1H, 13C and 15N resonance assignments of an N-terminal domain of CHD4

Chromatin-remodeling proteins have a pivotal role in normal cell function and development, catalyzing conformational changes in DNA that ultimately result in changes in gene expression patterns. Chromodomain helicase DNA-binding protein 4 (CHD4), the defining subunit of the nucleosome remodeling and deacetylase (NuRD) complex, is a nucleosome-remodeling protein of the SNF2/ISWI2 family, members of which contain two chromo domains and an ATP-dependent helicase module. CHD3, CHD4 and CHD5 also contain two contiguous PHD domains and have an extended N-terminal region that has not previously been characterized. We have identified a stable domain in the N-terminal region of CHD4 and report here the backbone and side chain resonance assignments for this domain at pH 7.5 and 25 °C (BMRB No. 18906).     

Observations on Abundance of Bluntnose Sixgill Sharks,Hexanchus griseus,in an Urban Waterway in Puget Sound, 2003-2005

The bluntnose sixgill shark, Hexanchus griseus, is a widely distributed but poorly understood large, apex predator. Anecdotal reports of diver-shark encounters in the late 1990’s and early 2000’s in the Pacific Northwest stimulated interest in the normally deep-dwelling shark and its presence in the shallow waters of Puget Sound. Analysis of underwater video documenting sharks at the Seattle Aquarium’s sixgill research site in Elliott Bay and mark-resight techniques were used to answer research questions about abundance and seasonality. Seasonal changes in relative abundance in Puget Sound from 2003–2005 are reported here. At the Seattle Aquarium study site, 45 sixgills were tagged with modified Floy visual marker tags, along with an estimated 197 observations of untagged sharks plus 31 returning tagged sharks, for a total of 273 sixgill observations recorded. A mark-resight statistical model based on analysis of underwater video estimated a range of abundance from a high of 98 sharks seen in July of 2004 to a low of 32 sharks seen in March of 2004. Both analyses found sixgills significantly more abundant in the summer months at the Seattle Aquarium’s research station.     

An Interferon Response Gene Signature Is Associated with the Therapeutic Response of Hepatitis C Patients

Infection with the hepatitis C virus (HCV) is a major cause of chronic liver diseases and hepatocellular carcinoma worldwide, and thus represents a significant public health problem. The type I interferon (IFN), IFNα, has been successful in treating HCV-infected patients, but current IFN-based treatment regimens for HCV have suboptimal efficacy, and relatively little is known about why IFN therapy eliminates the virus in some patients but not in others. Therefore, it is critical to understand the basic mechanisms that underlie the therapeutic resistance to IFN action in HCV-infected individuals, and there is an urgent need to identify those patients most likely to respond to IFN therapy for HCV. To characterize the response of HCV-infected patients to treatment with IFNα, the expression of an IFN-response gene signature comprised of IFN-stimulated genes and genes that play an important role in the innate immune response was examined in liver biopsies from HCV-infected patients enrolled in a clinical trial. In the present study we found that the expression of a subset of IFN-response genes was dysregulated in liver biopsy samples from nonresponsive hepatitis C patients as compared with virologic responders. Based on these findings, a statistical model was developed to help predict the response of patients to IFN therapy, and compared to results obtained to the IL28 mutation model, which is highly predictive of the response to IFN-based therapy in HCV-infected patients. We found that a model incorporating gene expression data can improve predictions of IFN responsiveness compared to IL28 mutation status alone.     

Chlamydia trachomatis,Human Immunodeficiency Virus (HIV) Distribution and Sexual Behaviors across Gender and Age Group in an African Setting

ObjectiveThe purpose of this study was to (1) describe the distribution of Chlamydia trachomatis (CT) and Human Immunodeficiency Virus (HIV) cases across gender and age groups in Libreville (Gabon); (2) examine Gabonese Sexually Transmitted Infections (STIs)-related risk behaviour.MethodsThe sampled population was people attending the “Laboratoire National de Santé Plublique”. Between 2007 and 2011, 14 667 and 9 542 people respectively, were tested for CT and HIV infections. 1 854 of them were tested for both infections. We calculated CT and HIV rates across gender and age groups. Also analysed was the groups'' contribution to the general CT and HIV epidemiology.STIs-related risk behaviours were assessed in 224 men and 795 women (between July 2011 and March 2013) who agreed and answered a questionnaire including questions on their marital status, number of sex partners, sexual practices, history of STIs, sex frequency and condom use.ResultsData showed a 24% dropped in the CT infection rate between 2007 and 2010, followed by a 14% increase in 2011. The HIV infection rates for the same period were between 15% and 16%. The risk of a CT-positive subject getting HIV is about 0.71 times the risk of a CT-negative subject.Young adult aged between 18 and 35 years old represented 65.2% of people who had STIs. 80% of women and 66% of men confessed to an inconsistent use of condoms. 11.6% of women and 48% of men declared having multiple sex partners. 61% of questioned women and 67% of men declared knowing their HIV status.ConclusionsIn this Gabonese setting, the population-aged from18 to 35 years is the most affected by STIs. Other matters of concern are the inconsistent use of protection and sex with non-spousal or non-life partners.     

Crystal Structures of HIV-1 gp120 Envelope Glycoprotein in Complex with NBD Analogues That Target the CD4-Binding Site

Efforts to develop therapeutic agents that inhibit HIV-1 entry have led to the identification of several small molecule leads. One of the most promising is the NBD series, which binds within a conserved gp120 cavity and possesses para-halogen substituted aromatic rings, a central oxalamide linker, and a tetramethylpiperidine moiety. In this study, we characterized structurally the interactions of four NBD analogues containing meta-fluoro substitution on the aromatic ring and various heterocyclic ring replacements of the tetramethylpiperidine group. The addition of a meta-fluorine to the aromatic ring improved surface complementarity and did not alter the position of the analogue relative to gp120. By contrast, heterocyclic ring replacements of the tetramethylpiperidine moiety exhibited diverse positioning and interactions with the vestibule of the gp120 cavity. Overall, the biological profile of NBD-congeners was modulated by ligand interactions with the gp120-cavity vestibule. Herein, six co-crystal structures of NBD-analogues with gp120 provide a structural framework for continued small molecule-entry inhibitor optimization.     

Mycoplasma pneumoniae CARDS Toxin Exacerbates Ovalbumin-Induced Asthma-Like Inflammation in BALB/c Mice

Mycoplasma pneumoniae causes a range of airway and extrapulmonary pathologies in humans. Clinically, M. pneumoniae is associated with acute exacerbations of human asthma and a worsening of experimentally induced asthma in mice. Recently, we demonstrated that Community Acquired Respiratory Distress Syndrome (CARDS) toxin, an ADP-ribosylating and vacuolating toxin synthesized by M. pneumoniae, is sufficient to induce an asthma-like disease in BALB/cJ mice. To test the potential of CARDS toxin to exacerbate preexisting asthma, we examined inflammatory responses to recombinant CARDS toxin in an ovalbumin (OVA) murine model of asthma. Differences in pulmonary inflammatory responses between treatment groups were analyzed by histology, cell differentials and changes in cytokine and chemokine concentrations. Additionally, assessments of airway hyperreactivity were evaluated through direct pulmonary function measurements. Analysis of histology revealed exaggerated cellular inflammation with a strong eosinophilic component in the CARDS toxin-treated group. Heightened T-helper type-2 inflammatory responses were evidenced by increased expression of IL-4, IL-13, CCL17 and CCL22 corresponding with increased airway hyperreactivity in the CARDS toxin-treated mice. These data demonstrate that CARDS toxin can be a causal factor in the worsening of experimental allergic asthma, highlighting the potential importance of CARDS toxin in the etiology and exacerbation of human asthma.     

The Sequential Application of Macroalgal Biosorbents for the Bioremediation of a Complex Industrial Effluent

Fe-treated biochar and raw biochar produced from macroalgae are effective biosorbents of metalloids and metals, respectively. However, the treatment of complex effluents that contain both metalloid and metal contaminants presents a challenging scenario. We test a multiple-biosorbent approach to bioremediation using Fe-biochar and biochar to remediate both metalloids and metals from the effluent from a coal-fired power station. First, a model was derived from published data for this effluent to predict the biosorption of 21 elements by Fe-biochar and biochar. The modelled outputs were then used to design biosorption experiments using Fe-biochar and biochar, both simultaneously and in sequence, to treat effluent containing multiple contaminants in excess of water quality criteria. The waste water was produced during ash disposal at an Australian coal-fired power station. The application of Fe-biochar and biochar, either simultaneously or sequentially, resulted in a more comprehensive remediation of metalloids and metals compared to either biosorbent used individually. The most effective treatment was the sequential use of Fe-biochar to remove metalloids from the waste water, followed by biochar to remove metals. Al, Cd, Cr, Cu, Mn, Ni, Pb, Zn were reduced to the lowest concentration following the sequential application of the two biosorbents, and their final concentrations were predicted by the model. Overall, 17 of the 21 elements measured were remediated to, or below, the concentrations that were predicted by the model. Both metalloids and metals can be remediated from complex effluent using biosorbents with different characteristics but derived from a single feedstock. Furthermore, the extent of remediation can be predicted for similar effluents using additive models.     

Pharmacogenetic-Based Efavirenz Dose Modification: Suggestions for an African Population and the Different CYP2B6 Genotypes

Background

Pharmacogenetics contributes to inter-individual variability in pharmacokinetics (PK) of efavirenz (EFV), leading to variations in both efficacy and toxicity. The purpose of this study was to assess the effect of genetic factors on EFV pharmacokinetics, treatment outcomes and genotype based EFV dose recommendations for adult HIV-1 infected Ugandans.

Methods

In total, 556 steady-state plasma EFV concentrations from 99 HIV infected patients (64 female) treated with EFV/lamivudine/zidovidine were analyzed. Patient genotypes for CYP2B6 (*6 & *11), CYP3A5 (*3,*6 & *7) and ABCB1 c.4046A>G, baseline biochemistries and CD4 and viral load change from baseline were determined. A one-compartment population PK model with first-order absorption (NONMEM) was used to estimate genotype effects on EFV pharmacokinetics. PK simulations were performed based upon population genotype frequencies. Predicted AUCs were compared between the product label and simulations for doses of 300 mg, 450 mg, and 600 mg.

Results

EFV apparent clearance (CL/F) was 2.2 and 1.74 fold higher in CYP2B6*6 (*1/*1) and CYP2B6*6 (*1/*6) compared CYP2B6*6 (*6/*6) carriers, while a 22% increase in F1 was observed for carriers of ABCB1 c.4046A>G variant allele. Higher mean AUC was attained in CYP2B6 *6/*6 genotypes compared to CYP2B6 *1/*1 (p<0.0001). Simulation based AUCs for 600 mg doses were 1.25 and 2.10 times the product label mean AUC for the Ugandan population in general and CYP2B6*6/*6 genotypes respectively. Simulated exposures for EFV daily doses of 300 mg and 450 mg are comparable to the product label. Viral load fell precipitously on treatment, with only six patients having HIV RNA >40 copies/mL after 84 days of treatment. No trend with exposure was noted for these six patients.

Conclusion

Results of this study suggest that daily doses of 450 mg and 300 mg might meet the EFV treatment needs of HIV-1 infected Ugandans in general and individuals homozygous for CYP2B6*6 mutation, respectively.