The application of self-limiting transgenic insects in managing resistance in experimental metapopulations

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.Data sharing: raw data for this study are available as supplementary data files.1. The mass release of transgenic insects carrying female lethal self-limiting genes can reduce pest insect populations. Theoretically, substantial releases can be a novel resistance management tool, since wild type alleles conferring susceptibility to pesticides can dilute resistance alleles in target populations. A potential barrier to the deployment of this technology is the need for large-scale area wide releases. Here we address whether localized releases of transgenic insects could provide an alternative, means of population suppression and resistance management, without serious loss of efficacy. 2. We used experimental mesocosms constituting insect metapopulations to explore the evolution of resistance to the Bacillus thuringiensis toxin Cry1Ac in a high-dose/refugia landscape in the insect Plutella xylostella. We ran two selection experiments, the first compared the efficacy of ‘everywhere’ releases and negative controls to a spatially density-dependent or ‘whack-a-mole’ strategy that concentrated release of transgenic insects in sub-populations with high levels of resistance. The second experiment tested the relative efficacy of whack-a-mole and everywhere releases under spatially homogenous and heterogeneous selection pressure. 3. The whack-a-mole releases were less effective than everywhere releases in terms of slowing the evolution of resistance, which in the first experiment, largely prevented the evolution of resistance. In contrast to predictions, heterogeneous whack-a-mole releases were not more effective under heterogeneous selection pressure. Heterogeneous selection pressure did, however, reduce total insect population sizes 4. Whack-a-mole releases provided early population suppression that was indistinguishable from homogeneous everywhere releases. However, insect population densities tracked the evolution of resistance in this system, as phenotypic resistance provides access to the 90% of experimental diet containing the toxin Cry1Ac. Thus, as resistance levels diverged between treatments, carrying capacities diverged and population sizes increased under the whack- a-mole approach. Synthesis and Applications Spatially density-dependent releases of transgenic insects, particularly those targeting source populations at landscape level, could suppress pest populations in the absence of blanket area-wide management. The resistance management benefits of self-limiting transgenic insects are, however, reduced in spatially localized releases, suggesting that they are not best suited for spatially restricted ‘spot’ treatment of problematic resistance. Nevertheless, area-wide and spatially heterogeneous releases could be used to support other resistance management interventions.This work was supported by the Biotechnology and Biological Sciences Research Council [grant numbers BB/L00948X/1 to MBB and NA, and BB/L00819X/1&2 to BR]

Aseptic Rearing and Infection with Gut Bacteria Improve the Fitness of Transgenic Diamondback Moth, Plutella xylostella

This is the final version. Available on open access from MDPI via the DOI in this recordMass insect rearing can have a range of applications, for example in biological control of pests. The competitive fitness of released insects is extremely important in a number of applications. Here, we investigated how to improve the fitness of a transgenic diamondback moth, which has shown variation in mating ability when reared in different insectaries. Specifically we tested whether infection with a gut bacteria, Enterobacter cloacae, and aseptic rearing of larvae could improve insect growth and male performance. All larvae were readily infected with E. cloacae. Under aseptic rearing, pupal weights were reduced and there was a marginal reduction in larval survival. However, aseptic rearing substantially improved the fitness of transgenic males. In addition, under aseptic rearing, inoculation with E. cloacae increased pupal weights and male fitness, increasing the proportion of transgenic progeny from 20% to 30% relative to uninfected insects. Aseptic conditions may improve the fitness of transgenic males by excluding microbial contaminants, while symbiont inoculation could further improve fitness by providing additional protection against infection, or by normalizing insect physiology. The simple innovation of incorporating antibiotic into diet, and inoculating insects with symbiotic bacteria that are resistant to that antibiotic, could provide a readily transferable tool for other insect rearing systemsBiotechnology and Biological Sciences Research Council (BBSRC

Effects of acute fatigue on the volitional and magnetically-evoked electromechanical delay of the knee flexors in males and females

Neuromuscular performance capabilities, including those measured by evoked responses, may be adversely affected by fatigue; however, the capability of the neuromuscular system to initiate muscle force rapidly under these circumstances is yet to be established. Sex-differences in the acute responses of neuromuscular performance to exercise stress may be linked to evidence that females are much more vulnerable to ACL injury than males. Optimal functioning of the knee flexors is paramount to the dynamic stabilisation of the knee joint, therefore the aim of this investigation was to examine the effects of acute maximal intensity fatiguing exercise on the voluntary and magnetically-evoked electromechanical delay in the knee flexors of males and females. Knee flexor volitional and magnetically-evoked neuromuscular performance was assessed in seven male and nine females prior to and immediately after: (i) an intervention condition comprising a fatigue trial of 30-seconds maximal static exercise of the knee flexors, (ii) a control condition consisting of no exercise. The results showed that the fatigue intervention was associated with a substantive reduction in volitional peak force (PFV) that was greater in males compared to females (15.0%, 10.2%, respectively, p < 0.01) and impairment to volitional electromechanical delay (EMDV) in females exclusively (19.3%, p < 0.05). Similar improvements in magnetically-evoked electromechanical delay in males and females following fatigue (21%, p < 0.001), however, may suggest a vital facilitatory mechanism to overcome the effects of impaired voluntary capabilities, and a faster neuromuscular response that can be deployed during critical times to protect the joint system

Eukaryotic Initiation Factor 4E (eIF4E) and angiogenesis: prognostic markers for breast cancer

BACKGROUND: The overexpression of eukaryotic translation initiation factor 4E (eIF4E), a key regulator of protein synthesis, is involved in the malignant progression of human breast cancer. This study investigates the relationship between eIF4E and angiogenesis, as well as their prognostic impact in patients with human breast cancer. METHODS: Immunohistochemical staining was used to determine protein expression of eIF4E, vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and CD105 in a set of 122 formalin-fixed, paraffin-embedded primary breast cancer tissues. Expression of eIF4E in positive cells was characterized by cytoplasmic staining. Evaluation of VEGF and IL-8 in the same tissue established the angiogenic profiles, while CD105 was used as an indicator of microvessel density (MVD). RESULTS: A significant relationship was found between the level of eIF4E expression and histological grade (P = 0.016). VEGF, IL-8, and MVD were closely related to tumor grade (P = 0.003, P = 0.022, and P < 0.001, respectively) and clinical stage (P = 0.007, P = 0.048, and P < 0.001, respectively). Expression of eIF4E was also significantly correlated with VEGF (P = 0.007), IL-8 (P = 0.007), and MVD (P = 0.006). Patients overexpressing eIF4E had significantly worse overall (P = 0.01) and disease-free survival (P = 0.006). When eIF4E, histological grade, tumor stage, ER, PR, Her-2 status and the levels of VEGF, IL-8, MVD were included in a multivariate Cox regression analysis, eIF4E emerged as an independent prognostic factor for breast cancer (P = 0.001), along with stage (P = 0.005), node status (P = 0.046), and MVD (P = 0.004). CONCLUSION: These results suggest that higher eIF4E expression correlates with both angiogenesis and vascular invasion of cancer cells, and could therefore serve as a useful histological predictor for less favorable outcome in breast cancer patients, as well as represent a potential therapeutic target

Reconstructing the three-dimensional GABAergic microcircuit of the striatum

A system's wiring constrains its dynamics, yet modelling of neural structures often overlooks the specific networks formed by their neurons. We developed an approach for constructing anatomically realistic networks and reconstructed the GABAergic microcircuit formed by the medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) of the adult rat striatum. We grew dendrite and axon models for these neurons and extracted probabilities for the presence of these neurites as a function of distance from the soma. From these, we found the probabilities of intersection between the neurites of two neurons given their inter-somatic distance, and used these to construct three-dimensional striatal networks. The MSN dendrite models predicted that half of all dendritic spines are within 100 mu m of the soma. The constructed networks predict distributions of gap junctions between FSI dendrites, synaptic contacts between MSNs, and synaptic inputs from FSIs to MSNs that are consistent with current estimates. The models predict that to achieve this, FSIs should be at most 1% of the striatal population. They also show that the striatum is sparsely connected: FSI-MSN and MSN-MSN contacts respectively form 7% and 1.7% of all possible connections. The models predict two striking network properties: the dominant GABAergic input to a MSN arises from neurons with somas at the edge of its dendritic field; and FSIs are interconnected on two different spatial scales: locally by gap junctions and distally by synapses. We show that both properties influence striatal dynamics: the most potent inhibition of a MSN arises from a region of striatum at the edge of its dendritic field; and the combination of local gap junction and distal synaptic networks between FSIs sets a robust input-output regime for the MSN population. Our models thus intimately link striatal micro-anatomy to its dynamics, providing a biologically grounded platform for further study

A risk prediction model for the assessment and triage of women with hypertensive disorders of pregnancy in low-resourced settings: the miniPIERS (Pre-eclampsia Integrated Estimate of RiSk) multi-country prospective cohort study.

BACKGROUND: Pre-eclampsia/eclampsia are leading causes of maternal mortality and morbidity, particularly in low- and middle- income countries (LMICs). We developed the miniPIERS risk prediction model to provide a simple, evidence-based tool to identify pregnant women in LMICs at increased risk of death or major hypertensive-related complications. METHODS AND FINDINGS: From 1 July 2008 to 31 March 2012, in five LMICs, data were collected prospectively on 2,081 women with any hypertensive disorder of pregnancy admitted to a participating centre. Candidate predictors collected within 24 hours of admission were entered into a step-wise backward elimination logistic regression model to predict a composite adverse maternal outcome within 48 hours of admission. Model internal validation was accomplished by bootstrapping and external validation was completed using data from 1,300 women in the Pre-eclampsia Integrated Estimate of RiSk (fullPIERS) dataset. Predictive performance was assessed for calibration, discrimination, and stratification capacity. The final miniPIERS model included: parity (nulliparous versus multiparous); gestational age on admission; headache/visual disturbances; chest pain/dyspnoea; vaginal bleeding with abdominal pain; systolic blood pressure; and dipstick proteinuria. The miniPIERS model was well-calibrated and had an area under the receiver operating characteristic curve (AUC ROC) of 0.768 (95% CI 0.735-0.801) with an average optimism of 0.037. External validation AUC ROC was 0.713 (95% CI 0.658-0.768). A predicted probability ≥25% to define a positive test classified women with 85.5% accuracy. Limitations of this study include the composite outcome and the broad inclusion criteria of any hypertensive disorder of pregnancy. This broad approach was used to optimize model generalizability. CONCLUSIONS: The miniPIERS model shows reasonable ability to identify women at increased risk of adverse maternal outcomes associated with the hypertensive disorders of pregnancy. It could be used in LMICs to identify women who would benefit most from interventions such as magnesium sulphate, antihypertensives, or transportation to a higher level of care

Tailoring the corrosion and tribological performance of Ti-modified MoS2-based films in simulated seawater

Film protection has become a crucial means to improve the corrosion and wear performance of key components in aggressive environment. In this study, the feasibility of using MoS2-based modified films in artificial seawater (3.5% NaCl solution) was evaluated by co-deposition of Ti to produce Ti-MoS2 composite and Ti/MoS2 multilayer films. The microstructure, wettability, mechanical, tribological and corrosion behavior of the Ti-modified MoS2-based films was contrasted to pure MoS2 film. The results show that the incorporation of Ti not only improves densification, but also promotes a transformation from a columnar to an amorphous film structure, leading to the improvement of mechanical properties of Ti-MoS2 composite film and Ti/MoS2 multilayer film. The friction coefficient curves of all of the three MoS2-based film in 3.5 wt% NaCl solution show stable values during the sliding process. The advantage of the preferential (002) growth orientation, improved mechanical properties and reduced hydrophobicity for both of the Ti-modified MoS2 films caused the decreased friction coefficient and wear rate in NaCl solution. The electrochemical results before and after friction show that the ranking of corrosion resistance is Ti/MoS2 multilayer > Ti-MoS2 composite film > pure MoS2 film, which is attributed to the compact microstructure and the presence of surface passive films

Structure of the TPR Domain of AIP: Lack of Client Protein Interaction with the C-Terminal alpha-7 Helix of the TPR Domain of AIP Is Sufficient for Pituitary Adenoma Predisposition

PMCID: PMC3534021This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited