Computational study of the hydrodefluorination of fluoroarenes at [Ru(NHC)(PR₃)<sub style="vertical-align: sub;">2</sub>(CO)(H)<sub style="vertical-align: sub;">2</sub>]: predicted scope and regioselectivities

Density functional theory calculations have been employed to investigate the scope and selectivity of the hydrodefluorination (HDF) of fluoroarenes, C6F6-nHn (n = 0-5), at catalysts of the type [Ru(NHC)(PR3)(2)(CO)(H)(2)]. Based on our previous study (Angew. Chem., Int. Ed., 2011, 50, 2783) two mechanisms featuring the nucleophilic attack of a hydride ligand at a fluoroarene substrate were considered: (i) a concerted process with Ru-H/C-F exchange occurring in one step; and (ii) a stepwise pathway in which the rate-determining transition state involves formation of HF and a Ru-sigma-fluoroaryl complex. The nature of the metal coordination environment and, in particular, the NHC ligand was found to play an important role in both promoting the HDF reaction and determining the regioselectivity of this process. Thus for the reaction of C6F5H, the full experimental system (NHC = IMes, R = Ph) promotes HDF through (i) more facile initial PR3/fluoroarene substitution and (ii) the ability of the NHC N-aryl substituents to stabilise the key C-F bond breaking transition state through F center dot center dot center dot HC interactions. This latter effect is maximised along the lower energy stepwise pathway when an ortho-H substituent is present and this accounts for the ortho-selectivity seen in the reaction of C6F5H to give 1,2,3,4-C6F4H2. Computed C-F bond dissociation energies (BDEs) for C6F6-nHn substrates show a general increase with larger n and are most sensitive to the number of ortho-F substituents present. However, HDF is always computed to remain significantly exothermic when a silane such as Me3SiH is included as terminal reductant. Computed barriers to HDF also generally increase with greater n, and for the concerted pathway a good correlation between C-F BDE and barrier height is seen. The two mechanisms were found to have complementary regioselectivities. For the concerted pathway the reaction is directed to sites with two ortho-F substituents, as these have the weakest C-F bonds. In contrast, reaction along the stepwise pathway is directed to sites with only one ortho-F substituent, due to difficulties in accommodating ortho-F substituents in the C-F bond cleavage transition state. Calculations predict that 1,2,3,5-C6F4H2 and 1,2,3,4-C6F4H2 are viable candidates for HDF at [Ru(IMes)(PPh3)(2)(CO)(H)(2)] and that this would proceed selectively to give 1,2,4-C6F3H3 and 1,2,3-C6F3H3, respectively.</p

Deconvolving mutational patterns of poliovirus outbreaks reveals its intrinsic fitness landscape.

Vaccination has essentially eradicated poliovirus. Yet, its mutation rate is higher than that of viruses like HIV, for which no effective vaccine exists. To investigate this, we infer a fitness model for the poliovirus viral protein 1 (vp1), which successfully predicts in vitro fitness measurements. This is achieved by first developing a probabilistic model for the prevalence of vp1 sequences that enables us to isolate and remove data that are subject to strong vaccine-derived biases. The intrinsic fitness constraints derived for vp1, a capsid protein subject to antibody responses, are compared with those of analogous HIV proteins. We find that vp1 evolution is subject to tighter constraints, limiting its ability to evade vaccine-induced immune responses. Our analysis also indicates that circulating poliovirus strains in unimmunized populations serve as a reservoir that can seed outbreaks in spatio-temporally localized sub-optimally immunized populations

Bacteriology in Veterinary Practice

In the past undergraduates in veterinary medicine were not able to envisage any practical use for their laboratory training in bacteriology. When a practitioner required a cultural examination it was necessary to submit the specimen to an established laboratory and three or more days would elapse before a reply was received. There has been a marked change in this approach to bacteriology within the last few years and it is the purpose of this presentatioll to explain how bacteriological methods can be used in a clinical practice

Electric-field noise from carbon-adatom diffusion on a Au(110) surface: first-principles calculations and experiments

The decoherence of trapped-ion quantum gates due to heating of their motional modes is a fundamental science and engineering problem. This heating is attributed to electric-field noise arising from the trap-electrode surfaces. In this work, we investigate the source of this noise by focusing on the diffusion of carbon-containing adsorbates on the surface of Au(110). We show by density functional theory, based on detailed scanning probe microscopy, how the carbon adatom diffusion on the gold surface changes the energy landscape, and how the adatom dipole moment varies with the diffusive motion. A simple model for the diffusion noise, which varies quadratically with the variation of the dipole moment, qualitatively reproduces the measured noise spectrum, and the estimate of the noise spectral density is in accord with measured values.Comment: 8 pages, 6 figure

Suicide and accidental death in Australia’s rural farming communities: a review of the literature

Introduction: Australia's farmers constitute a heterogeneous group within the rural population. This literature review incorporates four broad areas: an understanding of farming communities, families and individuals and the contexts in which they live and work; an exploration of the challenges to morbidity and mortality that these communities face; a description of the patterns of suicide and accidental death in farming communities; and an outline of what is missing from the current body of research. Recommendations will be made on how these gaps may be addressed. Methods: In developing this comprehensive literature review, a snowballing and saturation approach was adopted. Initial search terms included suicid*, farm*, accident*, fatal*, death, sudden death, rural OR remote, Australia and NOT Australia. Databases searched included SCOPUS, PubMed, Proquest and SafetyLit; research from 1995 onwards was examined for relevance. Earlier seminal texts were also included. Reference lists of retrieved articles were searched and citations explored for further relevant research material. The primary focus was on Australian peer-reviewed research with supplementary grey literature. International material was used as examples. Results: The literature variously describes farmers as members of both rural farming communities and farming families, and as individuals within an occupational classification. Within each of these classifications, there is evidence of the cumulative impact of a multiplicity of social, geographical and psychological factors relating to work, living and social arrangements that impact the health and wellbeing of Australia's farmers and their families, particularly accidental death and suicide. Research consistently demonstrates traumatic death to be at a greater rate than in the general Australian population, with reductions found more recently in some modes of farming-related accidental death. Patterns of accidental death and suicide are commonly linked to the changing shape of contemporary farming. Suicide rates are also frequently described in relation to lethality and accessibility of means. The limitations of suicide and accidental death data are considerable. Conclusion: While there is consistent reporting of heightened levels of risk for suicide and accidental death in farming communities the limitations of the research remain significant. There are substantial gaps in current knowledge, and the body of research to date lacks clarity, inclusiveness and contextual specificity. Absent from the literature is any investigation of the impact of these frequently preventable deaths on the families and communities in which they occur. Recommendations for future research are suggested

Design-of-experiments in vitro transcription yield optimization of self-amplifying RNA

Self-amplifying RNA (saRNA) vaccines are able to induce a higher antigen-specific immune response with a more cost-effective and rapid production process compared to plasmid DNA vaccines. saRNAs are synthesized through in vitro transcription (IVT) however; this process has mainly been optimized for relatively short mRNAs. Here, we optimized the IVT process for long saRNAs, approximately 9.4 kb through a design of experiment (DoE) approach to produce a maximal RNA yield and validated the optimal IVT method on various sizes of RNA. We found that magnesium has the highest impact on RNA yield with acetate ions enabling a higher yield than chloride ions. In addition, the interaction between magnesium and nucleoside triphosphates (NTPs) is highly essential for IVT. Further addition of sodium acetate (NaOAc) during IVT provided no added benefit in RNA yield. Moreover, pyrophosphatase was not essential for productive IVT. The optimal IVT method can be used to synthesize different lengths of RNA. These findings emphasize the ability to synthesize high quality and quantity of saRNA through IVT and that the optimal amount of each component is essential for their interactions to produce a high RNA yield

Design-of-experiments in vitro transcription yield optimization of self-amplifying RNA

Self-amplifying RNA (saRNA) vaccines are able to induce a higher antigen-specific immune response with a more cost-effective and rapid production process compared to plasmid DNA vaccines. saRNAs are synthesized through in vitro transcription (IVT) however; this process has mainly been optimized for relatively short mRNAs. Here, we optimized the IVT process for long saRNAs, approximately 9.4 kb through a design of experiment (DoE) approach to produce a maximal RNA yield and validated the optimal IVT method on various sizes of RNA. We found that magnesium has the highest impact on RNA yield with acetate ions enabling a higher yield than chloride ions. In addition, the interaction between magnesium and nucleoside triphosphates (NTPs) is highly essential for IVT. Further addition of sodium acetate (NaOAc) during IVT provided no added benefit in RNA yield. Moreover, pyrophosphatase was not essential for productive IVT. The optimal IVT method can be used to synthesize different lengths of RNA. These findings emphasize the ability to synthesize high quality and quantity of saRNA through IVT and that the optimal amount of each component is essential for their interactions to produce a high RNA yield

Considerations for the consumption of vitamin and mineral supplements in athlete populations

Vitamins and minerals are of fundamental importance to numerous human functions that are essential to optimise athlete performance. Athletes incur a high turnover of key vitamins and minerals and are therefore dependent on sufficient energy intake to replenish nutrient stores. However, many athletes are poor at servicing their energy replenishment needs, especially female athletes, and although a ‘food first approach’ to meeting nutrient requirements is the primary goal, it may be important for some athletes to consider a vitamin and/or mineral supplement to meet their daily needs. When working to determine if an athlete requires vitamin or mineral supplements, practitioners should use a robust framework to assess the overall energy requirements, current dietary practices and the biological and clinical status of their athletes. Of note, any supplementation plan should account for the various factors that may impact the efficacy of the approach (e.g. athlete sex, the nutrient recommended dietary intake, supplement dose/timing, co-consumption of other foods and any food–drug interactions). Importantly, there are numerous vitamins and minerals of key importance to athletes, each having specific relevance to certain situations (e.g. iron and B vitamins are significant contributors to haematological adaptation, calcium and vitamin D are important to bone health and folate is important in the female athlete); therefore, the appropriate supplement for a given situation should be carefully considered and consumed with the goal to augment an athlete’s diet

Comparative RNAi Screens in C. elegans and C. briggsae Reveal the Impact of Developmental System Drift on Gene Function

Although two related species may have extremely similar phenotypes, the genetic networks underpinning this conserved biology may have diverged substantially since they last shared a common ancestor. This is termed Developmental System Drift (DSD) and reflects the plasticity of genetic networks. One consequence of DSD is that some orthologous genes will have evolved different in vivo functions in two such phenotypically similar, related species and will therefore have different loss of function phenotypes. Here we report an RNAi screen in C. elegans and C. briggsae to identify such cases. We screened 1333 genes in both species and identified 91 orthologues that have different RNAi phenotypes. Intriguingly, we find that recently evolved genes of unknown function have the fastest evolving in vivo functions and, in several cases, we identify the molecular events driving these changes. We thus find that DSD has a major impact on the evolution of gene function and we anticipate that the C. briggsae RNAi library reported here will drive future studies on comparative functional genomics screens in these nematodes