules.

Beschreibung: Background Finding meaningful gene-gene interaction and the main Transcription Factors (TFs) in co-expression networks is one of the most important challenges in gene expression data mining. Results Here, we developed the R package “CeTF” that integrates the Partial Correlation with Information Theory (PCIT) and Regulatory Impact Factors (RIF) algorithms applied to gene expression data from microarray, RNA-seq, or single-cell RNA-seq platforms. This approach allows identifying the transcription factors most likely to regulate a given network in different biological systems — for example, regulation of gene pathways in tumor stromal cells and tumor cells of the same tumor. This pipeline can be easily integrated into the high-throughput analysis. To demonstrate the CeTF package application, we analyzed gastric cancer RNA-seq data obtained from TCGA (The Cancer Genome Atlas) and found the HOXB3 gene as the second most relevant TFs with a high regulatory impact (TFs-HRi) regulating gene pathways in the cell cycle. Conclusion This preliminary finding shows the potential of CeTF to list master regulators of gene networks. CeTF was designed as a user-friendly tool that provides many highly automated functions without requiring the user to perform many complicated processes. It is available on Bioconductor (http://bioconductor.org/packages/CeTF) and GitHub (http://github.com/cbiagii/CeTF).

Beschreibung: Blueberry (Vaccinium ssp.) is a perennial shrub belonging to the family Ericaceae, which is highly tolerant of acid soils and heavy metal pollution. In the present study, blueberry was subjected to cadmium (Cd) stress in simulated pot culture. The transcriptomics and rhizosphere fungal diversity of blueberry were analyzed, and the iron (Fe), manganese (Mn), copper (Cu), zinc (Zn) and cadmium (Cd) content of blueberry tissues, soil and DGT was determined. A correlation analysis was also performed. A total of 84 374 annotated genes were identified in the root, stem, leaf and fruit tissue of blueberry, of which 3370 were DEGs, and in stem tissue, of which 2521 were DEGs. The annotation data showed that these DEGs were mainly concentrated in a series of metabolic pathways related to signal transduction, defense and the plant–pathogen response. Blueberry transferred excess Cd from the root to the stem for storage, and the highest levels of Cd were found in stem tissue, consistent with the results of transcriptome analysis, while the lowest Cd concentration occurred in the fruit, Cd also inhibited the absorption of other metal elements by blueberry. A series of genes related to Cd regulation were screened by analyzing the correlation between heavy metal content and transcriptome results. The roots of blueberry rely on mycorrhiza to absorb nutrients from the soil. The presence of Cd has a significant effect on the microbial community composition of the blueberry rhizosphere. The fungal family Coniochaetaceae, which is extremely extremelytolerant, has gradually become the dominant population. The results of this study increase our understanding of the plant regulation mechanism for heavy metals, and suggest potential methods of soil remediation using blueberry.

Beschreibung: Several bioinformatic tools have been developed for genome-wide identification of orthologous and paralogous genes. However, no corresponding tool allows the detection of exon homology relationships. Here, we present ExOrthist, a fully reproducible Nextflow-based software enabling inference of exon homologs and orthogroups, visualization of evolution of exon-intron structures, and assessment of conservation of alternative splicing patterns. ExOrthist evaluates exon sequence conservation and considers the surrounding exon-intron context to derive genome-wide multi-species exon homologies at any evolutionary distance. We demonstrate its use in different evolutionary scenarios: whole genome duplication in frogs and convergence of Nova-regulated splicing networks (https://github.com/biocorecrg/ExOrthist).

Beschreibung: Objective To compare an objective with a subjective numeracy assessment for association with self-reported health status, where numeracy refers to “the degree to which individuals have the capacity to access, process, interpret, communicate, and act on numerical, quantitative, graphical, biostatistical, and probabilistic health information needed to make effective health decisions” Results We completed a secondary analysis of two population-based surveys, the Empire State Poll (n = 763) and the Program for the International Assessment of Adult Competencies (PIAAC; n = 2609). The first survey assessed numeracy with a 3-item subjective instrument. The second assessed numeracy with more than 20 math problems. Both used the same measure for self-reported health status. Lower numeracy, whether subjectively or objectively assessed, was associated with worse self-reported health, even after controlling for education and other sociodemographic confounders. The odds ratios for the association were very similar (0.91 and 0.90 respectively). A lengthy objective numeracy assessment and a brief self-report assessment had similar associations with health status. A brief self-report measure of numeracy has similar properties to a lengthy objective assessment and is likely to be more feasible to use to screen patients in practice.

Beschreibung: Background Sorghum yields in sub-Saharan Africa (SSA) are greatly reduced by parasitic plants of the genus Striga (witchweed). Vast global sorghum genetic diversity collections, as well as the availability of modern sequencing technologies, can be potentially harnessed to effectively manage the parasite. Results We used laboratory assays – rhizotrons to screen a global sorghum diversity panel to identify new sources of resistance to Striga; determine mechanisms of resistance, and elucidate genetic loci underlying the resistance using genome-wide association studies (GWAS). New Striga resistant sorghum determined by the number, size and biomass of parasite attachments were identified. Resistance was by; i) mechanical barriers that blocked parasite entry, ii) elicitation of a hypersensitive reaction that interfered with parasite development, and iii) the inability of the parasite to develop vascular connections with hosts. Resistance genes underpinning the resistance corresponded with the resistance mechanisms and included pleiotropic drug resistance proteins that transport resistance molecules; xylanase inhibitors involved in cell wall fortification and hormonal regulators of resistance response, Ethylene Response Factors. Conclusions Our findings are of fundamental importance to developing durable and broad-spectrum resistance against Striga and have far-reaching applications in many SSA countries where Striga threatens the livelihoods of millions of smallholder farmers that rely on sorghum as a food staple.

Beschreibung: Microbiome engineering is increasingly being employed as a solution to challenges in health, agriculture, and climate. Often manipulation involves inoculation of new microbes designed to improve function into a preexisting microbial community. Despite, increased efforts in microbiome engineering inoculants frequently fail to establish and/or confer long-lasting modifications on ecosystem function. We posit that one underlying cause of these shortfalls is the failure to consider barriers to organism establishment. This is a key challenge and focus of macroecology research, specifically invasion biology and restoration ecology. We adopt a framework from invasion biology that summarizes establishment barriers in three categories: (1) propagule pressure, (2) environmental filtering, and (3) biotic interactions factors. We suggest that biotic interactions is the most neglected factor in microbiome engineering research, and we recommend a number of actions to accelerate engineering solutions.

Beschreibung: Objective The use of mice as animal models in biomedical research allows the standardization of genetic background and environmental conditions, which both affect phenotypic variability. As the use of both sexes in experiments is strongly recommended, sex-specific phenotypic variability is discussed with regard to putative consequences on the group size which is necessary for achieving valid and reproducible results. In this study, the sex-specific variability of 25 clinical chemical and hematological parameters which represent a comprehensive blood screen of laboratory mice, was analyzed in data sets which have been submitted to the Mouse Phenome Database. Results The overall analysis comprising all 25 clinical chemical and hematological parameters showed no evidence for substantial and robust general sex-specific variability. A large range of the ratio of the female and male coefficient of variation (CV) was found for every parameter among the respective strain data sets. This clearly demonstrated the appearance of unpredictable major interactions between genotype and environment regarding the sex-specific variability of the blood parameters analyzed.

Beschreibung: Objective Reported rainfall data from multiple rain gauges and its corresponding estimate from Dual-Polarization (Dual-Pol) radar is presented here. The ordered set of data pairs were collected from multiple peer reviewed publications spanning across the last decade. Data description Taken from multiple sources, the data set represents several radar sites and rain gauge sites combined for 12,734 data points. The data is relevant in various applications of hydrometeorology and engineering as well as weather forecasting. Further, the importance of accuracy in radar precipitation estimates continues to increase, necessitating the incorporation of as much data as possible.

Beschreibung: Circular RNAs (circRNAs) have been reported to play crucial roles in the progression of various cancers, including colorectal cancer (CRC). SP1 (Sp1 transcription factor) is a well-recognized oncogene in CRC and is deemed to trigger the Wnt/β-catenin pathway. The present study was designed to investigate the role of circRNAs which shared the same pre-mRNA with SP1 in CRC cells. We identified that hsa_circ_0026628 (circ_0026628), a circular RNA that originated from SP1 pre-mRNA, was upregulated in CRC cells. Sanger sequencing and agarose gel electrophoresis verified the circular characteristic of circ_0026628. Functional assays including CCK-8, colony formation, transwell, immunofluorescence staining, and sphere formation assay revealed the function of circ_0026628. RNA pull-down and mass spectrometry disclosed the proteins interacting with circ_0026628. Mechanistic assays including RIP, RNA pull-down, CoIP, ChIP, and luciferase reporter assays demonstrated the interplays between molecules. The results depicted that circ_0026628 functioned as a contributor to CRC cell proliferation, migration, EMT, and stemness. Mechanistically, circ_0026628 served as the endogenous sponge of miR-346 and FUS to elevate SP1 expression at the post-transcriptional level, thus strengthening the interaction between SP1 and β-catenin to activate the Wnt/β-catenin pathway. In turn, the downstream gene of Wnt/β-catenin signaling, SOX2 (SRY-box transcription factor 2), transcriptionally activated SP1 and therefore boosted circ_0026628 level. On the whole, SOX2-induced circ_0026628 sponged miR-346 and recruited FUS protein to augment SP1, triggering the downstream Wnt/β-catenin pathway to facilitate CRC progression.

Beschreibung: With excellent creep resistance, good high-temperature microstructural stability and good irradiation resistance, oxide dispersion strengthened (ODS) alloys are a class of important alloys that are promising for high-temperature applications. However, plagued by a nerve-wracking fact that the oxide particles tend to aggregate at grain boundary of metal matrix, their improvement effect on the mechanical properties of metal matrix tends to be limited. In this work, we employ a unique in-house synthesized oxide@W core-shell nanopowder as precursor to prepare W-based ODS alloy. After low-temperature sintering and high-energy-rate forging, high-density oxide nanoparticles are dispersed homogeneously within W grains in the prepared alloy, accompanying with the intergranular oxide particles completely disappearing. As a result, our prepared alloy achieves a great enhancement of strength and ductility at room temperature. Our strategy using core-shell powder as precursor to prepare high-performance ODS alloy has potential to be applied to other dispersion-strengthened alloy systems.

Beschreibung: The widespread UbiD enzyme family utilises the prFMN cofactor to achieve reversible decarboxylation of acrylic and (hetero)aromatic compounds. The reaction with acrylic compounds based on reversible 1,3-dipolar cycloaddition between substrate and prFMN occurs within the confines of the active site. In contrast, during aromatic acid decarboxylation, substantial rearrangement of the substrate aromatic moiety associated with covalent catalysis presents a molecular dynamic challenge. Here we determine the crystal structures of the multi-subunit vanillic acid decarboxylase VdcCD. We demonstrate that the small VdcD subunit acts as an allosteric activator of the UbiD-like VdcC. Comparison of distinct VdcCD structures reveals domain motion of the prFMN-binding domain directly affects active site architecture. Docking of substrate and prFMN-adduct species reveals active site reorganisation coupled to domain motion supports rearrangement of the substrate aromatic moiety. Together with kinetic solvent viscosity effects, this establishes prFMN covalent catalysis of aromatic (de)carboxylation is afforded by UbiD dynamics.

Beschreibung: The human breast and ovine mammary gland undergo striking levels of postnatal development, leading to formation of terminal duct lobular units (TDLUs). Here we interrogate aspects of sheep TDLU growth as a model of breast development and to increase understanding of ovine mammogenesis. The distributions of epithelial nuclear Ki67 positivity differ significantly between younger and older lambs. Ki67 expression is polarised to the leading edge of the developing TDLUs. Intraepithelial ductal macrophages exhibit periodicity and considerably increased density in lambs approaching puberty. Stromal macrophages are more abundant centrally than peripherally. Intraepithelial T lymphocytes are more numerous in older lambs. Stromal hotspots of Ki67 expression colocalize with immune cell aggregates that exhibit distinct organisation consistent with tertiary lymphoid structures. The lamb mammary gland thus exhibits a dynamic mucosal and stromal immune microenvironment and constitutes a valuable model system that provides new insights into postnatal breast development.

Beschreibung: Melanoma cells rely on developmental programs during tumor initiation and progression. Here we show that the embryonic stem cell (ESC) factor Sall4 is re-expressed in the Tyr::NrasQ61K; Cdkn2a−/− melanoma model and that its expression is necessary for primary melanoma formation. Surprisingly, while Sall4 loss prevents tumor formation, it promotes micrometastases to distant organs in this melanoma-prone mouse model. Transcriptional profiling and in vitro assays using human melanoma cells demonstrate that SALL4 loss induces a phenotype switch and the acquisition of an invasive phenotype. We show that SALL4 negatively regulates invasiveness through interaction with the histone deacetylase (HDAC) 2 and direct co-binding to a set of invasiveness genes. Consequently, SALL4 knock down, as well as HDAC inhibition, promote the expression of an invasive signature, while inhibition of histone acetylation partially reverts the invasiveness program induced by SALL4 loss. Thus, SALL4 appears to regulate phenotype switching in melanoma through an HDAC2-mediated mechanism.

Beschreibung: Prostaglandins are important lipids involved in mediating many physiological processes, such as allergic responses, inflammation, and pregnancy. However, technical limitations of in-situ prostaglandin detection in tissue have led researchers to infer prostaglandin tissue distributions from localization of regulatory synthases, such as COX1 and COX2. Herein, we apply a novel mass spectrometry imaging method for direct in situ tissue localization of prostaglandins, and combine it with techniques for protein expression and RNA localization. We report that prostaglandin D2, its precursors, and downstream synthases co-localize with the highest expression of COX1, and not COX2. Further, we study tissue with a conditional deletion of transformation-related protein 53 where pregnancy success is low and confirm that PG levels are altered, although localization is conserved. Our studies reveal that the abundance of COX and prostaglandin D2 synthases in cellular regions does not mirror the regional abundance of prostaglandins. Thus, we deduce that prostaglandins tissue localization and abundance may not be inferred by COX or prostaglandin synthases in uterine tissue, and must be resolved by an in situ prostaglandin imaging.

Beschreibung: Background The abiotic stress such as soil salinization and heavy metal toxicity has posed a major threat to sustainable crop production worldwide. Previous studies revealed that halophytes were supposed to tolerate other stress including heavy metal toxicity. Though HMAD (heavy-metal-associated domain) was reported to play various important functions in Arabidopsis, little is known in Gossypium. Results A total of 169 G. hirsutum genes were identified belonging to the HMAD gene family with the number of amino acids ranged from 56 to 1011. Additionally, 84, 76 and 159 HMAD genes were identified in each G. arboreum, G. raimondii and G. barbadense, respectively. The phylogenetic tree analysis showed that the HMAD gene family were divided into five classes, and 87 orthologs of HMAD genes were identified in four Gossypium species, such as genes Gh_D08G1950 and Gh_A08G2387 of G. hirsutum are orthologs of the Gorai.004G210800.1 and Cotton_A_25987 gene in G. raimondii and G. arboreum, respectively. In addition, 15 genes were lost during evolution. Furthermore, conserved sequence analysis found the conserved catalytic center containing an anion binding (CXXC) box. The HMAD gene family showed a differential expression levels among different tissues and developmental stages in G. hirsutum with the different cis-elements for abiotic stress. Conclusions Current study provided important information about HMAD family genes under salt-stress in Gossypium genome, which would be useful to understand its putative functions in different species of cotton.

Beschreibung: Background Soybean is a globally important legume crop that provides a primary source of high-quality vegetable protein and oil. Seed protein content (SPC) is a valuable quality trait controlled by multiple genes in soybean. Results In this study, we performed quantitative trait loci (QTL) mapping, QTL-seq, and RNA sequencing (RNA-seq) to reveal the genes controlling protein content in the soybean by using the high protein content variety Nanxiadou 25. A total of 50 QTL for SPC distributed on 14 chromosomes except chromosomes 4, 12, 14, 17, 18, and 19 were identified by QTL mapping using 178 recombinant inbred lines (RILs). Among these QTL, the major QTL qSPC_20–1 and qSPC_20–2 on chromosome 20 were repeatedly detected across six tested environments, corresponding to the location of the major QTL detected using whole-genome sequencing-based QTL-seq. 329 candidate DEGs were obtained within the QTL region of qSPC_20–1 and qSPC_20–2 via gene expression profile analysis. Nine of which were associated with SPC, potentially representing candidate genes. Clone sequencing results showed that different single nucleotide polymorphisms (SNPs) and indels between high and low protein genotypes in Glyma.20G088000 and Glyma.16G066600 may be the cause of changes in this trait. Conclusions These results provide the basis for research on candidate genes and marker-assisted selection (MAS) in soybean breeding for seed protein content.

Beschreibung: The Ang–Tie signaling pathway is an important vascular signaling pathway regulating vascular growth and stability. Dysregulation in the pathway is associated with vascular dysfunction and numerous diseases that involve abnormal vascular permeability and endothelial cell inflammation. The understanding of the molecular mechanisms of the Ang–Tie pathway has been limited due to the complex reaction network formed by the ligands, receptors, and molecular regulatory mechanisms. In this study, we developed a mechanistic computational model of the Ang–Tie signaling pathway validated against experimental data. The model captures and reproduces the experimentally observed junctional localization and downstream signaling of the Ang–Tie signaling axis, as well as the time-dependent role of receptor Tie1. The model predicts that Tie1 modulates Tie2’s response to the context-dependent agonist Ang2 by junctional interactions. Furthermore, modulation of Tie1’s junctional localization, inhibition of Tie2 extracellular domain cleavage, and inhibition of VE-PTP are identified as potential molecular strategies for potentiating Ang2’s agonistic activity and rescuing Tie2 signaling in inflammatory endothelial cells.

Beschreibung: β cells may participate and contribute to their own demise during Type 1 diabetes (T1D). Here we report a role of their expression of Tet2 in regulating immune killing. Tet2 is induced in murine and human β cells with inflammation but its expression is reduced in surviving β cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate β cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells.Tet2-KO β cells show reduced expression of IFNγ-induced inflammatory genes that are needed to activate diabetogenic T cells. Here we show that Tet2 regulates pathologic interactions between β cells and immune cells and controls damaging inflammatory pathways. Our data suggests that eliminating TET2 in β cells may reduce activating pathologic immune cells and killing of β cells.

Beschreibung: Heterozygous missense variants in the WD repeat domain 11 (WDR11) gene are associated with hypogonadotropic hypogonadism in humans. In contrast, knockout of both alleles of Wdr11 in mice results in a more severe phenotype with growth and developmental delay, features of holoprosencephaly, heart defects and reproductive disorders. Similar developmental defects known to be associated with aberrant hedgehog signaling and ciliogenesis have been found in zebrafish after Wdr11 knockdown. We here report biallelic loss-of-function variants in the WDR11 gene in six patients from three independent families with intellectual disability, microcephaly and short stature. The findings suggest that biallelic WDR11 variants in humans result in an overlapping but milder phenotype compared to Wdr11-deficient animals. However, the observed human phenotype differs significantly from dominantly inherited variants leading to hypogonadotropic hypogonadism, suggesting that recessive WDR11 variants result in a clinically distinct entity.

Beschreibung: Ghrelin, also called “the hunger hormone”, is a gastric peptide hormone that regulates food intake, body weight, as well as taste sensation, reward, cognition, learning and memory. One unique feature of ghrelin is its acylation, primarily with an octanoic acid, which is essential for its binding and activation of the ghrelin receptor, a G protein-coupled receptor. The multifaceted roles of ghrelin make ghrelin receptor a highly attractive drug target for growth retardation, obesity, and metabolic disorders. Here we present two cryo-electron microscopy structures of Gq-coupled ghrelin receptor bound to ghrelin and a synthetic agonist, GHRP-6. Analysis of these two structures reveals a unique binding pocket for the octanoyl group, which guides the correct positioning of the peptide to initiate the receptor activation. Together with mutational and functional data, our structures define the rules for recognition of the acylated peptide hormone and activation of ghrelin receptor, and provide structural templates to facilitate drug design targeting ghrelin receptor.

Beschreibung: Functional genomics experiments, like ChIP-Seq or ATAC-Seq, produce results that are summarized as a region set. There is no way to objectively evaluate the effectiveness of region set similarity metrics. We present Bedshift, a tool for perturbing BED files by randomly shifting, adding, and dropping regions from a reference file. The perturbed files can be used to benchmark similarity metrics, as well as for other applications. We highlight differences in behavior between metrics, such as that the Jaccard score is most sensitive to added or dropped regions, while coverage score is most sensitive to shifted regions.

Beschreibung: Background Hypertrophy is a critical process for chondrocyte differentiation and maturation during endochondral ossification, which is responsible for the formation of long bone and postnatal longitudinal growth. Increasing evidence suggests that melatonin, an indole hormone, plays a pivotal role in chondrogenesis. However, little is known about the effects of melatonin on the terminal differentiation of chondrocytes. Methods Mesenchymal stem cell (MSC)-derived chondrocytes generated by a high-density micromass culture system were induced to undergo hypertrophic differentiation. Melatonin-mediated hypertrophic differentiation was examined by reverse transcription polymerase chain reaction analysis (RT-PCR) analysis, histological staining and immunohistochemistry. Activation of the Wnt signaling pathway was evaluated by PCR array, RT-PCR, western blotting and immunofluorescence. XAV-939, a Wnt signaling pathway antagonist, was further used to determine whether the effect of melatonin on chondrocyte hypertrophic differentiation was mediated occurred by activation of Wnt signaling pathway. Results Histological staining showed melatonin increased chondrocyte cell volume and the expression of type X collagen but decreased the expression of type II collagen compared with the control group. RT-PCR showed that melatonin significantly up-regulated the gene expressions of biomarkers of hypertrophic chondrocytes, including type X collagen, alkaline phosphatase, runt-related transcription factor 2, Indian hedgehog and parathyroid hormone-related protein receptor, and melatonin down-regulated the mRNA expression of hallmarks of chondrocytes, including parathyroid hormone-related protein. PCR array showed that the effect of melatonin on chondrocyte hypertrophic differentiation was accompanied by the up-regulation of multiple target genes of the canonical Wnt signaling pathway, and this effect was blocked by XAV-939. Conclusions The current findings demonstrate that melatonin enhances the hypertrophic differentiation of MSC-derived chondrocytes through the Wnt signaling pathway. Our findings add evidence to the role of melatonin in promoting bone development and highlight the positive effects of melatonin on terminal differentiation of chondrocytes.

Beschreibung: Novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2. The virus causes an exaggerated immune response, resulting in a cytokine storm and acute respiratory distress syndrome, the leading cause of COVID-19-related mortality and morbidity. So far, no therapies have succeeded in circumventing the exacerbated immune response or cytokine storm associated with COVID-19. Mesenchymal stem cells (MSCs), through their immunomodulatory and regenerative activities, mostly mediated by their paracrine effect and extracellular vesicle production, have therapeutic potential in many autoimmune, inflammatory, and degenerative diseases. In this paper, we review clinical studies on the use of MSCs for COVID-19 treatment, including the salutary effects of MSCs on the pathophysiology of COVID-19 and the immunomodulation of the cytokine storm. Ongoing clinical trial designs, cell sources, dose and administration, and populations are summarized, and the paracrine mode of benefit is discussed. We also offer suggestions for optimizing MSC-based therapies, including genetic engineering, strategies for cell surface modification, nanotechnology applications, and combination therapies.

Beschreibung: Acute myeloid leukemia (AML) is a serious, life-threatening, and hardly curable hematological malignancy that affects the myeloid cell progenies and challenges patients of all ages but mostly occurs in adults. Although several therapies are available including chemotherapy, allogeneic hematopoietic stem cell transplantation (alloHSCT), and receptor-antagonist drugs, the 5-year survival of patients is quietly disappointing, less than 30%. alloHSCT is the major curative approach for AML with promising results but the treatment has severe adverse effects such as graft-versus-host disease (GVHD). Therefore, as an alternative, more efficient and less harmful immunotherapy-based approaches such as the adoptive transferring T cell therapy are in development for the treatment of AML. As such, chimeric antigen receptor (CAR) T cells are engineered T cells which have been developed in recent years as a breakthrough in cancer therapy. Interestingly, CAR T cells are effective against both solid tumors and hematological cancers such as AML. Gradually, CAR T cell therapy found its way into cancer therapy and was widely used for the treatment of hematologic malignancies with successful results particularly with somewhat better results in hematological cancer in comparison to solid tumors. The AML is generally fatal, therapy-resistant, and sometimes refractory disease with a disappointing low survival rate and weak prognosis. The 5-year survival rate for AML is only about 30%. However, the survival rate seems to be age-dependent. Novel CAR T cell therapy is a light at the end of the tunnel. The CD19 is an important target antigen in AML and lymphoma and the CAR T cells are engineered to target the CD19. In addition, a lot of research goes on the discovery of novel target antigens with therapeutic efficacy and utilizable for generating CAR T cells against various types of cancers. In recent years, many pieces of research on screening and identification of novel AML antigen targets with the goal of generation of effective anti-cancer CAR T cells have led to new therapies with strong cytotoxicity against cancerous cells and impressive clinical outcomes. Also, more recently, an improved version of CAR T cells which were called modified or smartly reprogrammed CAR T cells has been designed with less unwelcome effects, less toxicity against normal cells, more safety, more specificity, longer persistence, and proliferation capability. The purpose of this review is to discuss and explain the most recent advances in CAR T cell-based therapies targeting AML antigens and review the results of preclinical and clinical trials. Moreover, we will criticize the clinical challenges, side effects, and the different strategies for CAR T cell therapy.

Beschreibung: In vivo bioprinting has recently emerged as a direct fabrication technique to create artificial tissues and medical devices on target sites within the body, enabling advanced clinical strategies. However, existing in vivo bioprinting methods are often limited to applications near the skin or require open surgery for printing on internal organs. Here, we report a ferromagnetic soft catheter robot (FSCR) system capable of in situ computer-controlled bioprinting in a minimally invasive manner based on magnetic actuation. The FSCR is designed by dispersing ferromagnetic particles in a fiber-reinforced polymer matrix. This design results in stable ink extrusion and allows for printing various materials with different rheological properties and functionalities. A superimposed magnetic field drives the FSCR to achieve digitally controlled printing with high accuracy. We demonstrate printing multiple patterns on planar surfaces, and considering the non-planar surface of natural organs, we then develop an in situ printing strategy for curved surfaces and demonstrate minimally invasive in vivo bioprinting of hydrogels in a rat model. Our catheter robot will permit intelligent and minimally invasive bio-fabrication.

Beschreibung: Background One of the major trends in angiosperm evolution was the shift from woody to herbaceous habit. However, reversals known as derived woodiness have also been reported in numerous, distantly related clades. Among theories evoked to explain the factors promoting the evolution of derived woodiness are moderate climate theory and cavitation theory. The first assumes that woody habit evolves in response to mild climate allowing for prolonged life span, which in turn leads to bigger and woodier bodies. The second sees woodiness as a result of natural selection for higher cavitation resistance in seasonally dry environments. Here, we compare climatic niches of woody and herbaceous, mostly southern African, umbellifers from the Lefebvrea clade to assess whether woody taxa in fact occur in markedly drier habitats. We also calibrate their phylogeny to estimate when derived woodiness evolved. Finally, we describe the wood anatomy of selected woody and herbaceous taxa to see if life forms are linked to any particular wood traits. Results The evolution of derived woodiness in chamaephytes and phanerophytes as well as the shifts to short-lived annual therophytes in the Lefebvrea clade took place at roughly the same time: in the Late Miocene during a trend of global climate aridification. Climatic niches of woody and herbaceous genera from the Cape Floristic Region overlap. There are only two genera with distinctly different climatic preferences: they are herbaceous and occur outside of the Cape Floristic Region. Therefore, studied herbs have an overall climatic niche wider than their woody cousins. Woody and herbaceous species do not differ in qualitative wood anatomy, which is more affected by stem architecture and, probably, reproductive strategy than by habit. Conclusions Palaeodrought was likely a stimulus for the evolution of derived woodiness in the Lefebvrea clade, supporting the cavitation theory. The concurrent evolution of short-lived annuals withering before summer exemplifies an alternative solution to the same problem of drought-induced cavitation. Changes of the life form were most likely neither spurred nor precluded by any qualitative wood traits, which in turn are more affected by internode length and probably also reproductive strategy.

Beschreibung: Research in the past decade has demonstrated that a single reference genome is not representative of a species’ diversity. MaizeGDB introduces a pan-genomic approach to hosting genomic data, leveraging the large number of diverse maize genomes and their associated datasets to quickly and efficiently connect genomes, gene models, expression, epigenome, sequence variation, structural variation, transposable elements, and diversity data across genomes so that researchers can easily track the structural and functional differences of a locus and its orthologs across maize. We believe our framework is unique and provides a template for any genomic database poised to host large-scale pan-genomic data.

Beschreibung: Reduced glucose uptake into the skeletal muscle is an important pathophysiological abnormality in type 2 diabetes, and is caused by impaired translocation of glucose transporter 4 (GLUT4) to the skeletal muscle cell surface. Here, we show a xanthene derivative, DS20060511, induces GLUT4 translocation to the skeletal muscle cell surface, thereby stimulating glucose uptake into the tissue. DS20060511 induced GLUT4 translocation and stimulated glucose uptake into differentiated L6-myotubes and into the skeletal muscles in mice. These effects were completely abolished in GLUT4 knockout mice. Induction of GLUT4 translocation by DS20060511 was independent of the insulin signaling pathways including IRS1-Akt-AS160 phosphorylation and IRS1-Rac1-actin polymerization, eNOS pathway, and AMPK pathway. Acute and chronic DS20060511 treatment attenuated the glucose intolerance in obese diabetic mice. Taken together, DS20060511 acts as a skeletal muscle-specific GLUT4 translocation enhancer to facilitate glucose uptake. Further studies of DS20060511 may pave the way for the development of novel antidiabetic medicines.

Beschreibung: Depression is a common mental disorder. The standard medical treatment is the selective serotonin reuptake inhibitors (SSRIs). All characterized SSRIs are competitive inhibitors of the serotonin transporter (SERT). A non-competitive inhibitor may produce a more favorable therapeutic profile. Vilazodone is an antidepressant with limited information on its molecular interactions with SERT. Here we use molecular pharmacology and cryo-EM structural elucidation to characterize vilazodone binding to SERT. We find that it exhibits non-competitive inhibition of serotonin uptake and impedes dissociation of [3H]imipramine at low nanomolar concentrations. Our SERT structure with bound imipramine and vilazodone reveals a unique binding pocket for vilazodone, expanding the boundaries of the extracellular vestibule. Characterization of the binding site is substantiated with molecular dynamics simulations and systematic mutagenesis of interacting residues resulting in decreased vilazodone binding to the allosteric site. Our findings underline the versatility of SERT allosteric ligands and describe the unique binding characteristics of vilazodone.

Beschreibung: p53 regulates several signaling pathways to maintain the metabolic homeostasis of cells and modulates the cellular response to stress. Deficiency or excess of nutrients causes cellular metabolic stress, and we hypothesized that p53 could be linked to glucose maintenance. We show here that upon starvation hepatic p53 is stabilized by O-GlcNAcylation and plays an essential role in the physiological regulation of glucose homeostasis. More specifically, p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augment protein levels of p53, and administration of these hormones to p53 deficient human hepatocytes and to liver-specific p53 deficient mice fails to increase glucose levels. Moreover, insulin decreases p53 levels, and over-expression of p53 impairs insulin sensitivity. Finally, protein levels of p53, as well as genes responsible of O-GlcNAcylation are elevated in the liver of type 2 diabetic patients and positively correlate with glucose and HOMA-IR. Overall these results indicate that the O-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis.

Beschreibung: Argonaute is the primary mediator of metazoan miRNA targeting (MT). Among the currently identified 〉1,500 human RNA-binding proteins (RBPs), there are only a handful of RBPs known to enhance MT and several others reported to suppress MT, leaving the global impact of RBPs on MT elusive. In this study, we have systematically analyzed transcriptome-wide binding sites for 150 human RBPs and evaluated the quantitative effect of individual RBPs on MT efficacy. In contrast to previous studies, we show that most RBPs significantly affect MT and that all of those MT-regulating RBPs function as MT enhancers rather than suppressors, by making the local secondary structure of the target site accessible to Argonaute. Our findings illuminate the unappreciated regulatory impact of human RBPs on MT, and as these RBPs may play key roles in the gene regulatory network governed by metazoan miRNAs, MT should be understood in the context of co-regulating RBPs.

Beschreibung: Background In most flowering plants, the plastid genome exhibits a quadripartite genome structure, comprising a large and a small single copy as well as two inverted repeat regions. Thousands of plastid genomes have been sequenced and submitted to public sequence repositories in recent years. The quality of sequence annotations in many of these submissions is known to be problematic, especially regarding annotations that specify the length and location of the inverted repeats: such annotations are either missing or portray the length or location of the repeats incorrectly. However, many biological investigations employ publicly available plastid genomes at face value and implicitly assume the correctness of their sequence annotations. Results We introduce , a Python package that automatically assesses the frequency of incomplete or incorrect annotations of the inverted repeats among publicly available plastid genomes. Specifically, the tool automatically retrieves plastid genomes from NCBI Nucleotide under variable search parameters, surveys them for length and location specifications of inverted repeats, and confirms any inverted repeat annotations through self-comparisons of the genome sequences. The package also includes functionality for automatic identification and removal of duplicate genome records and accounts for taxa that genuinely lack inverted repeats. A survey of the presence of inverted repeat annotations among all plastid genomes of flowering plants submitted to NCBI Nucleotide until the end of 2020 using , followed by a statistical analysis of potential associations with record metadata, highlights that release year and publication status of the genome records have a significant effect on the frequency of complete and equal-length inverted repeat annotations. Conclusion The number of plastid genomes on NCBI Nucleotide has increased dramatically in recent years, and many more genomes will likely be submitted over the next decade. enables researchers to automatically access and evaluate the inverted repeats of these plastid genomes as well as their sequence annotations and, thus, contributes to increasing the reliability of publicly available plastid genomes. The software is freely available via the Python package index at http://pypi.python.org/pypi/airpg.

Beschreibung: Objectives Peer support is rapidly being introduced into mental health services internationally, yet peer support interventions are often poorly described, limiting the usefulness of research in informing policy and practice. This paper reports the development of a peer support intervention that aims to improve outcomes of discharge from inpatient to community mental health care. People with experiential knowledge of using mental health services—peer workers and service user researchers—were involved in all stages of developing the intervention: generating intervention components; producing the intervention handbook; piloting the intervention. Results Systematic review and expert panels, including our Lived Experience Advisory Panel, identified 66 candidate intervention components in five domains: Recruitment and Role Description of Peer Workers; Training for Peer Workers; Delivery of Peer Support; Supervision and Support for Peer Workers; Organisation and Team. A series of Local Advisory Groups were used to prioritise components and explore implementation issues using consensus methods, refining an intervention blueprint. A peer support handbook and peer worker training programme were produced by the study team and piloted in two study sites. Feedback workshops were held with peer workers and their supervisors to produce a final handbook and training programme. The ENRICH trial is registered with the ISRCTN clinical trial register, number ISRCTN 10043328, and was overseen by an independent steering committee and a data monitoring committee.

Beschreibung: Background As effects of global climate change intensify, the interaction of biotic and abiotic stresses increasingly threatens current agricultural practices. The secondary cell wall is a vanguard of resistance to these stresses. Fusarium thapsinum (Fusarium stalk rot) and Macrophomina phaseolina (charcoal rot) cause internal damage to the stalks of the drought tolerant C4 grass, sorghum (Sorghum bicolor (L.) Moench), resulting in reduced transpiration, reduced photosynthesis, and increased lodging, severely reducing yields. Drought can magnify these losses. Two null alleles in monolignol biosynthesis of sorghum (brown midrib 6-ref, bmr6-ref; cinnamyl alcohol dehydrogenase, CAD; and bmr12-ref; caffeic acid O-methyltransferase, COMT) were used to investigate the interaction of water limitation with F. thapsinum or M. phaseolina infection. Results The bmr12 plants inoculated with either of these pathogens had increased levels of salicylic acid (SA) and jasmonic acid (JA) across both watering conditions and significantly reduced lesion sizes under water limitation compared to adequate watering, which suggested that drought may prime induction of pathogen resistance. RNA-Seq analysis revealed coexpressed genes associated with pathogen infection. The defense response included phytohormone signal transduction pathways, primary and secondary cell wall biosynthetic genes, and genes encoding components of the spliceosome and proteasome. Conclusion Alterations in the composition of the secondary cell wall affect immunity by influencing phenolic composition and phytohormone signaling, leading to the action of defense pathways. Some of these pathways appear to be activated or enhanced by drought. Secondary metabolite biosynthesis and modification in SA and JA signal transduction may be involved in priming a stronger defense response in water-limited bmr12 plants.

Beschreibung: The methyl-CpG-binding domain 2 (MBD2) interprets DNA methylome-encoded information through binding to the methylated CpG DNA, by which it regulates target gene expression at the transcriptional level. Although derailed DNA methylation has long been recognized to trigger or promote autoimmune responses in type 1 diabetes (T1D), the exact role of MBD2 in T1D pathogenesis, however, remains poorly defined. Herein, we generated an Mbd2 knockout model in the NOD background and found that Mbd2 deficiency exacerbated the development of spontaneous T1D in NOD mice. Adoptive transfer of Mbd2−/− CD4 T cells into NOD.scid mice further confirmed the observation. Mechanistically, Th1 stimulation rendered the Stat1 promoter to undergo a DNA methylation turnover featured by the changes of DNA methylation levels or patterns along with the induction of MBD2 expression, which then bound to the methylated CpG DNA within the Stat1 promoter, by which MBD2 maintains the homeostasis of Th1 program to prevent autoimmunity. As a result, ectopic MBD2 expression alleviated CD4 T cell diabetogenicity following their adoptive transfer into NOD.scid mice. Collectively, our data suggest that MBD2 could be a viable target to develop epigenetic-based therapeutics against T1D in clinical settings.

Beschreibung: Background Retinol binding protein 4 (RBP4) has been proposed to play a role in the pathophysiology of coronary artery disease (CAD), but previous findings on the association of RBP4 levels with CAD are inconsistent. Methods A meta-analysis based on observational studies was conducted to evaluate the association between circulating RBP4 levels and CAD. Databases including PubMed, Web of Science, Embase, Google Scholar and ClinicalTrials.gov database were searched for eligible studies published up to 12 July 2021. Standard mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using the inverse variance heterogeneity (IVhet) and random-effects model for data with moderate and high heterogeneity (I2 〉 30%) and data with low heterogeneity were analysed using a fixed-effects model (I2 ≤ 30%). Moreover, a bias-adjusted quality-effects model was generated, and the prediction interval was also calculated under the random-effects model. Results Two nested case-control studies, one cohort study and twelve case–control studies with a total of 7111 participants were included. Circulating RBP4 levels in patients with CAD were comparable to those in the controls under the IVhet model (SMD: 0.25, 95% CI: − 0.29-0.79, I2: 96.00%). The quality-effects model produced consistent results. However, the association turned to be significant under the random-effect model (SMD: 0.46, 95% CI: 0.17–0.75, I2: 96.00%), whereas the 95% predictive interval (PI) included null values (95% PI: − 0.82-1.74). Subgroup analyses illustrated a positive relationship between CAD and RBP4 levels in patients with complications (SMD: 1.34, 95% CI: 0.38–2.29, I2: 96.00%). The meta-regression analysis revealed that the mean BMI of patients (P = 0.03) and complication status (P = 0.01) influenced the variation in SMD. Conclusions There was low-quality evidence that patients with CAD exhibited similar circulating RBP4 levels compared with controls, and high inter-study heterogeneity was also observed. Thus, RBP4 might not be a potential risk factor for CAD. Comparisons among different subtypes of RBP4 with larger sample size are needed in the future.

Beschreibung: Background To understand the mechanism of glucosinolates (GSs) accumulation in the specific organs, combined analysis of physiological change and transcriptome sequencing were applied in the current study. Taking Chinese kale as material, seeds and silique walls were divided into different stages based on the development of the embryo in seeds and then subjected to GS analysis and transcriptome sequencing. Results The main GS in seeds of Chinese kale were glucoiberin and gluconapin and their content changed with the development of the seed. During the transition of the embryo from torpedo- to the early cotyledonary-embryo stage, the accumulation of GS in the seed was accompanied by the salient decline of GS in the corresponding silique wall. Thus, the seed and corresponding silique wall at these two stages were subjected to transcriptomic sequencing analysis. 135 genes related to GS metabolism were identified, of which 24 genes were transcription factors, 81 genes were related to biosynthetic pathway, 25 genes encoded catabolic enzymes, and 5 genes matched with transporters. The expression of GS biosynthetic genes was detected both in seeds and silique walls. The high expression of FMOGS-OX and AOP2, which is related to the production of gluconapin by side modification, was noted in seeds at both stages. Interestingly, the expression of GS biosynthetic genes was higher in the silique wall compared with that in the seed albeit lower content of GS existed in the silique wall than in the seed. Combined with the higher expression of transporter genes GTRs in silique walls than in seeds, it was proposed that the transportation of GS from the silique wall to the seed is an important source for seed GS accumulation. In addition, genes related to GS degradation expressed abundantly in the seed at the early cotyledonary-embryo stage indicating its potential role in balancing seed GS content. Conclusions Two stages including the torpedo-embryo and the early cotyledonary-embryo stage were identified as crucial in GS accumulation during seed development. Moreover, we confirmed the transportation of GS from the silique wall to the seed and proposed possible sidechain modification of GS biosynthesis may exist during seed formation.

Beschreibung: Background Drug–drug interactions (DDIs) refer to processes triggered by the administration of two or more drugs leading to side effects beyond those observed when drugs are administered by themselves. Due to the massive number of possible drug pairs, it is nearly impossible to experimentally test all combinations and discover previously unobserved side effects. Therefore, machine learning based methods are being used to address this issue. Methods We propose a Siamese self-attention multi-modal neural network for DDI prediction that integrates multiple drug similarity measures that have been derived from a comparison of drug characteristics including drug targets, pathways and gene expression profiles. Results Our proposed DDI prediction model provides multiple advantages: (1) It is trained end-to-end, overcoming limitations of models composed of multiple separate steps, (2) it offers model explainability via an Attention mechanism for identifying salient input features and (3) it achieves similar or better prediction performance (AUPR scores ranging from 0.77 to 0.92) compared to state-of-the-art DDI models when tested on various benchmark datasets. Novel DDI predictions are further validated using independent data resources. Conclusions We find that a Siamese multi-modal neural network is able to accurately predict DDIs and that an Attention mechanism, typically used in the Natural Language Processing domain, can be beneficially applied to aid in DDI model explainability.

Beschreibung: Background Modulating the microbiota is a leading-edge strategy for the restoration and maintenance of a healthy, balanced environment. The use of health-promoting bacteria has demonstrated some potential benefits as an alternative for skin microbiota intervention. Here, we investigate the manipulation of mice skin microbiota using B. subtilis incorporated into a supportive Pluronic F-127 hydrogel formulation. The formula plays an important role in delivering the bacteria to the desired action site. Results The B. subtilis challenge induced a shift in the composition and abundance of the skin microbiota. Containment of B. subtilis in the Pluronic F-127 hydrogel accelerated bacterial modulation compared with free B. subtilis. The abundance of both Staphylococcus and Corynebacterium spp. was altered as a result of the live bacterial intervention: the abundance of Corynebacterium increased while that of Staphylococcus decreased. Four days after last application of the B. subtilis formulation, B. subtilis counts returned to its initial level. Conclusions B. subtilis intervention can induce a shift in the skin microbiota, influencing the abundance of commensal, beneficial, and pathogenic bacteria. Containment of B. subtilis in Pluronic hydrogel accelerates the microbial alteration, probably by facilitating bacterial attachment and supporting continuous growth. Our results reveal the ability of B. subtilis in Pluronic to modulate the skin microbiota composition, suggesting that the formulation holds therapeutic potential for skin disease treatment.

Beschreibung: Background Mycotoxins are among the environmental stressors whose oxidative action is currently widely studied. The aim of this paper was to investigate the response of seedling leaves to zearalenone (ZEA) applied to the leaves (directly) and to the grains (indirectly) in tolerant and sensitive wheat cultivars. Results Biochemical analyses of antioxidant activity were performed for chloroplasts and showed a similar decrease in this activity irrespective of plant sensitivity and the way of ZEA application. On the other hand, higher amounts of superoxide radical (microscopic observations) were generated in the leaves of plants grown from the grains incubated in ZEA solution and in the sensitive cultivar. Electron paramagnetic resonance (EPR) studies showed that upon ZEA treatment greater numbers of Mn - aqua complexes were formed in the leaves of the tolerant wheat cultivar than in those of the sensitive one, whereas the degradation of Fe-protein complexes occurred independently of the cultivar sensitivity. Conclusion The changes in the quantity of stable, organic radicals formed by stabilizing reactive oxygen species on biochemical macromolecules, indicated greater potential for their generation in leaf tissues subjected to foliar ZEA treatment. This suggested an important role of these radical species in protective mechanisms mainly against direct toxin action. The way the defense mechanisms were activated depended on the method of the toxin application.

Beschreibung: Background Genome-wide data are invaluable to characterize differentiation and adaptation of natural populations. Reduced representation sequencing (RRS) subsamples a genome repeatedly across many individuals. However, RRS requires careful optimization and fine-tuning to deliver high marker density while being cost-efficient. The number of genomic fragments created through restriction enzyme digestion and the sequencing library setup must match to achieve sufficient sequencing coverage per locus. Here, we present a workflow based on published information and computational and experimental procedures to investigate and streamline the applicability of RRS. Results In an iterative process genome size estimates, restriction enzymes and size selection windows were tested and scaled in six classes of Antarctic animals (Ostracoda, Malacostraca, Bivalvia, Asteroidea, Actinopterygii, Aves). Achieving high marker density would be expensive in amphipods, the malacostracan target taxon, due to the large genome size. We propose alternative approaches such as mitogenome or target capture sequencing for this group. Pilot libraries were sequenced for all other target taxa. Ostracods, bivalves, sea stars, and fish showed overall good coverage and marker numbers for downstream population genomic analyses. In contrast, the bird test library produced low coverage and few polymorphic loci, likely due to degraded DNA. Conclusions Prior testing and optimization are important to identify which groups are amenable for RRS and where alternative methods may currently offer better cost-benefit ratios. The steps outlined here are easy to follow for other non-model taxa with little genomic resources, thus stimulating efficient resource use for the many pressing research questions in molecular ecology.

Beschreibung: Background Panicle is a harvesting organ of rice, and its morphology and development are closely associated with grain yield. The current study was carried on a mutant screened through an EMS (ethyl-methane sulphonate) mutagenized population of a Japonica cultivar Kitaake (WT). Results A mutant, named as asp-lsl (aberrant spikelet-long sterile lemma), showed a significant decrease in plant height, number of tillers, thousand-grains weight, seed setting rate, spikelet length, kernel length and effective number of grains per panicle as compared to WT. Asp-lsl showed a pleiotropic phenotype coupled with the obvious presence of a long sterile lemma. Cross-sections of lemma showed an increase in the cell volume rather than the number of cells. Genetic segregation analysis revealed its phenotypic trait is controlled by a single recessive nuclear gene. Primary and fine mapping indicated that candidate gene controlling the phenotype of asp-lsl was located in an interval of 212 kb on the short arm of chromosome 8 between RM22445 and RM22453. Further sequencing and indels markers analysis revealed LOC_Os08g06480 harbors a single base substitution (G→A), resulting in a change of 521st amino acid(Gly→Glu. The homology comparison and phylogenetic tree analysis revealed mutation was occurred in a highly conserved domain and had a high degree of similarity in Arabidopsis, corn, and sorghum. The CRISPR/Cas9 mutant line of ASP-LSL produced a similar phenotype as that of asp-lsl. Subcellular localization of ASP-LSL revealed that its protein is localized in the nucleus. Relative expression analysis revealed ASP-LSL was preferentially expressed in panicle, stem, and leaves. The endogenous contents of GA, CTK, and IAA were found significantly decreased in asp-lsl as compared to WT. Conclusions Current study presents the novel phenotype of asp-lsl and also validate the previously reported function of OsREL2 (ROMOSA ENHANCER LOCI2), / ASP1(ABERRANT SPIKELET AND PANICLE 1).

Beschreibung: Background Recent advances in sequencing technologies have driven studies identifying the microbiome as a key regulator of overall health and disease in the host. Both 16S amplicon and whole genome shotgun sequencing technologies are currently being used to investigate this relationship, however, the choice of sequencing technology often depends on the nature and experimental design of the study. In principle, the outputs rendered by analysis pipelines are heavily influenced by the data used as input; it is then important to consider that the genomic features produced by different sequencing technologies may emphasize different results. Results In this work, we use public 16S amplicon and whole genome shotgun sequencing (WGS) data from the same dogs to investigate the relationship between sequencing technology and the captured gut metagenomic landscape in dogs. In our analyses, we compare the taxonomic resolution at the species and phyla levels and benchmark 12 classification algorithms in their ability to accurately identify host phenotype using only taxonomic relative abundance information from 16S and WGS datasets with identical study designs. Our best performing model, a random forest trained by the WGS dataset, identified a species (Bacteroides coprocola) that predominantly contributes to the abundance of leuB, a gene involved in branched chain amino acid biosynthesis; a risk factor for glucose intolerance, insulin resistance, and type 2 diabetes. This trend was not conserved when we trained the model using 16S sequencing profiles from the same dogs. Conclusions Our results indicate that WGS sequencing of dog microbiomes detects a greater taxonomic diversity than 16S sequencing of the same dogs at the species level and with respect to four gut-enriched phyla levels. This difference in detection does not significantly impact the performance metrics of machine learning algorithms after down-sampling. Although the important features extracted from our best performing model are not conserved between the two technologies, the important features extracted from either instance indicate the utility of machine learning algorithms in identifying biologically meaningful relationships between the host and microbiome community members. In conclusion, this work provides the first systematic machine learning comparison of dog 16S and WGS microbiomes derived from identical study designs.

Beschreibung: Well-described evidence has demonstrated the critical roles of aerobic glycolysis in triple-negative breast cancer (TNBC) oncotherapy. Moreover, next-generation high-throughput sequencing indicates the potential regulation of energy metabolism by circular RNAs (circRNAs) in TNBC. However, circRNA modulation of TNBC aerobic glycolysis is still unclear. Here, the present research aimed to investigate the function and underlying mechanisms of novel circPDCD11 (hsa_circ_0019853) in TNBC aerobic glycolysis. The results revealed that circPDCD11 expression was significantly upregulated in TNBC tissues and cells. Clinical data demonstrated that the high expression of circPDCD11 was closely correlated with a poor prognosis and acted as an independent risk factor for TNBC prognosis. Functionally, in vitro gain- and loss-of-function experiments revealed that circPDCD11 accelerated glucose uptake, lactate production, ATP generation, and the extracellular acidification rate in TNBC cells. In vivo, circPDCD11 silencing repressed tumor growth. Mechanistically, circPDCD11 acted as a miRNA sponge to enhance LDHA expression by sponging miR-432-5p. In conclusion, these combined results demonstrated that circPDCD11 acts as an oncogene for TNBC, providing a promising prognostic biomarker for TNBC.

Beschreibung: Background Aberrant expression of Aldo-Keto reductase family 1 member B10 (AKR1B10) was associated with tumor size and metastasis of breast cancer in our published preliminary studies. However, little is known about the detailed function and underlying molecular mechanism of AKR1B10 in the pathological process of breast cancer. Methods The relationship between elevated AKR1B10 expression and the overall survival and disease-free survival of breast cancer patients was analyzed by Kaplan–Meier Plotter database. Breast cancer cell lines overexpressing AKR1B10 (MCF-7/AKR1B10) and breast cancer cell lines with knockdown of AKR1B10 (BT-20/shAKR1B10) were constructed to analyze the impact of AKR1B10 expression on cell proliferation and migration of breast cancer. The expression levels of AKR1B10 were detected and compared in the breast cancer cell lines and tissues by RT-qPCR, western blot and immunohistochemistry. The proliferation of breast cancer cells was monitored by CCK8 cell proliferation assay, and the migration and invasion of breast cancer cells was observed by cell scratch test and transwell assay. The proliferation- and EMT-related proteins including cyclinD1, c-myc, Survivin, Twist, SNAI1, SLUG, ZEB1, E-cadherin, PI3K, p-PI3K, AKT, p-AKT, IKBα, p-IKBα, NF-κB p65, p-NF-κB p65 were detected by western blot in breast cancer cells. MCF-7/AKR1B10 cells were treated with LY294002, a PI3K inhibitor, to consider the impact of AKR1B10 overexpression on the PI3K/AKT/NF-κB signal cascade and the presence of NF-κB p65 in nuclear. In vivo tumor xenograft experiments were used to observe the role of AKR1B10 in breast cancer growth in mice. Results AKR1B10 expression was significantly greater in breast cancer tissue compared to paired non-cancerous tissue. The expression of AKR1B10 positively correlated with lymph node metastasis, tumor size, Ki67 expression, and p53 expression, but inversely correlated with overall and disease-free survival rates. Gene Ontology analysis showed that AKR1B10 activity contributes to cell proliferation. Overexpression of AKR1B10 facilitated the proliferation of MCF-7 cells, and induced the migration and invasion of MCF-7 cells in vitro in association with induction of epithelial-mesenchymal transition (EMT). Conversely, knockdown of AKR1B10 inhibited these effects in BT-20 cells. Mechanistically, AKR1B10 activated PI3K, AKT, and NF-κB p65, and induced nuclear translocation of NF-κB p65, and expression of proliferation-related proteins including c-myc, cyclinD1, Survivin, and EMT-related proteins including ZEB1, SLUG, Twist, but downregulated E-cadherin expression in MCF-7 cells. AKR1B10 silencing reduced the phosphorylation of PI3K, AKT, and NF-κB p65, the nuclear translocation of NF-κB p65, and the expression of proliferation- and migration-related proteins in BT-20 cells. LY294002, a PI3K inhibitor, attenuated the phosphorylation of PI3K, AKT, and NF-κB p65, and the nuclear translocation of NF-κB p65. In vivo tumor xenograft experiments confirmed that AKR1B10 promoted breast cancer growth in mice. Conclusions AKR1B10 promotes the proliferation, migration and invasion of breast cancer cells via the PI3K/AKT/NF-κB signaling pathway and represents a novel prognostic indicator as well as a potential therapeutic target in breast cancer.

Beschreibung: Background The plant body in duckweed species has undergone reduction and simplification from the ancient Spirodela species towards more derived Wolffia species. Among the five duckweed genera, Wolffia members are rootless and represent the smallest and most reduced species. A better understanding of Wolffia frond architecture is necessary to fully explore duckweed evolution. Results We conducted a comprehensive study of the morphology and anatomy of Wolffia globosa, the only Wolffia species in China. We first used X-ray microtomography imaging to reveal the three-dimensional and internal structure of the W. globosa frond. This showed that new fronds rapidly budded from the hollow reproductive pocket of the mother fronds and that several generations at various developmental stages could coexist in a single W. globosa frond. Using light microscopy, we observed that the meristem area of the W. globosa frond was located at the base of the reproductive pocket and composed of undifferentiated cells that continued to produce new buds. A single epidermal layer surrounded the W. globosa frond, and the mesophyll cells varied from small and dense palisade-like parenchyma cells to large, vacuolated cells from the ventral to the dorsal part. Furthermore, W. globosa fronds contained all the same organelles as other angiosperms; the most prominent organelles were chloroplasts with abundant starch grains. Conclusions Our study revealed that the reproductive strategy of W. globosa plants enables the rapid accumulation of biomass and the wide distribution of this species in various habitats. The reduced body plan and size of Wolffia are consistent with our observation that relatively few cell types are present in these plants. We also propose that W. globosa plants are not only suitable for the study of structural reduction in higher plants, but also an ideal system to explore fundamental developmental processes of higher plants that cannot be addressed using other model plants.

Beschreibung: On the 〉1 µm scale the morphology of semicrystalline plastics like polyethylene or Nylon features spherulites, “shish-kebabs”, cylinddrites and other crystalline aggregates which strongly affect mechanical and other material properties. Current imaging techniques give only a 2D picture of these objects. Here we show how they can be visualized in 3D using fluorescent labels and confocal microscopy. As a result, we see spherulites in 3D, both in neat polymers and their nanocomposites, and observe how unevenly nanoparticles and other additives are distributed in the material. Images of i-polypropylene and biodegradable poly(lactic acid) reveal previously unsuspected morphologies such as “vases” and “goblets”, nonspherical “spherulites” and, unexpectedly, “shish-kebabs” grown from quiescent melt. Also surprisingly, in nanocomposite sheets spherulite nucleation is seen to be copied from one surface to another, mediated by crystallization-induced pressure drop and local melt-flow. These first results reveal unfamiliar modes of self-assembly in familiar plastics and open fresh perspectives on polymer microstructure.

Beschreibung: Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa.

Beschreibung: Background Structural variants (SVs) significantly drive genome diversity and environmental adaptation for diverse species. Unlike the prevalent small SVs (〈 kilobase-scale) in higher eukaryotes, large-size SVs rarely exist in the genome, but they function as one of the key evolutionary forces for speciation and adaptation. Results In this study, we discover and characterize several megabase-scale presence-absence variations (PAVs) in the maize genome. Surprisingly, we identify a 3.2 Mb PAV fragment that shows high integrity and is present as complete presence or absence in the natural diversity panel. This PAV is embedded within the nucleolus organizer region (NOR), where the suppressed recombination is found to maintain the PAV against the evolutionary variation. Interestingly, by analyzing the sequence of this PAV, we not only reveal the domestication trace from teosinte to modern maize, but also the footprints of its origin from Tripsacum, shedding light on a previously unknown contribution from Tripsacum to the speciation of Zea species. The functional consequence of the Tripsacum segment migration is also investigated, and environmental fitness conferred by the PAV may explain the whole segment as a selection target during maize domestication and improvement. Conclusions These findings provide a novel perspective that Tripsacum contributes to Zea speciation, and also instantiate a strategy for evolutionary and functional analysis of the “fossil” structure variations during genome evolution and speciation.