Architecture and Conservation of the Bacterial DNA Replication Machinery, an Underexploited Drug Target

New antibiotics with novel modes of action are required to combat the growing threat posed by multi-drug resistant bacteria. Over the last decade, genome sequencing and other high-throughput techniques have provided tremendous insight into the molecular processes underlying cellular functions in a wide range of bacterial species. We can now use these data to assess the degree of conservation of certain aspects of bacterial physiology, to help choose the best cellular targets for development of new broad-spectrum antibacterials

Architecture and conservation of the bacterial DNA replication machinery, an underexploited drug target

New antibiotics with novel modes of action are required to combat the growing threat posed by multi-drug resistant bacteria. Over the last decade, genome sequencing and other high-throughput techniques have provided tremendous insight into the molecular processes underlying cellular functions in a wide range of bacterial species. We can now use these data to assess the degree of conservation of certain aspects of bacterial physiology, to help choose the best cellular targets for development of new broad-spectrum antibacterials. DNA replication is a conserved and essential process, and the large number of proteins that interact to replicate DNA in bacteria are distinct from those in eukaryotes and archaea; yet none of the antibiotics in current clinical use acts directly on the replication machinery. Bacterial DNA synthesis thus appears to be an underexploited drug target. However, before this system can be targeted for drug design, it is important to understand which parts are conserved and which are not, as this will have implications for the spectrum of activity of any new inhibitors against bacterial species, as well as the potential for development of drug resistance. In this review we assess similarities and differences in replication components and mechanisms across the bacteria, highlight current progress towards the discovery of novel replication inhibitors, and suggest those aspects of the replication machinery that have the greatest potential as drug targets

Empirical evaluation of selective DNA pooling to map QTL in dairy cattle using a half-sib design by comparison to individual genotyping and interval mapping

This study represents the first attempt at an empirical evaluation of the DNA pooling methodology by comparing it to individual genotyping and interval mapping to detect QTL in a dairy half-sib design. The findings indicated that the use of peak heights from the pool electropherograms without correction for stutter (shadow) product and preferential amplification performed as well as corrected estimates of frequencies. However, errors were found to decrease the power of the experiment at every stage of the pooling and analysis. The main sources of errors include technical errors from DNA quantification, pool construction, inconsistent differential amplification, and from the prevalence of sire alleles in the dams. Additionally, interval mapping using individual genotyping gains information from phenotypic differences between individuals in the same pool and from neighbouring markers, which is lost in a DNA pooling design. These errors cause some differences between the markers detected as significant by pooling and those found significant by interval mapping based on individual selective genotyping. Therefore, it is recommended that pooled genotyping only be used as part of an initial screen with significant results to be confirmed by individual genotyping. Strategies for improving the efficiency of the DNA pooling design are also presented

Evolutionary predictions for a parasite metapopulation: Modelling salmon louse resistance to pest controls in aquaculture

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Prevention not cure: a review of methods to avoid sea lice infestations in salmon 1 aquaculture

The Atlantic salmon aquaculture industry still struggles with ectoparasitic sea lice despite decades of research and development invested into louse removal methods. In contrast, methods to prevent infestations before they occur have received relatively little research effort, yet may offer key benefits over treatment‐focused methods. Here, we summarise the range of potential and existing preventative methods, conduct a meta‐analysis of studies trialling the efficacy of existing preventative methods and discuss the rationale for a shift to the prevention‐focused louse management paradigm. Barrier technologies that minimise host–parasite encounter rates provide the greatest protection against lice, with a weighted median 76% reduction in infestation density in cages with plankton mesh ‘snorkels’ or ‘skirts’, and up to a 100% reduction for fully enclosed cages. Other methods such as geographic spatiotemporal management, manipulation of swimming depth, functional feeds, repellents and host cue masking can drive smaller reductions that may be additive when used in combination with barrier technologies. Finally, ongoing development of louse‐resistant salmon lineages may lead to long‐term improvements if genetic gain is maintained, while the development of an effective vaccine remains a key target. Preventative methods emphasise host resistance traits while simultaneously reducing host–parasite encounters. Effective implementation has the potential to dramatically reduce the need for delousing and thus improve fish welfare, productivity and sustainability in louse‐prone salmon farming regions.submittedVersio

A metapopulation model reveals connectivity-driven hotspots in treatment resistance evolution in a marine parasite

In salmon aquaculture, the sustainable management of salmon lice (Lepeophtheirus salmonis) is limited by the adaptive capacity of the parasite. This is evident in the repeated evolution of pesticide resistance in the salmon louse population. To better prepare for resistance, we constructed a numerical metapopulation model that predicts the evolutionary dynamics of lice across an interconnected farm network. This model integrates within-farm population dynamics and between-farm louse dispersal, the latter using outputs from a state-of-the-art particle-tracking model. Distinct from previous metapopulation models, it also simulates spatial and temporal genetic variation arising from selection. The model was parameterized to simulate the evolution of resistance to the pesticide azamethiphos on farms in southern Norway. It successfully reproduced the rapid (within 10 years) evolution of azamethiphos resistance following extensive delousing treatments. It also identified strong spatial patterns in resistance, with regions of high farm connectivity being potential hotspots of louse adaptation. Rates of infestation and evolution were significantly reduced when highly connected farms were excluded from the simulation, compared to when low-connectivity or random sites were excluded. This model can be a valuable tool for coordinating pest management at a regional scale, in a way that slows or prevents the spread of resistance.A metapopulation model reveals connectivity-driven hotspots in treatment resistance evolution in a marine parasitepublishedVersio

A guide to assess the use of gene editing in aquaculture

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Report on Offense Grading In New Jersey

The University of Pennsylvania Criminal Law Research Group was commissioned to do a study of offense grading in New Jersey. After an examination of New Jersey criminal law and a survey of New Jersey residents, the CLRG issued this Final Report. (For the report of a similar project for Pennsylvania, see Report on Offense Grading in Pennsylvania, http://ssrn.com/abstract=1527149, and for an article about the grading project, see The Modern Irrationalities of American Criminal Codes: An Empirical Study of Offense Grading, http://ssrn.com/abstract=1539083, Journal of Criminal Law and Criminology (forthcoming 2011).) The New Jersey study found serious conflicts between the relative grading judgments of New Jersey residents and those contained in existing New Jersey criminal law, as well as instances where mandatory minimum sentences often require sentences that exceed the maximum appropriate punishment, inconsistencies among the grading of similar offenses, overly broad offenses that impose similar grades on conduct of importantly different seriousness, and a flawed grading structure that provides too few grading categories, thereby assuring pervasive problems in failing to distinguish conduct of importantly different seriousness. These systemic failures risk undermining the criminal justice system\u27s moral credibility with the community, improperly delegate the value judgments inherent in grading decisions to individual sentencing judges ad hoc, fail to give citizens notice of the relative importance of conflicting duties, and invite application of different sentencing rules to similarly situated offenders. The Report examines how these grading problems came about, how they might be fixed, and how such grading irrationalities might be avoided in the future