Absolute binding free energy calculations of CBClip host-guest systems in the SAMPL5 blind challenge

Lee, Juyong,Tofoleanu, Florentina,Pickard IV, Frank C.,Kö,nig, Gerhard,Huang, Jing,Damjanović,, Ana,Baek, Minkyung,Seok, Chaok,Brooks, Bernard R. Springer-Verlag 2017 Journal of computer-aided molecular design Vol.31 No.1

<P>Herein, we report the absolute binding free energy calculations of CBClip complexes in the SAMPL5 blind challenge. Initial conformations of CBClip complexes were obtained using docking and molecular dynamics simulations. Free energy calculations were performed using thermodynamic integration (TI) with soft-core potentials and Bennett's acceptance ratio (BAR) method based on a serial insertion scheme. We compared the results obtained with TI simulations with soft-core potentials and Hamiltonian replica exchange simulations with the serial insertion method combined with the BAR method. The results show that the difference between the two methods can be mainly attributed to the van der Waals free energies, suggesting that either the simulations used for TI or the simulations used for BAR, or both are not fully converged and the two sets of simulations may have sampled difference phase space regions. The penalty scores of force field parameters of the 10 guest molecules provided by CHARMM Generalized Force Field can be an indicator of the accuracy of binding free energy calculations. Among our submissions, the combination of docking and TI performed best, which yielded the root mean square deviation of 2.94 kcal/mol and an average unsigned error of 3.41 kcal/mol for the ten guest molecules. These values were best overall among all participants. However, our submissions had little correlation with experiments.</P>

Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events

Wong, Vanessa K,Baker, Stephen,Pickard, Derek J,Parkhill, Julian,Page, Andrew J,Feasey, Nicholas A,Kingsley, Robert A,Thomson, Nicholas R,Keane, Jacqueline A,Weill, Franç,ois-Xavier,Edwards, Dav Nature Pub. Co 2015 Nature genetics Vol.47 No.6

The emergence of multidrug-resistant (MDR) typhoid is a major global health threat affecting many countries where the disease is endemic. Here whole-genome sequence analysis of 1,832 Salmonella enterica serovar Typhi (S. Typhi) identifies a single dominant MDR lineage, H58, that has emerged and spread throughout Asia and Africa over the last 30 years. Our analysis identifies numerous transmissions of H58, including multiple transfers from Asia to Africa and an ongoing, unrecognized MDR epidemic within Africa itself. Notably, our analysis indicates that H58 lineages are displacing antibiotic-sensitive isolates, transforming the global population structure of this pathogen. H58 isolates can harbor a complex MDR element residing either on transmissible IncHI1 plasmids or within multiple chromosomal integration sites. We also identify new mutations that define the H58 lineage. This phylogeographical analysis provides a framework to facilitate global management of MDR typhoid and is applicable to similar MDR lineages emerging in other bacterial species.

Molecular Surveillance Identifies Multiple Transmissions of Typhoid in West Africa

Wong, Vanessa K.,Holt, Kathryn E.,Okoro, Chinyere,Baker, Stephen,Pickard, Derek J.,Marks, Florian,Page, Andrew J.,Olanipekun, Grace,Munir, Huda,Alter, Roxanne,Fey, Paul D.,Feasey, Nicholas A.,Weill, F Public Library of Science 2016 PLoS neglected tropical diseases Vol.10 No.9

<▼1><P><B>Background</B></P><P>The burden of typhoid in sub-Saharan African (SSA) countries has been difficult to estimate, in part, due to suboptimal laboratory diagnostics. However, surveillance blood cultures at two sites in Nigeria have identified typhoid associated with <I>Salmonella enterica</I> serovar Typhi (<I>S</I>. Typhi) as an important cause of bacteremia in children.</P><P><B>Methods</B></P><P>A total of 128 <I>S</I>. Typhi isolates from these studies in Nigeria were whole-genome sequenced, and the resulting data was used to place these Nigerian isolates into a worldwide context based on their phylogeny and carriage of molecular determinants of antibiotic resistance.</P><P><B>Results</B></P><P>Several distinct <I>S</I>. Typhi genotypes were identified in Nigeria that were related to other clusters of <I>S</I>. Typhi isolates from north, west and central regions of Africa. The rapidly expanding <I>S</I>. Typhi clade 4.3.1 (H58) previously associated with multiple antimicrobial resistances in Asia and in east, central and southern Africa, was not detected in this study. However, antimicrobial resistance was common amongst the Nigerian isolates and was associated with several plasmids, including the IncHI1 plasmid commonly associated with <I>S</I>. Typhi.</P><P><B>Conclusions</B></P><P>These data indicate that typhoid in Nigeria was established through multiple independent introductions into the country, with evidence of regional spread. MDR typhoid appears to be evolving independently of the haplotype H58 found in other typhoid endemic countries. This study highlights an urgent need for routine surveillance to monitor the epidemiology of typhoid and evolution of antimicrobial resistance within the bacterial population as a means to facilitate public health interventions to reduce the substantial morbidity and mortality of typhoid.</P></▼1><▼2><P><B>Author Summary</B></P><P>Typhoid fever, a serious bloodstream infection caused by the bacterium <I>Salmonella</I> Typhi, is a major cause of disease and death around the world. There have been limited data on the epidemiology of typhoid in many countries in sub-Saharan African, including Nigeria. Recent evidence, however, showed that typhoid was an important cause of bacteraemia in children residing in two regions of Nigeria. Here, we analyzed the whole genome sequences of 128 <I>S</I>. Typhi isolates from two studies in order to elucidate the population structure and characterize the genetic components of antimicrobial resistance. We found that the multiple <I>S</I>. Typhi genotypes identified were closely related to other <I>S</I>. Typhi from neighboring regions of Africa and that multidrug resistance (MDR) was common among these isolates, and in many cases was associated with the IncHI1 plasmid known to cause MDR typhoid. These results provide evidence that typhoid was established in Nigeria as a result of several independent introductions into the country and that there has been extensive exchange of <I>S</I>. Typhi in and around the region of West Africa. This study emphasizes the importance of surveillance to improve our understanding of the epidemiology of typhoid, which is needed to underpin public health measures to reduce the spread of disease and facilitate patient management.</P></▼2>

Forisome based biomimetic smart materials

Shen, Amy Q.,Hamlington, B.D.,Knoblauch, Michael,Peters, Winfried S.,Pickard, William F. Techno-Press 2006 Smart Structures and Systems, An International Jou Vol.2 No.3

With the discovery in plants of the proteinaceous forisome crystalloid (Knoblauch, et al. 2003), a novel, non-living, ATP-independent biological material became available to the designer of smart materials for advanced actuating and sensing. The in vitro studies of Knoblauch, et al. show that forisomes (2-4 micron wide and 10-40 micron long) can be repeatedly stimulated to contract and expand anisotropically by shifting either the ambient pH or the ambient calcium ion concentration. Because of their unique abilities to develop and reverse strains greater than 20% in time periods less than one second, forisomes have the potential to outperform current smart materials as advanced, biomimetic, multi-functional, smart sensors or actuators. Probing forisome material properties is an immediate need to lay the foundation for synthesizing forisomebased smart materials for health monitoring of structural integrity in civil infrastructure and for aerospace hardware. Microfluidics is a growing, vibrant technology with increasingly diverse applications. Here, we use microfluidics to study the surface interaction between forisome and substrate and the conformational dynamics of forisomes within a confined geometry to lay the foundation for forisome-based smart materials synthesis in controlled and repeatable environment.

Forisome based biomimetic smart materials

B.D. Hamlington,Winfried S. Peters,Amy Q. Shen,Michael Knoblauch,William F. Pickard 국제구조공학회 2006 Smart Structures and Systems, An International Jou Vol.2 No.3

With the discovery in plants of the proteinaceous forisome crystalloid (Knoblauch, et al. 2003), a novel, non-living, ATP-independent biological material became available to the designer of smart materials for advanced actuating and sensing. The in vitro studies of Knoblauch, et al. show that forisomes (2-4 micron wide and 10-40 micron long) can be repeatedly stimulated to contract and expand anisotropically by shifting either the ambient pH or the ambient calcium ion concentration. Because of their unique abilities to develop and reverse strains greater than 20% in time periods less than one second, forisomes have the potential to outperform current smart materials as advanced, biomimetic, multi-functional, smart sensors or actuators. Probing forisome material properties is an immediate need to lay the foundation for synthesizing forisome-based smart materials for health monitoring of structural integrity in civil infrastructure and for aerospace hardware. Microfluidics is a growing, vibrant technology with increasingly diverse applications. Here, we use microfluidics to study the surface interaction between forisome and substrate and the conformational dynamics of forisomes within a confined geometry to lay the foundation for forisome-based smart materials synthesis in controlled and repeatable environment.

Cerebral critical closing pressure in hydrocephalus patients undertaking infusion tests.

Varsos, Georgios V,Czosnyka, Marek,Smielewski, Peter,Garnett, Matthew R,Liu, Xiuyun,Kim, Dong-Joo,Donnelly, Joseph,Adams, Hadie,Pickard, John D,Czosnyka, Zofia Butterworths [etc.] 2015 Neurological research Vol.37 No.8

<P>Links between cerebrospinal fluid (CSF) compensation and cerebral blood flow (CBF) have been studied in many clinical scenarios. In hydrocephalus, disturbed CSF circulation seems to be a primary problem, having been linked to CBF disturbances, particularly in white matter close to surface of dilated ventricles. We studied possible correlations between cerebral haemodynamic indices using transcranial Doppler (TCD) ultrasonography and CSF compensatory dynamics assessed during infusion tests.</P>