Abstract basins of attraction

Abstract basins appear naturally in different areas of several complex variables. In this survey we want to describe three different topics in which they play an important role, leading to interesting open problems

Virtual screening identifies broad-spectrum \u3b2-lactamase inhibitors with activity on clinically relevant serine- and metallo-carbapenemases

Bacteria are known to evade \u3b2-lactam antibiotic action by producing \u3b2-lactamases (BLs), including carbapenemases, which are able to hydrolyze nearly all available \u3b2-lactams. The production of BLs represents one of the best known and most targeted mechanisms of resistance in bacteria. We have performed the parallel screening of commercially available compounds against a panel of clinically relevant BLs: class A CTX-M-15 and KPC-2, subclass B1 NDM-1 and VIM-2 MBLs, and the class C P. aeruginosa AmpC. The results show that all BLs prefer scaffolds having electron pair donors: KPC-2 is preferentially inhibited by sulfonamide and tetrazole-based derivatives, NDM-1 by compounds bearing a thiol, a thiosemicarbazide or thiosemicarbazone moiety, while VIM-2 by triazole-containing molecules. Few broad-spectrum BLs inhibitors were identified; among these, compound 40 potentiates imipenem activity against an NDM-1-producing E. coli clinical strain. The binary complexes of the two most promising compounds binding NDM-1 and VIM-2 were obtained at high resolution, providing strong insights to improve molecular docking simulations, especially regarding the interaction of MBLs with inhibitors

Understanding transmission and control of Cystic Echinococcosis and other taeniid infections in the Falkland Islands

Cystic echinococcosis, caused by the larval form of the cestode parasite Echinococcus granulosus, has been identified as an important public health risk in the Falkland Islands since the early 1940s. This prompted the instigation of an intensive control scheme in the mid-1960s, comprised of regular dosing of domestic dogs with the anthelmintic praziquantel and education of local people about safe disposal of potentially infected offal. This scheme has remained in place to the current day and is generally considered to be a successful programme– resulting in a reduction in the prevalence of infection in sheep has reduced from >50% in the 1950s to less than 1 % now and there has not been a case of human hydatid disease for more than 20 years. However, concerns remain that hydatid cysts are still identified in a small number of sheep at slaughter (0.004% in 2017) and occurring every year subsequently suggesting transmission is still occurring. This is also supported by the observation that sheep continue to be infected at higher levels with the (non-zoonotic) cestode Taenia hydatigena, also transmitted by dogs. In 2010, all dogs on the Falkland Islands were tested by Copro-PCR, resulting in eight dogs (1.4%) testing positive. The dog population was tested again in 2012, where there were no cases but when tested in 2014 by Coproantigen testing, six (1.04%) were positive for E. granulosus coproantigens. This project used questionnaires, coproantigen and coproPCR analysis, abattoir data surveillance, DNA sequencing, environmental sample analysis and mathematical modelling to study Echinococcus granulosus and other taeniids endemic in the Falklands and investigate how their continued transmission can occur in the face of the prolonged intensive control programme. A questionnaire survey identified possible methods of disposal of offal that in a previous study, were associated with canine coproantigen positivity. The entire dog population was analysed via coproantigen techniques in 2018, and four (0.68%) dogs were coproantigen positive, though none of these were confirmed by PCR. From 2018 to 2020, five cases of CE were identified in sheep at the Sand Bay abattoir in the Falklands (0.01%), with one of the cases coming from a positive farm in 2018. There were two cases from farms with positive dogs in 2010 and one from a farm with a positive dog in 2014. To investigate environmental contamination on farms and potentially identify historical dog infections, soil samples taken from kennel sites were analysed for the presence of coproantigens, with five farms having positive results, one farm matching with a positive dog in 2018. To identify key processes fuelling the transmission of E. granulosus in the Falklands, a mechanically informed compartmental model was created, estimating the basic reproduction number (R0) for the parasite, and identifying scenarios where this estimate increased above one suggesting continued transmission could occur. Seven scenarios where lapses in control measures could result in the R0 estimate increasing above one and continued transmission of E. granulosus could occur. The results of this project show clear evidence of dogs still being involved in the transmission of taeniid parasites in the Falklands, with key areas of the eradication programme such as the inadequate disposal of offal and dogs gaining access to offal allowing the transmission cycle to be completed and transmission of E. granulosus and other taeniids to occur. Rectifying these lapses in control measures and focussing control and surveillance to a more localised control approach will help strengthen the control programme and move the Falklands closer towards the complete eradication of Cystic Echinococcosis

Determinants and consequences of international migration

This chapter provides a simple overview of the canonical model of international migration, discusses the consequences of migration on both sending and receiving countries and draws some considerations on future research prospects for the international migration literature

Regulation of neuraminidase expression in Streptococcus pneumoniae

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2180/12/200 Extent: 12p.BackgroundSialic acid (N-acetylneuraminic acid; NeuNAc) is one of the most important carbohydrates for Streptococcus pneumoniae due of its role as a carbon and energy source, receptor for adhesion and invasion and molecular signal for promotion of biofilm formation, nasopharyngeal carriage and invasion of the lung.ResultsIn this work, NeuNAc and its metabolic derivative N-acetyl mannosamine (ManNAc) were used to analyze regulatory mechanisms of the neuraminidase locus expression. Genomic and metabolic comparison to Streptococcus mitis, Streptococcus oralis, Streptococcus gordonii and Streptococcus sanguinis elucidates the metabolic association of the two amino sugars to different parts of the locus coding for the two main pneumococcal neuraminidases and confirms the substrate specificity of the respective ABC transporters. Quantitative gene expression analysis shows repression of the locus by glucose and induction of all predicted transcriptional units by ManNAc and NeuNAc, each inducing with higher efficiency the operon encoding for the transporter with higher specificity for the respective amino sugar. Cytofluorimetric analysis demonstrated enhanced surface exposure of NanA on pneumococci grown in NeuNAc and ManNAc and an activity assay allowed to quantify approximately twelve times as much neuraminidase activity on induced cells as opposed to glucose grown cells.ConclusionsThe present data increase the understanding of metabolic regulation of the nanAB locus and indicate that experiments aimed at the elucidation of the relevance of neuraminidases in pneumococcal virulence should possibly not be carried out on bacteria grown in glucose containing media.Luciana Gualdi, Jasvinder Kaur Hayre, Alice Gerlini, Alessandro Bidossi, Leonarda Colomba, Claudia Trappetti, Gianni Pozzi, Jean-Denis Docquier, Peter Andrew, Susanna Ricci and Marco R Oggion

Spectroscopic and Mechanistic Studies of Heterodimetallic Forms of Metallo-β-lactamase NDM-1

In an effort to characterize the roles of each metal ion in metallo-β-lactamase NDM-1, heterodimetallic analogues (CoCo-, ZnCo-, and CoCd-) of the enzyme were generated and characterized. UV–vis, 1H NMR, EPR, and EXAFS spectroscopies were used to confirm the fidelity of the metal substitutions, including the presence of a homogeneous, heterodimetallic cluster, with a single-atom bridge. This marks the first preparation of a metallo-β-lactamase selectively substituted with a paramagnetic metal ion, Co(II), either in the Zn1 (CoCd-NDM-1) or in the Zn2 site (ZnCo-NDM-1), as well as both (CoCo-NDM-1). We then used these metal-substituted forms of the enzyme to probe the reaction mechanism, using steady-state and stopped-flow kinetics, stopped-flow fluorescence, and rapid-freeze-quench EPR. Both metal sites show significant effects on the kinetic constants, and both paramagnetic variants (CoCd- and ZnCo-NDM-1) showed significant structural changes on reaction with substrate. These changes are discussed in terms of a minimal kinetic mechanism that incorporates all of the data

Kinetic characterization of GES-22 beta-lactamase harboring the M169L clinical mutation

The class A p-lactamase GES-22 has been identified in Acinetobacter baumannii isolates in Turkey, and subsequently shown to differ from GES-11 by a single substitution (M169L). Because M169 is part of the omega loop, a structure that is known to have major effects on substrate selectivity in class A beta-lactamases, we expressed, purified and kinetically characterized this novel variant. Our results show that compared with GES-11(6xHis), GES-22(6xHis) displays more efficient hydrolysis of penicillins, and aztreonam, but a loss of efficiency against ceftazidime. In addition, the M169L substitution confers on GES-22 more efficient hydrolysis of the mechanistic inhibitors clavulanic acid and sulbactam. These effects are highly similar to other mutations at the homologous position in other class A beta-lactamases, suggesting that this methionine has a key structural role in aligning active site residues and in substrate selectivity across the class.Recep Tayyip Erdogan University:BAP-2013.102.03.12 Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK): TUBITAK-113Z054 United States Department of Health & Human Services National Institutes of Health (NIH) - USA 1R15AI082416 Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) 2214-

The RIP140 Gene Is a Transcriptional Target of E2F1

RIP140 is a transcriptional coregulator involved in energy homeostasis and ovulation which is controlled at the transcriptional level by several nuclear receptors. We demonstrate here that RIP140 is a novel target gene of the E2F1 transcription factor. Bioinformatics analysis, gel shift assay, and chromatin immunoprecipitation demonstrate that the RIP140 promoter contains bona fide E2F response elements. In transiently transfected MCF-7 breast cancer cells, the RIP140 promoter is transactivated by overexpression of E2F1/DP1. Interestingly, RIP140 mRNA is finely regulated during cell cycle progression (5-fold increase at the G1/S and G2/M transitions). The positive regulation by E2F1 requires sequences located in the proximal region of the promoter (−73/+167), involves Sp1 transcription factors, and undergoes a negative feedback control by RIP140. Finally, we show that E2F1 participates in the induction of RIP140 expression during adipocyte differentiation. Altogether, this work identifies the RIP140 gene as a new transcriptional target of E2F1 which may explain some of the effect of E2F1 in both cancer and metabolic diseases

Selection of massive bone allografts using shape-matching 3-dimensional registration

Background and purpose Massive bone allografts are used when surgery causes large segmental defects. Shape-matching is the primary criterion for selection of an allograft. The current selection method, based on 2-dimensional template comparison, is inefficient for 3-dimensional complex bones. We have analyzed a 3-dimensional (3-D) registration method to match the anatomy of the allograft with that of the recipient