279 research outputs found
Molecular Interactions of Prodiginines with the BH3 Domain of Anti-Apoptotic Bcl-2 Family Members
Prodigiosin and obatoclax, members of the prodiginines family, are small molecules with anti-cancer properties that are
currently under preclinical and clinical trials. The molecular target(s) of these agents, however, is an open question.
Combining experimental and computational techniques we find that prodigiosin binds to the BH3 domain in some BCL-2
protein families, which play an important role in the apoptotic programmed cell death. In particular, our results indicate
a large affinity of prodigiosin for MCL-1, an anti-apoptotic member of the BCL-2 family. In melanoma cells, we demonstrate
that prodigiosin activates the mitochondrial apoptotic pathway by disrupting MCL-1/BAK complexes. Computer simulations
with the PELE software allow the description of the induced fit process, obtaining a detailed atomic view of the molecular
interactions. These results provide new data to understand the mechanism of action of these molecules, and assist in the
development of more specific inhibitors of anti-apoptotic BCL-2 proteins.Spanish government and the European Union (FIS-PI10/00338) and from the ERC-2009-Adg
25027-PELE European project
Minimally important difference of the Treatment Satisfaction with Medicines Questionnaire (SATMED-Q)
The Interdomain Linker of AAV-2 Rep68 Is an Integral Part of Its Oligomerization Domain: Role of a Conserved SF3 Helicase Residue in Oligomerization
The four Rep proteins of adeno-associated virus (AAV) orchestrate all aspects of its viral life cycle, including transcription regulation, DNA replication, virus assembly, and site-specific integration of the viral genome into the human chromosome 19. All Rep proteins share a central SF3 superfamily helicase domain. In other SF3 members this domain is sufficient to induce oligomerization. However, the helicase domain in AAV Rep proteins (i.e. Rep40/Rep52) as shown by its monomeric characteristic, is not able to mediate stable oligomerization. This observation led us to hypothesize the existence of an as yet undefined structural determinant that regulates Rep oligomerization. In this document, we described a detailed structural comparison between the helicase domains of AAV-2 Rep proteins and those of the other SF3 members. This analysis shows a major structural difference residing in the small oligomerization sub-domain (OD) of Rep helicase domain. In addition, secondary structure prediction of the linker connecting the helicase domain to the origin-binding domain (OBD) indicates the potential to form α-helices. We demonstrate that mutant Rep40 constructs containing different lengths of the linker are able to form dimers, and in the presence of ATP/ADP, larger oligomers. We further identified an aromatic linker residue (Y224) that is critical for oligomerization, establishing it as a conserved signature motif in SF3 helicases. Mutation of this residue critically affects oligomerization as well as completely abolishes the ability to produce infectious virus. Taken together, our data support a model where the linker residues preceding the helicase domain fold into an α-helix that becomes an integral part of the helicase domain and is critical for the oligomerization and function of Rep68/78 proteins through cooperative interaction with the OBD and helicase domains
A comprehensive safety analysis confirms rhabdomyolysis as an uncommon adverse reaction in patients treated with trabectedin
Missed opportunities for tobacco use screening and brief cessation advice in South African primary health care: a cross-sectional study
BACKGROUND: Primary health care (PHC) settings offer opportunities for tobacco use screening and brief cessation advice, but data on such activities in South Africa are limited. The aim of this study was to determine the extent to which participants were screened for and advised against tobacco use during consultations. METHODS: This cross-sectional study involved 500 participants, 18 years and older, attended by doctors or PHC nurses. Using an exit-interview questionnaire, information was obtained on participants' tobacco use status, reason(s) for seeking medical care, whether participants had been screened for and advised about their tobacco use and patients' level of comfort about being asked about and advised to quit tobacco use. Main outcome measures included patients' self-reports on having been screened and advised about tobacco use during their current clinic visit and/or any other visit within the last year. Data analysis included the use of chi-square statistics, t-tests and multiple logistic regression analysis. RESULTS: Of the 500 participants, 14.9% were current smokers and 12.1% were smokeless tobacco users. Only 12.9% of the participants were screened for tobacco use during their current visit, indicating the vast majority were not screened. Among the 134 tobacco users, 11.9% reported being advised against tobacco use during the current visit and 35.1% during any other visit within the last year. Of the participants not screened, 88% indicated they would be 'very comfortable' with being screened. A pregnancy-related clinic visit was the single most significant predictor for being screened during the current clinic visit (OR = 4.59; 95%CI = 2.13-9.88). CONCLUSION: Opportunities for tobacco use screening and brief cessation advice were largely missed by clinicians. Incorporating tobacco use status into the clinical vital signs as is done for pregnant patients during antenatal care visits in South Africa has the potential to improve tobacco use screening rates and subsequent cessation
Incidence and mortality rates of selected infection-related cancers in Puerto Rico and in the United States
<p>Abstract</p> <p>Background</p> <p>In 2002, 17.8% of the global cancer burden was attributable to infections. This study assessed the age-standardized incidence and mortality rates of stomach, liver, and cervical cancer in Puerto Rico (PR) for the period 1992-2003 and compared them to those of Hispanics (USH), non-Hispanic Whites (NHW), and non-Hispanic Blacks (NHB) in the United States (US).</p> <p>Methods</p> <p>Age-standardized rates [ASR(World)] were calculated based on cancer incidence and mortality data from the PR Cancer Central Registry and SEER, using the direct method and the world population as the standard. Annual percent changes (APC) were calculated using the Poisson regression model from 1992-2003.</p> <p>Results</p> <p>The incidence and mortality rates from stomach, liver and cervical cancer were lower in NHW than PR; with the exception of mortality from cervical cancer which was similar in both populations. Meanwhile, the incidence rates of stomach, liver and cervical cancers were similar between NHB and PR; except for NHB women who had a lower incidence rate of liver cancer than women in PR. NHB had a lower mortality from liver cancer than persons in PR, and similar mortality from stomach cancer.</p> <p>Conclusions</p> <p>The burden of liver, stomach, and cervical cancer in PR compares to that of USH and NHB and continues to be a public health priority. Public health efforts are necessary to further decrease the burden of cancers associated to infections in these groups, the largest minority population groups in the US. Future studies need to identify factors that may prevent infections with cancer-related agents in these populations. Strategies to increase the use of preventive strategies, such as vaccination and screening, among minority populations should also be developed.</p
Phylogenetic congruence and ecological coherence in terrestrial Thaumarchaeota
This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. Acknowledgements We would like to thank Dr Robert Griffith/CEH for providing DNA from soil samples and Dr Anthony Travis for his help with BioLinux. Sequencing was performed in NERC platform in Liverpool. CG-R was funded by a NERC fellowship NE/J019151/1. CQ was funded by a MRC fellowship (MR/M50161X/1) as part of the cloud infrastructure for microbial genomics consortium (MR/L015080/1).Peer reviewedPublisher PD
A diarylamine derived from anthranilic acid inhibits ZIKV replication
Zika virus (ZIKV) is a mosquito-transmitted Flavivirus, originally identified in Uganda in 1947 and recently associated with a large outbreak in South America. Despite extensive efforts there are currently no approved antiviral compounds for treatment of ZIKV infection. Here we describe the antiviral activity of diarylamines derived from anthranilic acid (FAMs) against ZIKV. A synthetic FAM (E3) demonstrated anti-ZIKV potential by reducing viral replication up to 86%. We analyzed the possible mechanisms of action of FAM E3 by evaluating the intercalation of this compound into the viral dsRNA and its interaction with the RNA polymerase of bacteriophage SP6. However, FAM E3 did not act by these mechanisms. In silico results predicted that FAM E3 might bind to the ZIKV NS3 helicase suggesting that this protein could be one possible target of this compound. To test this, the thermal stability and the ATPase activity of the ZIKV NS3 helicase domain (NS3Hel) were investigated in vitro and we demonstrated that FAM E3 could indeed bind to and stabilize NS3Hel
Coadministration of the Three Antigenic Leishmania infantum Poly (A) Binding Proteins as a DNA Vaccine Induces Protection against Leishmania major Infection in BALB/c Mice
Highly conserved intracellular proteins from Leishmania have been described as antigens in natural and experimental infected mammals. The present study aimed to evaluate the antigenicity and prophylactic properties of the Leishmania infantum Poly (A) binding proteins (LiPABPs). Three different members of the LiPABP family have been described. Recombinant tools based on these proteins were constructed: recombinant proteins and DNA vaccines. The three recombinant proteins were employed for coating ELISA plates. Sera from human and canine patients of visceral leishmaniasis and human patients of mucosal leishmaniasis recognized the three LiPABPs. In addition, the protective efficacy of a DNA vaccine based on the combination of the three Leishmania PABPs has been tested in a model of progressive murine leishmaniasis: BALB/c mice infected with Leishmania major. The induction of a Th1-like response against the LiPABP family by genetic vaccination was able to down-regulate the IL-10 predominant responses elicited by parasite LiPABPs after infection in this murine model. This modulation resulted in a partial protection against L. major infection. LiPABP vaccinated mice showed a reduction on the pathology that was accompanied by a decrease in parasite burdens, in antibody titers against Leishmania antigens and in the IL-4 and IL-10 parasite-specific mediated responses in comparison to control mice groups immunized with saline or with the non-recombinant plasmid. The results presented here demonstrate for the first time the prophylactic properties of a new family of Leishmania antigenic intracellular proteins, the LiPABPs. The redirection of the immune response elicited against the LiPABP family (from IL-10 towards IFN-γ mediated responses) by genetic vaccination was able to induce a partial protection against the development of the disease in a highly susceptible murine model of leishmaniasisThe study was supported in Spain by grants from Ministerio de Ciencia e Innovación FIS
PI11/00095 and FISPI14/00366 from the Instituto de Salud Carlos III within the Network of TropicalDiseases Research (VI P I+D+I 2008-2011, ISCIII -Subdirección General de Redes y Centros de Investigación Cooperativa (RD12/0018/0009)). This work was also supported in Brazil by a grant from CNPq (Ciencia sem Fronteiras-PVE 300174/2014-4). A CBMSO institutional grant from Fundación Ramón Areces is also acknowledged. EAFC is a grant recipient of CNPq. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip
Characterization of the major histocompatibility complex locus association with Behçet’s disease in Iran
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