Palladium(II) saccharinate complexes trans-[Pd(sac)(2)(LH)(2)] with amino- and acetylamino-pyridine co-ligands: molecular structures of trans-[PdCl2(2-ampyH)(2)].2dmf (2-ampyH=2-amino-3-methylpyridine) and trans-[Pd(kappa(2)-2-acmpy)(2)] (2-acmpyH=2-acetylamino-3-methylpyridine)

Reaction of Na2[PdCl4] with two equivalents of amino- or acetylamino-pyridines (LH) affords trans-[PdCl2-(LH)2] {LH = 2-amino-3-methylpyridine (2-ampyH), 3-aminopyridine (3-apyH), 2-acetylamino-3-methylpyridine (2-acmpyH), 3-acetylamino-pyridine (3-acpyH)}. An X-ray crystal structure of trans-[PdCl2(2-ampyH)2] shows that the 2-ampy-H ligands are coordinated in a monodentate fashion via the nitrogen atoms of the pyridine rings. Treatment of trans-[PdCl2(2-acmpyH)2] with NEt3 affords the cyclometalated complex, trans-[Pd(κ2-2-acmpy)2], the X-ray structure of which shows that the 2-acmpy ligand is coordinated to palladium in a bidentate fashion via the nitrogen atom of the pyridine ring and oxygen. Reaction of trans-[PdCl2(LH)2] with two equivalents of sodium saccharinate affords the bis(saccharinate) complexes, trans-[Pd(sac)2(LH)2], in which the saccharinate anions are coordinated via the amide nitrogen atom

Maladaptation and the paradox of robustness in evolution

Background. Organisms use a variety of mechanisms to protect themselves against perturbations. For example, repair mechanisms fix damage, feedback loops keep homeostatic systems at their setpoints, and biochemical filters distinguish signal from noise. Such buffering mechanisms are often discussed in terms of robustness, which may be measured by reduced sensitivity of performance to perturbations. Methodology/Principal Findings. I use a mathematical model to analyze the evolutionary dynamics of robustness in order to understand aspects of organismal design by natural selection. I focus on two characters: one character performs an adaptive task; the other character buffers the performance of the first character against perturbations. Increased perturbations favor enhanced buffering and robustness, which in turn decreases sensitivity and reduces the intensity of natural selection on the adaptive character. Reduced selective pressure on the adaptive character often leads to a less costly, lower performance trait. Conclusions/Significance. The paradox of robustness arises from evolutionary dynamics: enhanced robustness causes an evolutionary reduction in the adaptive performance of the target character, leading to a degree of maladaptation compared to what could be achieved by natural selection in the absence of robustness mechanisms. Over evolutionary time, buffering traits may become layered on top of each other, while the underlying adaptive traits become replaced by cheaper, lower performance components. The paradox of robustness has widespread implications for understanding organismal design

Clonal expansion during Staphylococcus aureus infection dynamics reveals the effect of antibiotic intervention

This is the final version of the article. Available from Public Library of Science via the DOI in this recordTo slow the inexorable rise of antibiotic resistance we must understand how drugs impact on pathogenesis and influence the selection of resistant clones. Staphylococcus aureus is an important human pathogen with populations of antibiotic-resistant bacteria in hospitals and the community. Host phagocytes play a crucial role in controlling S. aureus infection, which can lead to a population "bottleneck" whereby clonal expansion of a small fraction of the initial inoculum founds a systemic infection. Such population dynamics may have important consequences on the effect of antibiotic intervention. Low doses of antibiotics have been shown to affect in vitro growth and the generation of resistant mutants over the long term, however whether this has any in vivo relevance is unknown. In this work, the population dynamics of S. aureus pathogenesis were studied in vivo using antibiotic-resistant strains constructed in an isogenic background, coupled with systemic models of infection in both the mouse and zebrafish embryo. Murine experiments revealed unexpected and complex bacterial population kinetics arising from clonal expansion during infection in particular organs. We subsequently elucidated the effect of antibiotic intervention within the host using mixed inocula of resistant and sensitive bacteria. Sub-curative tetracycline doses support the preferential expansion of resistant microorganisms, importantly unrelated to effects on growth rate or de novo resistance acquisition. This novel phenomenon is generic, occurring with methicillin-resistant S. aureus (MRSA) in the presence of β-lactams and with the unrelated human pathogen Pseudomonas aeruginosa. The selection of resistant clones at low antibiotic levels can result in a rapid increase in their prevalence under conditions that would previously not be thought to favor them. Our results have key implications for the design of effective treatment regimes to limit the spread of antimicrobial resistance, where inappropriate usage leading to resistance may reduce the efficacy of life-saving drugs.This work was funded by a Wellcome Trust Project Grant (Reference Number WT089981MA), an EU project: Predicting Antibiotic Resistance (PAR, Reference Number 241476) and from the European Community's Seventh Framework Programme [FP7-PEOPLE-2011-ITN] under grant agreement no. PITN-GA-2011-289209 for the Marie-Curie Initial Training Network FishForPharma. SAR is supported by an MRC Senior Clinical Fellowship (Reference Number: G0701932). Aquarium staff were supported by MRC Centre grant G0700091

Clonal Expansion during Staphylococcus aureus Infection Dynamics Reveals the Effect of Antibiotic Intervention

To slow the inexorable rise of antibiotic resistance we must understand how drugs impact on pathogenesis and influence the selection of resistant clones. Staphylococcus aureus is an important human pathogen with populations of antibiotic-resistant bacteria in hospitals and the community. Host phagocytes play a crucial role in controlling S. aureus infection, which can lead to a population “bottleneck” whereby clonal expansion of a small fraction of the initial inoculum founds a systemic infection. Such population dynamics may have important consequences on the effect of antibiotic intervention. Low doses of antibiotics have been shown to affect in vitro growth and the generation of resistant mutants over the long term, however whether this has any in vivo relevance is unknown. In this work, the population dynamics of S. aureus pathogenesis were studied in vivo using antibiotic-resistant strains constructed in an isogenic background, coupled with systemic models of infection in both the mouse and zebrafish embryo. Murine experiments revealed unexpected and complex bacterial population kinetics arising from clonal expansion during infection in particular organs. We subsequently elucidated the effect of antibiotic intervention within the host using mixed inocula of resistant and sensitive bacteria. Sub-curative tetracycline doses support the preferential expansion of resistant microorganisms, importantly unrelated to effects on growth rate or de novo resistance acquisition. This novel phenomenon is generic, occurring with methicillin-resistant S. aureus (MRSA) in the presence of β-lactams and with the unrelated human pathogen Pseudomonas aeruginosa. The selection of resistant clones at low antibiotic levels can result in a rapid increase in their prevalence under conditions that would previously not be thought to favor them. Our results have key implications for the design of effective treatment regimes to limit the spread of antimicrobial resistance, where inappropriate usage leading to resistance may reduce the efficacy of life-saving drugs

Impacts of Co-Solvent Flushing on Microbial Populations Capable of Degrading Trichloroethylene

With increased application of co-solvent flushing technologies for removal of nonaqueous phase liquids from groundwater aquifers, concern over the effects of the solvent on native microorganisms and their ability to degrade residual contaminant has also arisen. This study assessed the impact of ethanol flushing on the numbers and activity potentials of trichloroethylene (TCE)-degrading microbial populations present in aquifer soils taken immediately after and 2 years after ethanol flushing of a former dry cleaners site. Polymerase chain reaction analysis revealed soluble methane monooxygenase genes in methanotrophic enrichments, and 16S rRNA analysis identified Methylocystis parvus with 98% similarity, further indicating the presence of a type II methanotroph. Dissimilatory sulfite reductase genes in sulfate-reducing enrichments prepared were also observed. Ethanol flushing was simulated in columns packed with uncontaminated soils from the dry cleaners site that were dosed with TCE at concentrations observed in the field; after flushing, the columns were subjected to a continuous flow of 500 pore volumes of groundwater per week. Total acridine orange direct cell counts of the flushed and nonflushed soils decreased over the 15-week testing period, but after 5 weeks, the flushed soils maintained higher cell counts than the nonflushed soils. Inhibition of methanogenesis by sulfate reduction was observed in all column soils, as was increasing removal of total methane by soils incubated under methanotrophic conditions. These results showed that impacts of ethanol were not as severe as anticipated and imply that ethanol may mitigate the toxicity of TCE to the microorganisms

Degeneracy: a link between evolvability, robustness and complexity in biological systems

A full accounting of biological robustness remains elusive; both in terms of the mechanisms by which robustness is achieved and the forces that have caused robustness to grow over evolutionary time. Although its importance to topics such as ecosystem services and resilience is well recognized, the broader relationship between robustness and evolution is only starting to be fully appreciated. A renewed interest in this relationship has been prompted by evidence that mutational robustness can play a positive role in the discovery of adaptive innovations (evolvability) and evidence of an intimate relationship between robustness and complexity in biology. This paper offers a new perspective on the mechanics of evolution and the origins of complexity, robustness, and evolvability. Here we explore the hypothesis that degeneracy, a partial overlap in the functioning of multi-functional components, plays a central role in the evolution and robustness of complex forms. In support of this hypothesis, we present evidence that degeneracy is a fundamental source of robustness, it is intimately tied to multi-scaled complexity, and it establishes conditions that are necessary for system evolvability

Patient experience of CT colonography and colonoscopy after fecal occult blood test in a national screening programme

OBJECTIVE: To investigate patient experience of CT colonography (CTC) and colonoscopy in a national screening programme. METHODS: Retrospective analysis of patient experience postal questionnaires. We included screenees from a fecal occult blood test (FOBt) based screening programme, where CTC was performed when colonoscopy was incomplete or deemed unsuitable. We analyzed questionnaire responses concerning communication of test risks, test-related discomfort and post-test pain, as well as complications. CTC and colonoscopy responses were compared using multilevel logistic regression. RESULTS: Of 67,114 subjects identified, 52,805 (79 %) responded. Understanding of test risks was lower for CTC (1712/1970 = 86.9 %) than colonoscopy (48783/50975 = 95.7 %, p < 0.0001). Overall, a slightly greater proportion of screenees found CTC unexpectedly uncomfortable (506/1970 = 25.7 %) than colonoscopy (10,705/50,975 = 21.0 %, p < 0.0001). CTC was tolerated well as a completion procedure for failed colonoscopy (unexpected discomfort; CTC = 26.3 %: colonoscopy = 57.0 %, p < 0.001). Post-procedural pain was equally common (CTC: 288/1970,14.6 %, colonoscopy: 7544/50,975,14.8 %; p = 0.55). Adverse event rates were similar in both groups (CTC: 20/2947 = 1.2 %; colonoscopy: 683/64,312 = 1.1 %), but generally less serious with CTC. CONCLUSIONS: Even though CTC was reserved for individuals either unsuitable for or unable to complete colonoscopy, we found only small differences in test-related discomfort. CTC was well tolerated as a completion procedure and was extremely safe. CTC can be delivered across a national screening programme with high patient satisfaction. KEY POINTS: • High patient satisfaction at CTC is deliverable across a national screening programme. • Patients who cannot tolerate screening colonoscopy are likely to find CTC acceptable. • CTC is extremely safe; complications are rare and almost never serious. • Patients may require more detailed information regarding the expected discomfort of CTC

Patient factors associated with non-attendance at colonoscopy after a positive screening faecal occult blood test

BACKGROUND: Screening participants with abnormal faecal occult blood test results who do not attend further testing are at high risk of colorectal cancer, yet little is known about their reasons for non-attendance. METHODS: We conducted a medical record review of 170 patients from two English Bowel Cancer Screening Programme centres who had abnormal guaiac faecal occult blood test screening tests between November 2011 and April 2013 but did not undergo colonoscopy. Using information from patient records, we coded and categorized reasons for non-attendance. RESULTS: Of the 170 patients, 82 were eligible for review, of whom 66 had at least one recorded reason for lack of colonoscopy follow-up. Reasons fell into seven main categories: (i) other commitments, (ii) unwillingness to have the test, (iii) a feeling that the faecal occult blood test result was a false positive, (iv) another health issue taking priority, (v) failing to complete bowel preparation, (vi) practical barriers (e.g. lack of transport), and (vii) having had or planning colonoscopy elsewhere. The most common single reasons were unwillingness to have a colonoscopy and being away. CONCLUSIONS: We identify a range of apparent reasons for colonoscopy non-attendance after a positive faecal occult blood test screening. Education regarding the interpretation of guaiac faecal occult blood test findings, offer of alternative confirmatory test options, and flexibility in the timing or location of subsequent testing might decrease non-attendance of diagnostic testing following positive faecal occult blood test

Evolutionary connectionism: algorithmic principles underlying the evolution of biological organisation in evo-devo, evo-eco and evolutionary transitions

The mechanisms of variation, selection and inheritance, on which evolution by natural selection depends, are not fixed over evolutionary time. Current evolutionary biology is increasingly focussed on understanding how the evolution of developmental organisations modifies the distribution of phenotypic variation, the evolution of ecological relationships modifies the selective environment, and the evolution of reproductive relationships modifies the heritability of the evolutionary unit. The major transitions in evolution, in particular, involve radical changes in developmental, ecological and reproductive organisations that instantiate variation, selection and inheritance at a higher level of biological organisation. However, current evolutionary theory is poorly equipped to describe how these organisations change over evolutionary time and especially how that results in adaptive complexes at successive scales of organisation (the key problem is that evolution is self-referential, i.e. the products of evolution change the parameters of the evolutionary process). Here we first reinterpret the central open questions in these domains from a perspective that emphasises the common underlying themes. We then synthesise the findings from a developing body of work that is building a new theoretical approach to these questions by converting well-understood theory and results from models of cognitive learning. Specifically, connectionist models of memory and learning demonstrate how simple incremental mechanisms, adjusting the relationships between individually-simple components, can produce organisations that exhibit complex system-level behaviours and improve the adaptive capabilities of the system. We use the term “evolutionary connectionism” to recognise that, by functionally equivalent processes, natural selection acting on the relationships within and between evolutionary entities can result in organisations that produce complex system-level behaviours in evolutionary systems and modify the adaptive capabilities of natural selection over time. We review the evidence supporting the functional equivalences between the domains of learning and of evolution, and discuss the potential for this to resolve conceptual problems in our understanding of the evolution of developmental, ecological and reproductive organisations and, in particular, the major evolutionary transitions

Cardiovascular changes after administration of aerosolized salbutamol in horses: five cases

Prevention and treatment of intraoperative hypoxemia in horses is difficult and both efficacy and safety of therapeutic maneuvers have to be taken into account. Inhaled salbutamol has been suggested as treatment of hypoxia in horses during general anesthesia, due to safety and ease of the technique. The present report describes the occurrence of clinically relevant unwanted cardiovascular effects (i.e. tachycardia and blood pressure modifications) in 5 horses undergoing general anesthesia in dorsal recumbency after salbutamol inhalation. Balanced anesthesia based on inhalation of isoflurane in oxygen or oxygen and air and continuous rate infusion (CRI) of lidocaine, romifidine, or combination of lidocaine and guaifenesine and ketamine was provided. Supportive measures were necessary to restore normal cardiovascular function in all horses but no long-term adverse effects were noticed in any of the cases