Embracing Mystery: Radiation Risks and Popular Science Writing in the Early Cold War.

Narrative form is crucial to the understanding of science in popular culture. This is particularly true with subjects such as radiation, in which the technical details at hand are often remote from everyday experience-as well as contested or uncertain among experts. This article examines the narrative choices made by three popular texts that publicized radiation risks to the public during the Cold War: John Hersey's Hiroshima, David Bradley's No Place to Hide, and Ralph Lapp's The Voyage of the Lucky Dragon. It contends that each author borrowed from well-established literary genres and that this borrowing was crucial to coherence and effective messaging of the argument. At the same time, placing the arguments in such a familiar form served to blunt some of the radical potential in those same messages.

Structure-based design of guanosine analogue inhibitors targeting GTP cyclohydrolase IB towards a new class of antibiotics.

GTP cyclohydrolase (GCYH-I) is an enzyme in the folate biosynthesis pathway that has not been previously exploited as an antibiotic target, although several pathogens including N. gonorrhoeae use a form of the enzyme GCYH-IB that is structurally distinct from the human homologue GCYH-IA. A comparison of the crystal structures of GCYH-IA and -IB with the nM inhibitor 8-oxo-GTP bound shows that the active site of GCYH-IB is larger and differently shaped. Based on this structural information, we designed and synthesized a small set of 8-oxo-G derivatives with ether linkages at O6 and O8 expected to displace water molecules from the expanded active site of GCYH-IB. The most potent of these compounds, G3, is selective for GCYH-IB, supporting the premise that potent and selective inhibitors of GCYH-IB could constitute a new class of small molecule antibiotics.

Discovery of cyclic guanidine-linked sulfonamides as inhibitors of LMTK3 kinase.

Lemur tyrosine kinase 3 (LMTK3) is oncogenic in various cancers. In breast cancer, LMTK3 phosphorylates and modulates the activity of estrogen receptor-α (ERα) and is essential for the growth of ER-positive cells. LMTK3 is highly expressed in ER-negative breast cancer cells, where it promotes invasion via integrin ß1. LMTK3 abundance and/or high nuclear expression have been linked to shorter disease free and overall survival time in a variety of cancers, supporting LMTK3 as a potential target for anticancer drug development. We sought to identify small molecule inhibitors of LMTK3 with the ultimate goal to pharmacologically validate this kinase as a novel target in cancer. We used a homogeneous time resolve fluorescence (HTRF) assay to screen a collection of mixture-based combinatorial chemical libraries containing over 18 million compounds. We identified several cyclic guanidine-linked sulfonamides with sub-micromolar activity and evaluated their binding mode using a 3D homology model of the LMTK3 KD.

Whole-genome analysis reveals the evolution and transmission of an MDR DH/NAP11/106 Clostridium difficile clone in a paediatric hospital.

Background: Clostridium difficile strain DH/NAP11/106, a relatively antibiotic-susceptible strain, is now the most common cause of C. difficile infection (CDI) among adults in the USA. Objectives: To identify mechanisms underlying the evolution and transmission of an MDR DH/NAP11/106 clone. Methods: WGS (Illumina MiSeq), restriction endonuclease analysis (REA) and antibiotic susceptibility testing were performed on 134 C. difficile isolates collected from paediatric patients with CDI over a 2 year period. Results: Thirty-one of 134 (23%) isolates were REA group DH. Pairwise single-nucleotide variant (SNV) analyses identified a DH clone causing seven instances of CDI in two patients. During the 337 days between the first and second CDI, Patient 1 (P1) received 313 days of antibiotic therapy. Clindamycin and rifaximin resistance, and reduced vancomycin susceptibility (MIC 0.5-2 mg/L), were newly identified in the relapsed isolate. This MDR clone was transmitted to Patient 2 (P2) while P1 and P2 received care in adjacent private rooms. P1 and P2 each developed two additional CDI relapses. Comparative genomics analyses demonstrated SNVs in multiple antibiotic resistance genes, including rpoB (rifaximin resistance), gyrB and a gene encoding PBP; gyrB and PBP mutations did not consistently confer a resistance phenotype. The clone also acquired a 46 000 bp genomic element, likely a conjugative plasmid, which contained ermB (clindamycin resistance). The element shared 99% identity with the genomic sequence of Faecalibacterium prausnitzii, an enteric commensal. Conclusions: These data highlight the emergence of MDR in C. difficile strain DH/NAP11/106 through multiple independent mechanisms probably as a consequence of profound antibiotic pressure.

Why we write (nuclear) history.

Nuclear history always compels. Scholars (and readers) can immerse themselves in the existential threat posed by the atomic bomb and its successor weapons, the tantalizing prospect of carbon-free energy, or the study of a natural phenomenon deeply at odds with our everyday experience of the world. There is thus always something profound at stake when we write nuclear history - be it physical, economic or intellectual. And while it may seem that the end of the Cold War should have diminished the academic attention accorded to the subject, it actually just allowed the historiography to evolve. To the wealth of technical and political studies that once dominated nuclear history, we can now add a host of excellent cultural, environmental, literary and transnational studies. Those of us who entered the field shortly after the break-up of the Soviet Union have been able to follow these developments first-hand, from the initial uncertainty of where nuclear history would go without its original raison d'être to seeing the possibilities opened up in a post-Cold War world. The books under review here provide important and timely additions to this historiography. Luis A. Campos's Radium and the Secret Life provides a rigorous and compelling account of the uses of radium in early twentieth-century biology; Timothy J. Jorgensen's Strange Glow: The Story of Radiation offers an accessible and illuminating analysis of the benefits and risks of radiation. The books also make for a fascinating juxtaposition. They complement each other well, but also contain some intriguing differences that allow us to reflect on the nature of nuclear history in the early twenty-first century.

Fluoroquinolone and Macrolide Exposure Predict Clostridium difficile Infection with the Highly Fluoroquinolone- and Macrolide-Resistant Epidemic C. difficile Strain BI/NAP1/027.

Antibiotics have been shown to influence the risk of infection with specific Clostridium difficile strains as well as the risk of C. difficile infection (CDI). We performed a retrospective case-control study of patients infected with the epidemic BI/NAP1/027 strain in a U.S. hospital following recognition of increased CDI severity and culture of stools positive by C. difficile toxin immunoassay. Between 2005 and 2007, 72% (103/143) of patients with first-episode CDIs were infected with the BI strain by restriction endonuclease analysis (REA) typing. Most patients received multiple antibiotics within 6 weeks of CDI onset (median of 3 antibiotic classes). By multivariate analysis, fluoroquinolone and macrolide exposure was more frequent among BI cases than among non-BI-infected controls (odds ratio [OR] for fluoroquinolones, 3.2; 95% confidence interval [CI], 1.3 to 7.5; (P < 0.001; OR for macrolides, 5.2; 95% CI, 1.1 to 24.0; P = 0.04)). In contrast, clindamycin use was less frequent among the BI cases than among the controls (OR, 0.1; 95% CI, 0.03 to 0.4; P = 0.001). High-level resistance to moxifloxacin and azithromycin was more frequent among BI strains (moxifloxacin, 49/102 [48%] BI versus 0/40 non-BI, P = 0.0001; azithromycin, 100/102 [98%] BI versus 22/40 [55%] non-BI, P = 0.0001). High-level resistance to clindamycin was more frequent among non-BI strains (22/40 [55%] non-BI versus 7/102 [7%] BI, P = 0.0001). Fluoroquinolone use, macrolide use, and C. difficile resistance to these antibiotic classes were associated with infection by the epidemic BI strain of C. difficile in a U.S. hospital during a time when CDI rates were increasing nationally due to the highly fluoroquinolone-resistant BI/NAP1/027 strain.

Differences in the Molecular Epidemiology and Antibiotic Susceptibility of Clostridium difficile Isolates in Pediatric and Adult Patients.

The rising incidence of Clostridium difficile infections (CDIs) in adults is partly related to the global spread of fluoroquinolone-resistant strains, namely, BI/NAP1/027. Although CDIs are also increasingly diagnosed in children, BI/NAP1/027 is relatively uncommon in children. Little is known about the antibiotic susceptibility of pediatric CDI isolates. C. difficile was cultured from tcdB-positive stools collected from children diagnosed with CDI between December 2012 and December 2013 at an academic children's hospital. CDI isolates were grouped by restriction endonuclease analysis (REA). MICs were measured by agar dilution method for 7 antibiotics. Susceptibility breakpoints were based on guidelines from CLSI and/or the European Committee on Antimicrobial Susceptibility Testing (EUCAST). MICs and REA groupings of C. difficile isolates from 74 adult patients (29 isolates underwent REA) from a temporally and geographically similar adult cohort were compared to those of pediatric isolates. Among 122 pediatric and 74 adult isolates, respectively, the rates of resistance were as follows: metronidazole, 0% and 0%; vancomycin, 0% and 8% (P = 0.003); rifaximin, 1.6% and 6.7% (P = 0.11); clindamycin, 18.9% and 25.3% (P = 0.29); and moxifloxacin, 2.5% and 36% (P = <0.0001). Only 1 of 122 (0.8%) BI/NAP1/027 isolates was identified among the children, compared to 9 of 29 (31%) isolates identified among the adults (P = <0.0001). The 3 moxifloxacin-resistant pediatric isolates were of REA groups BI and CF and a nonspecific group. The 2 rifaximin-resistant pediatric isolates were of REA groups DH and Y. The 21 clindamycin-resistant pediatric isolates were distributed among 9 REA groups (groups A, CF, DH, G, L, M, and Y and 2 unique nonspecific REA groups). These data suggest that a diverse array of relatively antibiotic-susceptible C. difficile strains predominate in a cohort of children with CDI compared to adults.

Emergence and evolution of an international cluster of MDR Bacteroides fragilis isolates.

OBJECTIVES: The aim of this study was to examine the antibiotic resistance profiles, antibiotic resistance mechanisms and possible 'clonal' nature of some MDR Bacteroides fragilis strains that simultaneously harboured cfiA, nimB, IS1186 and IS4351. METHODS: Antibiotic susceptibilities were determined by Etests and antibiotic resistance genes and different genetic elements were detected by applying PCR methods. The environments of the cfiA and nimB genes were also determined by sequencing. The transferability of the cfiA, nimB and tet(Q) genes was tested by conjugation. The genetic relatedness of the test strains was tested by ERIC-PCR or PFGE. The complete genome sequences of two strains (B. fragilis BF8 and O:21) were determined by next-generation sequencing. RESULTS: Most of the seven B. fragilis strains tested displayed multidrug resistance phenotypes; five strains were resistant to at least five types of antibiotics. Besides the common genetic constitution, ERIC-PCR implied high genetic relatedness. Similarities in some of the antibiotic resistance mechanisms [carbapenems (cfiA) and metronidazole (nimB)] also confirmed their common origin, but some other resistance mechanisms {MLSB [erm(F)] and tetracycline [tet(Q)]} and PFGE typing revealed differences. In B. fragilis BF8 and O:21, erm(F) and tet(X) genes were found with IS4351 borders, thus constituting Tn4351. All the strains were tet(Q) positive and transferred this gene in conjugation experiments, but not the cfiA and nimB genes. CONCLUSIONS: An international cluster of MDR B. fragilis strains has been identified and characterized. This 'clone' may have emerged early in the evolution of division II B. fragilis strains, which was suggested by the low-complexity ERIC profiles and differences in the PFGE patterns.

Diversity of Clostridium perfringens isolates from various sources and prevalence of conjugative plasmids.

Clostridium perfringens is an important pathogen, causing food poisoning and other mild to severe infections in humans and animals. Some strains of C. perfringens contain conjugative plasmids, which may carry antimicrobial resistance and toxin genes. We studied genomic and plasmid diversity of 145 C. perfringens type A strains isolated from soils, foods, chickens, clinical samples, and domestic animals (porcine, bovine and canine), from different geographic areas in the United States between 1994 and 2006, using multiple-locus variable-number tandem repeat analysis (MLVA) and/or pulsed-field gel electrophoresis (PFGE). MLVA detected the genetic diversity in a majority of the isolates. PFGE, using SmaI and KspI, confirmed the MLVA results but also detected differences among the strains that could not be differentiated by MLVA. All of the PFGE profiles of the strains were different, except for a few of the epidemiologically related strains, which were identical. The PFGE profiles of strains isolated from the same domestic animal species were clustered more closely with each other than with other strains. However, a variety of C. perfringens strains with distinct genetic backgrounds were found among the clinical isolates. Variation was also observed in the size and number of plasmids in the strains. Primers for the internal fragment of a conjugative tcpH gene of C. perfringens plasmid pCPF4969 amplified identical size fragments from a majority of strains tested; and this gene hybridized to the various-sized plasmids of these strains. The sequences of the PCR-amplified tcpH genes from 12 strains showed diversity among the tcpH genes. Regardless of the sources of the isolates, the genetic diversity of C. perfringens extended to the plasmids carrying conjugative genes.

Changes in the antibiotic susceptibility of anaerobic bacteria from 2007-2009 to 2010-2012 based on the CLSI methodology.

Antimicrobial susceptibility testing of anaerobic isolates was conducted at four independent sites from 2010 to 2012 and compared to results from three sites during the period of 2007-2009. This data comparison shows significant changes in antimicrobial resistance in some anaerobic groups. Therefore, we continue to recommend institutions regularly perform susceptibility testing when anaerobes are cultured from pertinent sites. Annual generation of an institutional-specific antibiogram is recommended for tracking of resistance trends over time.

Exploiting Atropisomerism to Increase the Target Selectivity of Kinase Inhibitors.

Many biologically active molecules exist as rapidly interconverting atropisomeric mixtures. Whereas one atropisomer inhibits the desired target, the other can lead to off-target effects. Herein, we study atropisomerism as a possibility to improve the selectivities of kinase inhibitors through the synthesis of conformationally stable pyrrolopyrimidines. Each atropisomer was isolated by HPLC on a chiral stationary phase and subjected to inhibitor profiling across a panel of 18 tyrosine kinases. Notably different selectivity patterns between atropisomers were observed, as well as improved selectivity compared to a rapidly interconverting parent molecule. Computational docking studies then provided insights into the structure-based origins of these effects. This study is one of the first examples of the intentional preorganization of a promiscuous scaffold along an atropisomeric axis to increase target selectivity, and provides fundamental insights that may be applied to other atropisomeric target scaffolds.

Kibdelomycin is a potent and selective agent against toxigenic Clostridium difficile.

Clostridium difficile is the causative agent of C. difficile-associated diarrhea (CDAD), with increased risk in elderly populations. Kibdelomycin, a novel natural-product inhibitor of type II topoisomerase enzymes, was evaluated for activity against C. difficile and gastrointestinal anaerobic organisms. Toxigenic C. difficile isolates (n=168) from U.S. hospitals and anaerobic Gram-positive and Gram-negative organisms (n=598) from Chicago-area hospitals were tested. Kibdelomycin showed potent activity against toxigenic C. difficile (MIC90=0.25 µg/ml) and most Gram-positive aerobic organisms but had little activity against Bacteroides species (MIC50>32 µg/ml; n=270). Potent anti-C. difficile activity was also observed in the hamster model of C. difficile colitis. Dosing at 1.6 mg/kg (twice-daily oral dose) resulted in protection from a lethal infection and a 2-log reduction in C. difficile cecal counts. A 6.25-mg/kg twice-daily oral dose completely eliminated detectable C. difficile counts in cecal contents. A single 6.25-mg/kg oral dose showed that cecal contents were exposed to the drug at >2 µM (eightfold higher than the MIC), with no significant plasma exposure. These findings support further exploration of kibdelomycin for development of an anti-C. difficile agent.

Real-time sonographically guided percutaneous dilatational tracheostomy using a long-axis approach compared to the landmark technique.

OBJECTIVES: Sonographic evaluation of neck anatomy before performing percutaneous dilatational tracheostomy (PDT) has been shown to predict PDT success. In this study, we compared the real-time, long-axis, in-plane approach to the traditional bronchoscopically guided landmark technique. METHODS: Data were analyzed from a prospectively maintained PDT database at a university tertiary care medical intensive care unit. A convenience sample of adult patients requiring PDT for prolonged mechanical ventilation dependence was enrolled. Critical care fellows, under direct supervision of an attending intensivist, performed all PDTs. Tracheostomy performance from the sonographically guided and landmark techniques was compared. RESULTS: Twenty-three patients were enrolled: 11 in the sonography group and 12 in the landmark group. Initial midline introducer needle puncture was achieved in 72.7% in the sonography group compared to 8.3% in the landmark group (P< .001). The mean number of introducer needle punctures ± SD was significantly lower in the sonography group compared to the landmark group (1.4 ± 0.7 versus 2.6 ± 0.9; P < .001). The total tracheostomy time was 11.4 ± 4.2 minutes in the sonography group versus 15.3 ± 6.8 minutes in the landmark group (P = .12). Sonography accurately predicted tracheal ring space insertion in 90.9% of patients. Procedural complications did not differ significantly between the groups. CONCLUSIONS: Percutaneous dilatational tracheostomy under real-time sonographic guidance using a long-axis approach may increase the rate of midline punctures and decrease the number of needle punctures when compared to the landmark technique. Sonographic guidance can also help guide accurate and efficient placement of a tracheostomy tube into the desired tracheal ring space.

Modeling the evolution of drug resistance in malaria.

Plasmodium falciparum, the causal agent of malaria, continues to evolve resistance to frontline therapeutics such as chloroquine and sulfadoxine-pyrimethamine. Here we study the amino acid replacements in dihydrofolate reductase (DHFR) that confer resistance to pyrimethamine while still binding the natural DHFR substrate, 7,8-dihydrofolate, and cofactor, NADPH. The chain of amino acid replacements that has led to resistance can be inferred in a computer, leading to a broader understanding of the coevolution between the drug and target. This in silico approach suggests that only a small set of specific active site replacements in the proper order could have led to the resistant strains in the wild today. A similar approach can be used on any target of interest to anticipate likely pathways of future resistance for more effective drug development.

Transcranial direct current stimulation facilitates decision making in a probabilistic guessing task.

In a random sequence of binary events where one alternative occurs more often than the other, humans tend to guess which of the two alternatives will occur next by trying to match the frequencies of previous occurrences. Based on split-brain and unilaterally damaged patients' performances, it has been proposed that the left hemisphere (LH) tends to match the frequencies, while the right hemisphere (RH) tends toward maximizing and always choosing the most frequent alternative. The current study used transcranial direct current stimulation (tDCS) to test this hemispheric asymmetry hypothesis by stimulating the dorsolateral prefrontal cortex of each hemisphere and simultaneously inhibiting the corresponding region in the homotopic hemisphere, while participants were engaged in a probabilistic guessing task. Results showed no difference in strategy between the three groups (RH anodal/LH cathodal, LH anodal/RH cathodal, no stimulation) as participants predominantly matched the frequencies of the two alternatives. However, when anodal tDCS was applied to the LH and cathodal tDCS applied to the RH, participants became quicker to select the most frequent alternative. This finding is in line with previous evidence on the involvement of the LH in probabilistic learning and reasoning and adds to a number of demonstrations of anodal tDCS leading to some behavioral enhancement or change in bias.

Structural-based analysis of dihydrofolate reductase evolution.

The evolution of dihydrofolate reductase (DHFR) was studied through a comprehensive structural-based analysis. An amino acid sequence alignment was generated from a superposition of experimentally determined X-ray crystal structures of wild-type (wt) DHFR from the Protein Data Bank (PDB). Using this structure-based alignment of DHFR, a metric was generated for the degree of conservation at each alignment site - not only in terms of amino acid residue, but also secondary structure, and residue class. A phylogenetic tree was generated using the alignment that compared favorably with the canonical phylogeny. This structure-based alignment was used to confirm that the degree of conservation of active-site residues in terms of both sequence as well as structure was significantly greater than non-active site residues. These results can be used in helping to understand the likely future evolution of DHFR in response to novel therapies.

High conductivity transparent carbon nanotube films deposited from superacid.

Carbon nanotubes (CNTs) were deposited from a chlorosulfonic superacid solution onto PET substrates by a filtration/transfer method. The sheet resistance and transmission (at 550 nm) of the films were 60 Ω/sq and 90.9% respectively, which corresponds to a DC conductivity of 12,825 S cm(-1) and a DC/optical conductivity ratio of 64.1. This is the highest DC conductivity reported for CNT thin films to date, and attributed to both the high quality of the CNT material and the exfoliation/doping by the superacid. This work demonstrates that CNT transparent films have not reached the conductivity limit; continued improvements will enable these films to be used as the transparent electrode for applications in solid state lighting, LCD displays, touch panels, and photovoltaics.

Lessons learned from the anaerobe survey: historical perspective and review of the most recent data (2005-2007).

BACKGROUND: The rationale and lessons learned through the evolution of the National Survey for the Susceptibility of Bacteroides fragilis Group from its initiation in 1981 through 2007 are reviewed here. The survey was conceived in 1980 to track emerging antimicrobial resistance in Bacteroides species. METHODS: Data from the last 11 years of the survey (1997-2007), including 6574 isolates from 13 medical centers, were analyzed for in vitro antimicrobial resistance to both frequently used and newly developed anti-anaerobic agents. The minimum inhibitory concentrations of the antibiotics were determined using agar dilution in accordance with Clinical and Laboratory Standards Institute recommendations. RESULTS: The analyses revealed that the carbapenems (imipenem, meropenem, ertapenem, and doripenem) and piperacillin-tazobactam were the most active agents against these pathogens, with resistance rates of 0.9%-2.3%. In the most recent 3 years of the survey (2005-2007), resistance to some agents was shown to depend on the species, such as ampicillin-sulbactam against Bacteroides distasonis (20.6%) and tigecycline against Bacteroides uniformis and Bacteroides eggerthii ( approximately 7%). Very high resistance rates (>50%) were noted for moxifloxacin and trovafloxacin, particularly against Bacteroides vulgatus. During that period of study, non-B. fragilis Bacteroides species had >40% resistance to clindamycin. Metronidazole-resistant Bacteroides strains were also first reported during that period. CONCLUSIONS: In summary, resistance to antibiotics was greater among non-B. fragilis Bacteroides species than among B. fragilis and was especially greater among species with a low frequency of isolation, such as Bacteroides caccae and B. uniformis. The emergence of resistance among the non-B. fragilis Bacteroides species underscores the need for speciation of B. fragilis group isolates and for clinicians to be aware of associations between species and drug resistance.

Phenotypic and genotypic characterization of tetracycline and minocycline resistance in Clostridium perfringens.

The aim of this study was to determine the incidence of tetracycline resistance and the prevalence of tetracycline-resistance genes in strains of Clostridium perfringens isolated from different sources between 1994 and 2005. Susceptibility to tetracycline and minocycline in strains from humans (35 isolates), chickens (15 isolates), food (21 isolates), soil (16 isolates) and veterinary sources (6 isolates) was determined, and tetracycline-resistance genes were detected. Resistance was most common in strains isolated from chickens, followed by those from soils, clinical samples and foods. The most highly resistant strains were found among clinical and food isolates. tetA(P) was the most common resistance gene, and along with tetB(P) was found in all resistant strains and some sensitive strains. One tetracycline-resistant food isolate had an intact tet(M) gene. However, PCR fragments of 0.4 or 0.8 kb with high degrees of identity to parts of the tet(M) sequences of other bacteria were found, mainly in clinical isolates, and often in isolates with tetB(P). No correlation between level of sensitivity to tetracycline or minocycline and the presence of tetA(P), tetB(P) or part of tet(M) was found. The presence of part of tet(M) in some strains of C. perfringens containing tetB(P) may have occurred by recent gene transfer.