Screening Level of PAHs in Sediment Core from Lake Hongfeng, Southwest China

Using data from a 25-year retrospective of polycyclic aromatic hydrocarbons (PAHs) in sediment core from Lake Hongfeng, Southwest China, their possible sources and potential toxicologic significance were investigated. The total PAH concentrations (16 priority PAHs as proposed by the United States Environmental Protection Agency) in sediments ranged from 2936.1 to 5282.3 ng/g and gradually increased from the analyzed deeper sediments to surface sediments. PAHs were dominated by low molecular-weight components, especially phenanthrene (PHEN) and fluorene (FLU). However, a significantly increased number of high molecular-weight (HMW) PAHs was found in upper segments. The temporal trends of individual PAH species suggest that there may have been a change in energy use from low- to high-temperature combustion, especially after approximately 2001. PAH input to Lake Hongfeng originated mainly from domestic coal combustion and biomass burning, whereas fuel combustion characteristics have also been found in recent years. Sediment-quality assessment implied that potential adverse biologic impact could be a probability for most low-ring PAHs (including naphthalene, acenaphthylene, acenaphthylene, FLU, PHEN, and anthracene). Nevertheless, more concern should be paid to HMW PAHs in the future due to their rapidly increasing trends in upper sediments. Because only one core was analyzed in this study, more work is needed to confirm the sources and toxicity of PAHs in Lake Hongfeng

Modulating signaling networks by CRISPR/Cas9-mediated transposable element insertion

In a recent past, transposable elements (TEs) were referred to as selfish genetic components only capable of copying themselves with the aim of increasing the odds of being inherited. Nonetheless, TEs have been initially proposed as positive control elements acting in synergy with the host. Nowadays, it is well known that TE movement into host genome comprises an important evolutionary mechanism capable of increasing the adaptive fitness. As insights into TE functioning are increasing day to day, the manipulation of transposition has raised an interesting possibility of setting the host functions, although the lack of appropriate genome engineering tools has unpaved it. Fortunately, the emergence of genome editing technologies based on programmable nucleases, and especially the arrival of a multipurpose RNA-guided Cas9 endonuclease system, has made it possible to reconsider this challenge. For such purpose, a particular type of transposons referred to as miniature inverted-repeat transposable elements (MITEs) has shown a series of interesting characteristics for designing functional drivers. Here, recent insights into MITE elements and versatile RNA-guided CRISPR/Cas9 genome engineering system are given to understand how to deploy the potential of TEs for control of the host transcriptional activity.Fil: Vaschetto, Luis Maria Benjamin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Diversidad y Ecología Animal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Diversidad y Ecología Animal; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Cátedra de Diversidad Animal I; Argentin

Sirtinol Treatment Reduces Inflammation in Human Dermal Microvascular Endothelial Cells

Histone deacetylases (HDAC) are key enzymes in the epigenetic control of gene expression. Recently, inhibitors of class I and class II HDAC have been successfully employed for the treatment of different inflammatory diseases such as rheumatoid arthritis, colitis, airway inflammation and asthma. So far, little is known so far about a similar therapeutic effect of inhibitors specifically directed against sirtuins, the class III HDAC. In this study, we investigated the expression and localization of endogenous sirtuins in primary human dermal microvascular endothelial cells (HDMEC), a cell type playing a key role in the development and maintenance of skin inflammation. We then examined the biological activity of sirtinol, a specific sirtuin inhibitor, in HDMEC response to pro-inflammatory cytokines. We found that, even though sirtinol treatment alone affected only long-term cell proliferation, it diminishes HDMEC inflammatory responses to tumor necrosis factor (TNF)α and interleukin (IL)-1β. In fact, sirtinol significantly reduced membrane expression of adhesion molecules in TNFã- or IL-1β-stimulated cells, as well as the amount of CXCL10 and CCL2 released by HDMEC following TNFα treatment. Notably, sirtinol drastically decreased monocyte adhesion on activated HDMEC. Using selective inhibitors for Sirt1 and Sirt2, we showed a predominant involvement of Sirt1 inhibition in the modulation of adhesion molecule expression and monocyte adhesion on activated HDMEC. Finally, we demonstrated the in vivo expression of Sirt1 in the dermal vessels of normal and psoriatic skin. Altogether, these findings indicated that sirtuins may represent a promising therapeutic target for the treatment of inflammatory skin diseases characterized by a prominent microvessel involvement

Dengue 1 Diversity and Microevolution, French Polynesia 2001–2006: Connection with Epidemiology and Clinics

The molecular characterization of 181 serotype 1 Dengue fever (DENV-1) viruses collected regularly during the 2001–2006 period in French Polynesia (FP) from patients experiencing various clinical presentations revealed that the virus responsible for the severe 2001 outbreak was introduced from South-East Asia, and evolved under an endemic mode until a new epidemic five years later. The dynamics of DENV-1 epidemics in FP did not follow the model of repeated virus introductions described in other South Pacific islands. They were characterized by a long sustained viral circulation and the absence of new viral introduction over a six-year period. Viral genetic variability was not observed only during outbreaks. In contrast with conventional thinking, a significant part of DENV-1 evolution may occur during endemic periods, and may reflect adaptation to the mosquito vector. However, DENV-1 evolution was globally characterized by strong purifying selection pressures leading to genome conservation, like other DENV serotypes and other arboviruses subject to constraints imposed by the host-vector alternating replication of viruses. Severe cases—dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS)—may be linked to both viral and host factors. For the first time, we report a significant correlation between intra-host viral genetic variability and clinical outcome. Severe cases were characterized by more homogeneous viral populations with lower intra-host genetic variability

Recent Emergence of Dengue Virus Serotype 4 in French Polynesia Results from Multiple Introductions from Other South Pacific Islands

BACKGROUND: Infection by dengue virus (DENV) is a major public health concern in hundreds of tropical and subtropical countries. French Polynesia (FP) regularly experiences epidemics that initiate, or are consecutive to, DENV circulation in other South Pacific Island Countries (SPICs). In January 2009, after a decade of serotype 1 (DENV-1) circulation, the first cases of DENV-4 infection were reported in FP. Two months later a new epidemic emerged, occurring about 20 years after the previous circulation of DENV-4 in FP. In this study, we investigated the epidemiological and molecular characteristics of the introduction, spread and genetic microevolution of DENV-4 in FP. METHODOLOGY/PRINCIPAL FINDINGS: Epidemiological data suggested that recent transmission of DENV-4 in FP started in the Leeward Islands and this serotype quickly displaced DENV-1 throughout FP. Phylogenetic analyses of the nucleotide sequences of the envelope (E) gene of 64 DENV-4 strains collected in FP in the 1980s and in 2009-2010, and some additional strains from other SPICs showed that DENV-4 strains from the SPICs were distributed into genotypes IIa and IIb. Recent FP strains were distributed into two clusters, each comprising viruses from other but distinct SPICs, suggesting that emergence of DENV-4 in FP in 2009 resulted from multiple introductions. Otherwise, we observed that almost all strains collected in the SPICs in the 1980s exhibit an amino acid (aa) substitution V287I within domain I of the E protein, and all recent South Pacific strains exhibit a T365I substitution within domain III. CONCLUSIONS/SIGNIFICANCE: This study confirmed the cyclic re-emergence and displacement of DENV serotypes in FP. Otherwise, our results showed that specific aa substitutions on the E protein were present on all DENV-4 strains circulating in SPICs. These substitutions probably acquired and subsequently conserved could reflect a founder effect to be associated with epidemiological, geographical, eco-biological and social specificities in SPICs

Resveratrol Increases Glucose Induced GLP-1 Secretion in Mice: A Mechanism which Contributes to the Glycemic Control

Resveratrol (RSV) is a potent anti-diabetic agent when used at high doses. However, the direct targets primarily responsible for the beneficial actions of RSV remain unclear. We used a formulation that increases oral bioavailability to assess the mechanisms involved in the glucoregulatory action of RSV in high-fat diet (HFD)-fed diabetic wild type mice. Administration of RSV for 5 weeks reduced the development of glucose intolerance, and increased portal vein concentrations of both Glucagon-like peptid-1 (GLP-1) and insulin, and intestinal content of active GLP-1. This was associated with increased levels of colonic proglucagon mRNA transcripts. RSV-mediated glucoregulation required a functional GLP-1 receptor (Glp1r) as neither glucose nor insulin levels were modulated in Glp1r-/- mice. Conversely, levels of active GLP-1 and control of glycemia were further improved when the Dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin was co-administered with RSV. In addition, RSV treatment modified gut microbiota and decreased the inflammatory status of mice. Our data suggest that RSV exerts its actions in part through modulation of the enteroendocrine axis in vivo

Histone deacetylase inhibitors: clinical implications for hematological malignancies

Histone modifications have widely been implicated in cancer development and progression and are potentially reversible by drug treatments. The N-terminal tails of each histone extend outward through the DNA strand containing amino acid residues modified by posttranslational acetylation, methylation, and phosphorylation. These modifications change the secondary structure of the histone protein tails in relation to the DNA strands, increasing the distance between DNA and histones, and thus allowing accessibility of transcription factors to gene promoter regions. A large number of HDAC inhibitors have been synthesized in the last few years, most being effective in vitro, inducing cancer cells differentiation or cell death. The majority of the inhibitors are in clinical trials, unlike the suberoylanilide hydroxamic acid, a pan-HDACi, and Romidepsin (FK 228), a class I-selective HDACi, which are only approved in the second line treatment of refractory, persistent or relapsed cutaneous T-cell lymphoma, and active in approximately 150 clinical trials, in monotherapy or in association. Preclinical studies investigated the use of these drugs in clinical practice, as single agents and in combination with chemotherapy, hypomethylating agents, proteasome inhibitors, and MTOR inhibitors, showing a significant effect mostly in hematological malignancies. The aim of this review is to focus on the biological features of these drugs, analyzing the possible mechanism(s) of action and outline an overview on the current use in the clinical practice

Knockdown of the Drosophila Fused in Sarcoma (FUS) Homologue Causes Deficient Locomotive Behavior and Shortening of Motoneuron Terminal Branches

Mutations in the fused in sarcoma/translated in liposarcoma gene (FUS/TLS, FUS) have been identified in sporadic and familial forms of amyotrophic lateral sclerosis (ALS). FUS is an RNA-binding protein that is normally localized in the nucleus, but is mislocalized to the cytoplasm in ALS, and comprises cytoplasmic inclusions in ALS-affected areas. However, it is still unknown whether the neurodegeneration that occurs in ALS is caused by the loss of FUS nuclear function, or by the gain of toxic function due to cytoplasmic FUS aggregation. Cabeza (Caz) is a Drosophila orthologue of human FUS. Here, we generated Drosophila models with Caz knockdown, and investigated their phenotypes. In wild-type Drosophila, Caz was strongly expressed in the central nervous system of larvae and adults. Caz did not colocalize with a presynaptic marker, suggesting that Caz physiologically functions in neuronal cell bodies and/or their axons. Fly models with neuron-specific Caz knockdown exhibited reduced climbing ability in adulthood and anatomical defects in presynaptic terminals of motoneurons in third instar larvae. Our results demonstrated that decreased expression of Drosophila Caz is sufficient to cause degeneration of motoneurons and locomotive disability in the absence of abnormal cytoplasmic Caz aggregates, suggesting that the pathogenic mechanism underlying FUS-related ALS should be ascribed more to the loss of physiological FUS functions in the nucleus than to the toxicity of cytoplasmic FUS aggregates. Since the Caz-knockdown Drosophila model we presented recapitulates key features of human ALS, it would be a suitable animal model for the screening of genes and chemicals that might modify the pathogenic processes that lead to the degeneration of motoneurons in ALS