CXCL1: Gene, Promoter, Regulation of Expression, mRNA Stability, Regulation of Activity in the Intercellular Space

CXCL1 is one of the most important chemokines, part of a group of chemotactic cytokines involved in the development of many inflammatory diseases. It activates CXCR2 and, at high levels, CXCR1. The expression of CXCL1 is elevated in inflammatory reactions and also has important functions in physiology, including the induction of angiogenesis and recruitment of neutrophils. Due to a lack of reviews that precisely describe the regulation of CXCL1 expression and function, in this paper, we present the mechanisms of CXCL1 expression regulation with a special focus on cancer. We concentrate on the regulation of CXCL1 expression through the regulation of CXCL1 transcription and mRNA stability, including the involvement of NF-κB, p53, the effect of miRNAs and cytokines such as IFN-γ, IL-1β, IL-17, TGF-β and TNF-α. We also describe the mechanisms regulating CXCL1 activity in the extracellular space, including proteolytic processing, CXCL1 dimerization and the influence of the ACKR1/DARC receptor on CXCL1 localization. Finally, we explain the role of CXCL1 in cancer and possible therapeutic approaches directed against this chemokine.

Genetic studies of human–chimpanzee divergence using stem cell fusions

Complete genome sequencing has identified millions of DNA changes that differ between humans and chimpanzees. Although a subset of these changes likely underlies important phenotypic differences between humans and chimpanzees, it is currently difficult to distinguish causal from incidental changes and to map specific phenotypes to particular genome locations. To facilitate further genetic study of human–chimpanzee divergence, we have generated human and chimpanzee autotetraploids and allotetraploids by fusing induced pluripotent stem cells (iPSCs) of each species. The resulting tetraploid iPSCs can be stably maintained and retain the ability to differentiate along ectoderm, mesoderm, and endoderm lineages. RNA sequencing identifies thousands of genes whose expression differs between humans and chimpanzees when assessed in single-species diploid or autotetraploid iPSCs. Analysis of gene expression patterns in interspecific allotetraploid iPSCs shows that human–chimpanzee expression differences arise from substantial contributions of both cis-acting changes linked to the genes themselves and trans-acting changes elsewhere in the genome. To enable further genetic mapping of species differences, we tested chemical treatments for stimulating genome-wide mitotic recombination between human and chimpanzee chromosomes, and CRISPR methods for inducing species-specific changes on particular chromosomes in allotetraploid cells. We successfully generated derivative cells with nested deletions or interspecific recombination on the X chromosome. These studies confirm an important role for the X chromosome in trans regulation of expression differences between species and illustrate the potential of this system for more detailed cis and trans mapping of the molecular basis of human and chimpanzee evolution.

Regulation of effector gene expression as concerted waves in Leptosphaeria maculans: a two-players game

During infection, plant pathogenic fungi secrete a set of molecules collectively known as effectors, involved in overcoming the host immune system and in disease establishment. Effector genes are concertedly expressed as waves all along plant pathogenic fungi lifecycle. However, little is known about how coordinated expression of effector genes is regulated. Since many effector genes are located in repeat-rich regions, the role of chromatin remodeling in the regulation of effector expression was recently investigated. In Leptosphaeria maculans, causing stem canker of oilseed rape, we established that the repressive histone modification H3K9me3 (trimethylation of Lysine 9 of Histone H3), deposited by the histone methyltransferase KMT1, was involved in the regulation of expression of genes highly expressed during infection, including effectors. Nevertheless, inactivation of KMT1 did not induce expression of these genes at the same level as observed during infection of oilseed rape, suggesting that a second regulator, such as a transcription factor (TF), might be involved. Pf2, a TF belonging to the Zn2Cys6 fungal specific TF family, was described in several Dothideomycete species as essential for pathogenicity and effector gene expression. We identified the orthologue of Pf2 in L. maculans, LmPf2, and investigated the role of LmPf2 together with KMT1, by inactivating and over-expressing LmPf2 in a wild type (WT) strain and a ∆kmt1 mutant. Functional analyses of the corresponding transformants highlighted an essential role of LmPf2 in the establishment of pathogenesis. Transcriptomic analyses during axenic growth showed that LmPf2 is involved in the control of effector gene expression. We observed an enhanced effect of the over-expression of LmPf2 on effector gene expression in a ∆kmt1 background, suggesting an antagonist role between KMT1 and LmPf2.

Chlorogenic Acid Protects against Advanced Alcoholic Steatohepatitis in Rats via Modulation of Redox Homeostasis, Inflammation, and Lipogenesis

The aim of this study was to evaluate the therapeutic effects of chlorogenic acid (CGA) in rats with advanced alcoholic steatohepatitis. The rats were fed on a high-fat diet and gavaged with ethanol (4 g/kg) for 8 weeks. The livers of ethanol-treated rats showed steatosis; necrosis and mononuclear infiltration; and significant upregulation of the mRNA expression of the prooxidant (Cyp2e1, iNos), lipogenic (Srebp1, Acc), proinflammatory (Tlr4, Nf-κb, TnfA, Il-1B, and Il-6), and profibrogenic (TgfB, Col1, VegfA) genes. Simultaneously, a downregulation of level of Sod and Nrf2 was observed, which was accompanied by increased serum transaminase, TnfA, and serum and liver triglycerides levels. CGA administration (40 and 80 mg/kg, 8 weeks) to ethanol-fed group reduced the liver expression levels of Cyp2e1 and iNos, whereas it markedly enhanced the expression of Sod, Nrf2, and Ho-1. CGA at both doses downregulated the expressions of lipogenic, proinflammatory, and profibrogenic genes, while the expression of Tlr4 was lowered only after the higher dose of CGA. The higher dose of CGA efficiently prevented the progression of alcohol-induced steatosis and reduced inflammation through regulation of the expression of genes encoding the proteins involved in the Tlr4/Nf-κB signaling pathway and fibrosis. The study revealed hepatoprotective and anti-inflammatory effects of CGA through the regulation of expression of genes encoding Cyp2e1/Nrf2 involved in oxidative stress modulation. These results demonstrate CGA as a therapeutic candidate for the prevention and treatment of alcoholic steatohepatitis.

Ribosome profiling of porcine reproductive and respiratory syndrome virus reveals novel features of viral gene expression

Porcine reproductive and respiratory syndrome virus (PRRSV) is an arterivirus which causes significant economic losses to the swine industry worldwide. Here, we use ribosome profiling (RiboSeq) and parallel RNA sequencing (RNASeq) to characterise the transcriptome and translatome of both species of PRRSV and analyse the host response to infection. We quantified viral gene expression over a timecourse of infection, and calculated the efficiency of programmed ribosomal frameshifting (PRF) at both sites on the viral genome. At the nsp2 frameshift site (a rare example of protein-stimulated frameshifting), −2 PRF efficiency increases over time, likely facilitated by accumulation of the PRF-stimulatory viral protein (nsp1β) during infection. This marks arteriviruses as the second example of temporally regulated PRF. Surprisingly, we also found PRF efficiency at the canonical ORF1ab frameshift site increases over time, in apparent contradiction of the common assumption that RNA structure-directed frameshift sites operate at a fixed efficiency. This has potential implications for the numerous other viruses with canonical PRF sites. Furthermore, we discovered several highly translated additional viral ORFs, the translation of which may be facilitated by multiple novel viral transcripts. For example, we found a 125-codon ORF overlapping nsp12, which is expressed as highly as nsp12 itself at late stages of replication, and is likely translated from novel subgenomic (sg) RNA transcripts that overlap the 3′ end of ORF1b. Similar transcripts were discovered for both PRRSV-1 and PRRSV-2, suggesting a potential conserved mechanism for temporal regulation of expression of the 3′-proximal region of ORF1b. In addition, we identified a highly translated, short upstream ORF (uORF) in the 5′ UTR, the presence of which is highly conserved amongst PRRSV-2 isolates. This is the first application of RiboSeq to arterivirus-infected cells, and reveals new features which add to the complexity of gene expression programmes in this important family of nidoviruses.

Freedom Of Expression And Freedom Of Movement In The Immigration Space: Substance Over Forum

<p>Globalisation and the availability of information through television and the internet have been a boon for the spread of ideas and for freedom of expression. These trends have also created challenges for the regulation of expression. Those with hateful views or harmful information have just as much access to modern communication tools as the rest of us. How policy makers respond to the free flow of information raises a multitude of questions. However there is no doubt that the state still holds the upper hand in controlling the freedom of movement between borders. Despite the availability of information technology there is still a need for interpersonal communication to facilitate the freedom of expression. The freedom of movement is therefore important to enabling the freedom of expression, and states can restrict the later by restricting the former. The aim of this paper is to comprehensively scrutinise the different approaches taken to regulating freedom of movement for the purpose of regulating freedom of expression. It looks with judicial reviews within common law jurisdictions and how the issue is managed within their existing human rights legal frameworks. Firstly the paper will lay out a preferred approach to dealing with the regulation of freedom of expression in an immigration context, bearing in mind the rights which states have to control their borders and the justifications for doing so. The approach places strong emphasis on protecting the freedom of expression for all groups without seeking to challenge the existence or legitimacy of the ways states choose to regulate expression within their borders. It suggests that regulation should be limited to situations where it is likely that the visitor would choose to break the laws of the state they seek to visit, or where their visit could spark disruption involving violence which could not reasonably be controlled by law enforcement. Secondly the paper will examine four cases from two common law jurisdictions in detail. There is an emphasis on understanding two themes. The first is explaining the broader context of human rights protection within those jurisdictions and how their approach to immigration control reflects or contradicts that protection. The second is upon critiquing and understanding the administrative law implications of the standards of review applied. Reference is made back to the preferred framework to help understand to what extent the cases stand for genuine protection of freedom of expression.</p>

Freedom Of Expression And Freedom Of Movement In The Immigration Space: Substance Over Forum

<p>Globalisation and the availability of information through television and the internet have been a boon for the spread of ideas and for freedom of expression. These trends have also created challenges for the regulation of expression. Those with hateful views or harmful information have just as much access to modern communication tools as the rest of us. How policy makers respond to the free flow of information raises a multitude of questions. However there is no doubt that the state still holds the upper hand in controlling the freedom of movement between borders. Despite the availability of information technology there is still a need for interpersonal communication to facilitate the freedom of expression. The freedom of movement is therefore important to enabling the freedom of expression, and states can restrict the later by restricting the former. The aim of this paper is to comprehensively scrutinise the different approaches taken to regulating freedom of movement for the purpose of regulating freedom of expression. It looks with judicial reviews within common law jurisdictions and how the issue is managed within their existing human rights legal frameworks. Firstly the paper will lay out a preferred approach to dealing with the regulation of freedom of expression in an immigration context, bearing in mind the rights which states have to control their borders and the justifications for doing so. The approach places strong emphasis on protecting the freedom of expression for all groups without seeking to challenge the existence or legitimacy of the ways states choose to regulate expression within their borders. It suggests that regulation should be limited to situations where it is likely that the visitor would choose to break the laws of the state they seek to visit, or where their visit could spark disruption involving violence which could not reasonably be controlled by law enforcement. Secondly the paper will examine four cases from two common law jurisdictions in detail. There is an emphasis on understanding two themes. The first is explaining the broader context of human rights protection within those jurisdictions and how their approach to immigration control reflects or contradicts that protection. The second is upon critiquing and understanding the administrative law implications of the standards of review applied. Reference is made back to the preferred framework to help understand to what extent the cases stand for genuine protection of freedom of expression.</p>

Human FKBP5 negatively regulates transcription through inhibition of P-TEFb complex formation

Although large number of recent studies indicate strong association of FKBP5 (aka FKBP51) functions with various stress-related psychiatric disorder, the overall mechanisms are poorly understood. Beyond a few studies indicating its functions in regulating glucocorticoid receptor-, and AKT-signalling pathways, other functional roles (if any) are unclear. In this study, we report an anti-proliferative role of human FKBP5 through negative regulation of expression of proliferation-related genes. Mechanistically, we show that, owing to same region of interaction on CDK9, human FKBP5 directly competes with CyclinT1 for functional P-TEFb complex formation. In vitro biochemical coupled with cell-based assays, showed strong negative effect of FKBP5 on P-TEFb-mediated phosphorylation of diverse substrates. Consistently, FKBP5 knockdown showed enhanced P-TEFb complex formation leading to increased global RNA polymerase II CTD phosphorylation and expression of proliferation-related genes and subsequent proliferation. Thus, our results show an important role of FKBP5 in negative regulation of P-TEFb functions within mammalian cells.

Warthy-Basaloid Squamous Cell Carcinoma of Penile – Case Report

ObjectiveThe aim of the study was to present a case of penile squamous cell carcinoma and immunohistochemical identification and evaluation of E-cadherin and β-catenin expression.MethodsWe are presenting a 70-year old man with a variant of penile squamous cell carcinoma with mixed warty and basaloid features. After diagnosis, the patient underwent partial penectomy. Samples taken from the material after surgery were subjected to basic histological staining and immunohistochemical identification of E-cadherin and β-catenin. A Real-time PCR study was conducted to investigate the expression of E-cadherin and β-catenin.ResultsRoutine histopathological examinations revealed the characteristic features of warty-basaloid squamous cell carcinoma. In the case studied, a positive immunohistochemical reaction was observed for E-cadherin and β-catenin. QRT-PCR analysis showed a statistically significant decrease in E-cadherin expression in tumor samples compared to healthy tissue. In contrast, expression of the gene encoding β-catenin was slightly higher in tumor samples compared to normal tissue.ConclusionsThe reduced level of the complex of adhesive elements, E-cadherin-β-catenin, disturbs cell differentiation, promotes a more invasive phenotype-stromal infiltration and the formation of distant metastases. In the described case of the penile tumor, a decrease in E-cadherin expression was noted, which could be related to the occurrence of neoplastic infiltration of the spongy body space. In summary, E-cadherin and β-catenin expression and the immunoreactivity of these proteins are expressed at different levels in tumor cells and in penile interstitial cells. Regulation of expression during various physiological and pathophysiological processes indicates a potentially important role of E-cadherin and β-catenin in cell proliferation and adhesion.