73 research outputs found
Design, synthesis, and evaluation of peptide-imidazo[1,2-a]pyrazine bioconjugates as potential bivalent inhibitors of the VirB11 ATPase HP0525
Helicobacter pylori (H. pylori) infections have been implicated in the development of gastric ulcers and various cancers: however, the success of current therapies is compromised by rising antibiotic resistance. The virulence and pathogenicity of H. pylori is mediated by the type IV secretion system (T4SS), a multiprotein macromolecular nanomachine that transfers toxic bacterial factors and plasmid DNA between bacterial cells, thus contributing to the spread of antibiotic resistance. A key component of the T4SS is the VirB11 ATPase HP0525, which is a hexameric protein assembly. We have previously reported the design and synthesis of a series of novel 8-amino imidazo[1,2-a]pyrazine derivatives as inhibitors of HP0525. In order to improve their selectivity, and potentially develop these compounds as tools for probing the assembly of the HP0525 hexamer, we have explored the design and synthesis of potential bivalent inhibitors. We used the structural details of the subunit-subunit interactions within the HP0525 hexamer to design peptide recognition moieties of the subunit interface. Different methods (cross metathesis, click chemistry, and cysteine-malemide) for bioconjugation to selected 8-amino imidazo[1,2-a]pyrazines were explored, as well as peptides spanning larger or smaller regions of the interface. The IC50 values of the resulting linker-8-amino imidazo[1,2-a]pyrazine derivatives, and the bivalent inhibitors, were related to docking studies with the HP0525 crystal structure and to molecular dynamics simulations of the peptide recognition moieties
Glecaprevir-Pibrentasvir for 8 or 12 Weeks in HCV Genotype 1 or 3 Infection
The trials (NCT02604017, NCT02640157) were funded by AbbVie Inc
Mechanism of adsorption of actives onto microporous functionalised calcium carbonate (FCC)
Microporous âfunctionalisedâ calcium carbonate (FCC) has potential for use as a carrier for the controlled release of âactivesâ, by permeation and diffusion. We have investigated the nature of the FCC surface and the mechanism of adsorption of two typical actives, namely the anti-inflammatory drug aspirin and the flavour compound vanillin, from chloroform and aqueous ethanolic solutions. There is indirect evidence from the quantitative perturbation of TĂłth isotherms that their adsorption is hindered by a stagnant diffusion layer of water trapped in the micro-porosity of the FCC. To complement previous studies of the surface of FCC, it was also tested with the cationic probe benzyltrimethylammonium bromide and the anionic probe sodium 2-naphthalenesulphonate. Experimental procedures were validated by comparison with adsorption onto ground calcium carbonate and high surface area talc
Toll-like receptor 9 partially regulates lung inflammation induced following exposure to chicken barn air
Understanding consistencies and gaps between desired forest futures: An analysis of visions from stakeholder groups in Sweden
Gene Ontology Consortium: going forward
The Gene Ontology (GO; http://www.geneontology.org) is a community-based bioinformatics resource that supplies information about gene product function using ontologies to represent biological knowledge. Here we describe improvements and expansions to several branches of the ontology, as well as updates that have allowed us to more efficiently disseminate the GO and capture feedback from the research community. The Gene Ontology Consortium (GOC) has expanded areas of the ontology such as cilia-related terms, cell-cycle terms and multicellular organism processes. We have also implemented new tools for generating ontology terms based on a set of logical rules making use of templates, and we have made efforts to increase our use of logical definitions. The GOC has a new and improved web site summarizing new developments and documentation, serving as a portal to GO data. Users can perform GO enrichment analysis, and search the GO for terms, annotations to gene products, and associated metadata across multiple species using the all-new AmiGO 2 browser. We encourage and welcome the input of the research community in all biological areas in our continued effort to improve the Gene Ontology
Long-term safety and efficacy of tenofovir disoproxil fumarate substitution for hepatitis B immunoglobulin following liver transplantation
Background and Aims: Limitations to the use of long-term Hepatitis B Immunoglobulin (HBIg) following liver transplantation for hepatitis B (HBV) have led to the substitution of HBIg with oral nucleo(s)tide analogue prophylaxis. We prospectively assessed the long-term safety and efficacy of switching to tenofovir disoproxil fumarate (TDF) from HBIg. Methods: An open-label, multicenter switch study was conducted to evaluate the substitution of TDF for HBIg whilst continuing lamivudine (LAM) therapy in preventing the recurrence of HBV in patients who had been maintained as hepatitis B surface antigen (HBsAg)-negative posttransplantation for at least 12âmonths. Results: Eighteen patients were enrolled (median age 66âyears, range 42-78 years); 84% were male, and 78% on calcineurin inhibitors. Median time after transplantation was 14âyears (range 5-19), and median duration of HBIg/LAM prior to the switch was 10 years (range 1-14). Median follow-up was 5 years (range 5-8). Of 18 patients, 16 (89%) remained HBsAg and HBV DNA negative at the end of follow-up. Two patients had re-emergence of HBsAg without a detectable HBV DNA and no clinical sequelae. Creatinine clearance significantly reduced (median 59âmL/min to 51âmL/min, P = 0.03), necessitating dose reduction of TDF in six (33%) participants, with two eventually ceasing TDF. One patient switched back to HBIg by choice. All patients who changed therapy maintained an undetectable HBsAg. Conclusion: Substitution of HBIg with TDF in patients on LAM is well tolerated and effective for the long-term prevention of HBV recurrence posttransplantation. Renal dysfunction occurs frequently in the posttransplant setting and can require dose adjustment of TDF or change of therapy
Olfactory and taste dysfunction among mild-to-moderate symptomatic COVID-19 positive healthcare workers: an international survey
OBJECTIVE: To determine the prevalence of olfactory and taste dysfunction (OD; TD) among COVIDâ19 positive health care workers (HCWs), their associated risk factors and prognosis.
METHODS:
Between May and June 2020, a longitudinal multicenter study was conducted on symptomatic COVIDâ19 PCR confirmed HCWs (COVIDâ19 positive) in London and Padua.
RESULTS:
Hundred and fourteen COVIDâ19 positive HCWs were surveyed with a response rate of 70.6% over a median followâup period of 52âdays. UK prevalence of OD and TD was 73.1% and 69.2%, respectively. There was a male to female ratio of 1:3 with 81.6% being white, 43.7% being nurses/health care assistants (HCAs), and 39.3% being doctors. In addition, 53.2% of them worked on COVIDâ19 wards. Complete recovery was reported in 31.8% for OD and 47.1% for TD with a 52âdays followâup. The job role of doctors and nurses negatively influenced smell (P =â.04 and P =â.02) and taste recovery (P =â.02 and P =â.01). Ethnicity (being white) showed to positively influence only taste recovery (P =â.04). Sex (being female) negatively influenced OD and TD recovery only in Paduan HCWs (P =â.02 and P =â.011, respectively). Working on a COVIDâ19 ward did not influence prognosis.
CONCLUSIONS: The prevalence of OD and TD was considerably higher in HCWs. The prognosis for OD and TD recovery was worse for nurses/HCAs and doctors but working on a COVIDâ19 ward did not influence prognosis. Sixtyâeight percent of surveyed HCWs at 52âdays continued to experience OD or TD requiring additional future medical management capacity.
LEVEL OF EVIDENCE:
4
Ritonavir-boosted danoprevir-based regimens in treatment-naive and prior null responders with HCV genotype 1 or 4 and compensated cirrhosis
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