Causes and consequences of female mate choice in Drosophila melanogaster: A hemiclonal analysis

One of Darwin’s greatest questions, the reason why females prefer elaborate sexually selected male traits and displays, was elucidated by the Fisherian coevolution of male traits and female preferences. While variation in male attractiveness and ornamentation has received much attention, there has been little attempt to evaluate the causes and consequences of intraspecific variation in components of female preference. Furthermore, demonstrating a genetic basis to female preference does not answer the question of how within-population genetic variation is maintained. Understanding the sources of variation in potential mating interactions between males and females is important because this variation determines the strength and the direction that evolution via sexual selection will proceed. Using cytogenetic cloning techniques developed for Drosophila melanogaster – an important model species for sexual selection and sexual conflict research – I examined not only the contribution of genetic variation from in each sex to observed phenotypic variation in biologically important traits such as mating speed, copulation duration, and subsequent offspring production, but also quantified the magnitude of intersexual genetic correlations (Chapter 2). By decomposing the genetic components of interacting phenotypes in mating behaviours between the sexes, we identified possible mechanisms maintaining genetic variation (i.e. sexual conflict) due to the presence of a negative genetic correlation between male attractiveness and female choosiness. These results may provide a framework to improve theoretical models of sexual selection and to provide a more cohesive understanding of the coevolutionary dynamics between male attractiveness and female choosiness for future empirical studies. Even traits that have a strong genetic basis can be profoundly influenced by environmental conditions, such that the same genotype may yield quantitatively or qualitatively different phenotypes in different environments. While Chapter 2 confirmed genetic variation for female responsiveness, whether or not components of female preference, mainly choosiness, varied with individual condition had yet to be determined. In Chapter 3 I experimentally manipulated female condition by varying the larval density for hemiclonal females (the same lines from Chapter 2) to determine if a genotype-by-environment (GxE) existed for female choosiness. The absence of a GxE interaction for female choosiness suggests that this component of female preference may not be condition dependent. Since GxE interactions may be potentially important to sexual selection, especially if both sexually selected male traits and female preferences are subject to GxEs (and genetic correlations between the two are central to many models of sexual selection), more empirical work on the condition-dependence of female choosiness is needed to strengthen predictions of GxEs for sexually selected traits. These results demonstrate, to the best of our knowledge, findings regarding the causes and consequences of variation in female mate choice using hemiclonal analysis. Furthermore, the importance of quantifying genetic variation in female mate choice –including how it is maintained – is necessary for theoretical models of sexual selection

The Story of Hannah Weston: and Her Part in the First Naval Engagement of the Revolution, June 12, 1775

A brief history of the area of Machias, Maine and events that led to the capture of the Margaretta in the first naval battle of the American Revolution. The text describes the efforts of Hannah and Rebecca Weston to respond to a message that more powder, lead and pewter were needed sixteen miles away in Machias

Caenorhabditis elegans dnj-14, the orthologue of the DNAJC5 gene mutated in adult onset neuronal ceroid lipofuscinosis, provides a new platform for neuroprotective drug screening and identifies a SIR-2.1-independent action of resveratrol

Adult onset neuronal lipofuscinosis (ANCL) is a human neurodegenerative disorder characterized by progressive neuronal dysfunction and premature death. Recently, the mutations that cause ANCL were mapped to the DNAJC5 gene, which encodes cysteine string protein alpha. We show here that mutating dnj-14, the Caenorhabditis elegans orthologue of DNAJC5, results in shortened lifespan and a small impairment of locomotion and neurotransmission. Mutant dnj-14 worms also exhibited age-dependent neurodegeneration of sensory neurons, which was preceded by severe progressive chemosensory defects. A focussed chemical screen revealed that resveratrol could ameliorate dnj-14 mutant phenotypes, an effect mimicked by the cAMP phosphodiesterase inhibitor, rolipram. In contrast to other worm neurodegeneration models, activation of the Sirtuin, SIR-2.1, was not required, as sir-2.1; dnj-14 double mutants showed full lifespan rescue by resveratrol. The Sirtuin-independent neuroprotective action of resveratrol revealed here suggests potential therapeutic applications for ANCL and possibly other human neurodegenerative diseases

Cost-effectiveness of external cephalic version for term breech presentation

<p>Abstract</p> <p>Background</p> <p>External cephalic version (ECV) is recommended by the American College of Obstetricians and Gynecologists to convert a breech fetus to vertex position and reduce the need for cesarean delivery. The goal of this study was to determine the incremental cost-effectiveness ratio, from society's perspective, of ECV compared to scheduled cesarean for term breech presentation.</p> <p>Methods</p> <p>A computer-based decision model (TreeAge Pro 2008, Tree Age Software, Inc.) was developed for a hypothetical base case parturient presenting with a term singleton breech fetus with no contraindications for vaginal delivery. The model incorporated actual hospital costs (e.g., $8,023 for cesarean and$5,581 for vaginal delivery), utilities to quantify health-related quality of life, and probabilities based on analysis of published literature of successful ECV trial, spontaneous reversion, mode of delivery, and need for unanticipated emergency cesarean delivery. The primary endpoint was the incremental cost-effectiveness ratio in dollars per quality-adjusted year of life gained. A threshold of $50,000 per quality-adjusted life-years (QALY) was used to determine cost-effectiveness.</p> <p>Results</p> <p>The incremental cost-effectiveness of ECV, assuming a baseline 58$7,900/QALY. If the estimated probability of successful ECV is less than 32%, then ECV costs more to society and has poorer QALYs for the patient. However, as the probability of successful ECV was between 32% and 63%, ECV cost more than cesarean delivery but with greater associated QALY such that the cost-effectiveness ratio was less than $50,000/QALY. If the probability of successful ECV was greater than 63%, the computer modeling indicated that a trial of ECV is less costly and with better QALYs than a scheduled cesarean. The cost-effectiveness of a trial of ECV is most sensitive to its probability of success, and not to the probabilities of a cesarean after ECV, spontaneous reversion to breech, successful second ECV trial, or adverse outcome from emergency cesarean.</p> <p>Conclusions</p> <p>From society's perspective, ECV trial is cost-effective when compared to a scheduled cesarean for breech presentation provided the probability of successful ECV is > 32%. Improved algorithms are needed to more precisely estimate the likelihood that a patient will have a successful ECV.</p

Sub-Sets of Cancer Stem Cells Differ Intrinsically in Their Patterns of Oxygen Metabolism

PMCID: PMC3640080This 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

Application of pharmacogenomics and bioinformatics to exemplify the utility of human <i>ex vivo</i> organoculture models in the field of precision medicine

Here we describe a collaboration between industry, the National Health Service (NHS) and academia that sought to demonstrate how early understanding of both pharmacology and genomics can improve strategies for the development of precision medicines. Diseased tissue ethically acquired from patients suffering from chronic obstructive pulmonary disease (COPD), was used to investigate inter-patient variability in drug efficacy using ex vivo organocultures of fresh lung tissue as the test system. The reduction in inflammatory cytokines in the presence of various test drugs was used as the measure of drug efficacy and the individual patient responses were then matched against genotype and microRNA profiles in an attempt to identify unique predictors of drug responsiveness. Our findings suggest that genetic variation in CYP2E1 and SMAD3 genes may partly explain the observed variation in drug response

Low-cost liquid medium for in vitro cultivation of Leishmania parasites in low-income countries

Background: Cutaneous Leishmaniasis (CL) induced by Leishmania aethiopica has two clinical manifestations: ulcerating, self-healing CL and non-ulcerating, non-healing CL. The grossly disfiguring multiple nodules on the face and exterior surface of limbs during non-ulcerative CL are sometimes misdiagnosed as other skin infections. Thus the need for definitive and prompt laboratory diagnosis will be required. Identifying Leishmania parasite by culture method is considered as a definitive method for initiation of treatment and as an effective component of leishmaniasis control methods. Recently the involvement of Fas (CD95) and Tumor Necrosis Factor (TNF) Related Apoptosis Inducing Ligand (TRAIL) induced apoptotic pathways were proposed to be involved in tissue destruction and ulceration during L. major induced CL. Aims: 1) to develop an alternative culture media that could minimize the cost for culturing Leishmania from patient lesions. 2) to investigate if the expression of FasL and TRAIL differs in ulcerating and non- ulcerative CL. Methods: GALF-1 media was formulated in our lab and compared to RPMI 1640 medium and conventional Locke s semi solid media (LSSM) which is one of the modifications of Novy-MacNeal-Nicolle (NNN) culture media. Amastigotes transformation, cryopreservation, recovery of parasites, cost and mass cultivation were analysed. Expression of Fas ligand (FasL), TRAIL and apoptosis were assessed by immunohistology in human skin biopsies from L. aethiopica induced ulcerative or non-ulcerative CL. FasL and TRAIL blocking experiments were performed in a murine model of CL. Results and discussion: GALF-1 is cheap and its ingredients available in a low income country such as Ethiopia. GALF-1 was able to transform amastigotes from Ethiopian patients samples and could be used to cultivate promastigotes in large quantities. Cost analysis showed 80% to 95 % decreased costs as compared to conventional media. Promastigotes cultured with GALF-1 could be cryopreserved in liquid nitrogen with comparable re-culture potential to conventional media. Affordability of diagnostic assays is a key issue for resource poor countries and the possibility to cut the cost of the efficient culture method for diagnosis through the use of inexpensive local formulated reagents could improve the diagnosis of leishmaniasis in low income endemic countries. More FasL expressing cells were detected in dermis of ulcerative CL as compared to non-ulcerative CL and controls. TRAIL expression was higher in ulcerative CL as compared to non-ulcerative CL and controls in both epidermis and dermis. Increased dermal expression of FasL and TRAIL was associated with ulcer formation during CL. This correlated with an inhibition of the ulcerative process in a murine CL model during FasL and TRAIL neutralisation.The mechanisms of the involvement of FasL and TRAIL in ulceration was not elucidated and putative reason(s) for the difference in dysregulation of apoptosis are discussed

Arterial oxygen content is precisely maintained by graded erythrocytotic responses in settings of high/normal serum iron levels, and predicts exercise capacity: an observational study of hypoxaemic patients with pulmonary arteriovenous malformations.

Oxygen, haemoglobin and cardiac output are integrated components of oxygen transport: each gram of haemoglobin transports 1.34 mls of oxygen in the blood. Low arterial partial pressure of oxygen (PaO2), and haemoglobin saturation (SaO2), are the indices used in clinical assessments, and usually result from low inspired oxygen concentrations, or alveolar/airways disease. Our objective was to examine low blood oxygen/haemoglobin relationships in chronically compensated states without concurrent hypoxic pulmonary vasoreactivity.165 consecutive unselected patients with pulmonary arteriovenous malformations were studied, in 98 cases, pre/post embolisation treatment. 159 (96%) had hereditary haemorrhagic telangiectasia. Arterial oxygen content was calculated by SaO2 x haemoglobin x 1.34/100.There was wide variation in SaO2 on air (78.5-99, median 95)% but due to secondary erythrocytosis and resultant polycythaemia, SaO2 explained only 0.1% of the variance in arterial oxygen content per unit blood volume. Secondary erythrocytosis was achievable with low iron stores, but only if serum iron was high-normal: Low serum iron levels were associated with reduced haemoglobin per erythrocyte, and overall arterial oxygen content was lower in iron deficient patients (median 16.0 [IQR 14.9, 17.4]mls/dL compared to 18.8 [IQR 17.4, 20.1]mls/dL, p<0.0001). Exercise tolerance appeared unrelated to SaO2 but was significantly worse in patients with lower oxygen content (p<0.0001). A pre-defined athletic group had higher Hb:SaO2 and serum iron:ferritin ratios than non-athletes with normal exercise capacity. PAVM embolisation increased SaO2, but arterial oxygen content was precisely restored by a subsequent fall in haemoglobin: 86 (87.8%) patients reported no change in exercise tolerance at post-embolisation follow-up.Haemoglobin and oxygen measurements in isolation do not indicate the more physiologically relevant oxygen content per unit blood volume. This can be maintained for SaO2 ≥78.5%, and resets to the same arterial oxygen content after correction of hypoxaemia. Serum iron concentrations, not ferritin, seem to predict more successful polycythaemic responses

Timing of birth for women with a twin pregnancy at term: a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>There is a well recognized risk of complications for both women and infants of a twin pregnancy, increasing beyond 37 weeks gestation. Preterm birth prior to 37 weeks gestation is a recognized complication of a twin pregnancy, however, up to 50% of twins will be born after this time.</p> <p>The aims of this randomised trial are to assess whether elective birth at 37 weeks gestation compared with standard care in women with a twin pregnancy affects the risk of perinatal death, and serious infant complications.</p> <p>Methods/Design</p> <p>Design: Multicentred randomised trial.</p> <p>Inclusion Criteria: women with a twin pregnancy at 36⁶weeks or more without contraindication to continuation of pregnancy.</p> <p>Trial Entry & Randomisation: Following written informed consent, eligible women will be randomised from 36⁺⁶weeks gestation. The randomisation schedule uses balanced variable blocks, with stratification for centre of birth and planned mode of birth. Women will be randomised to either elective birth or standard care.</p> <p>Treatment Schedules: Women allocated to the elective birth group will be planned for elective birth from 37 weeks gestation. Where the plan is for vaginal birth, this will involve induction of labour. Where the plan is for caesarean birth, this will involve elective caesarean section. For women allocated to standard care, birth will be planned for 38 weeks gestation or later. Where the plan is for vaginal birth, this will involve either awaiting the spontaneous onset of labour, or induction of labour if required. Where the plan is for caesarean birth, this will involve elective caesarean section (after 38 and as close to 39 weeks as possible).</p> <p>Primary Study Outcome: A composite of perinatal mortality or serious neonatal morbidity.</p> <p>Sample Size: 460 women with a twin pregnancy to show a reduction in the composite outcome from 16.3% to 6.7% with adjustment for the clustering of twin infants within mothers (p = 0.05, 80% power).</p> <p>Discussion</p> <p>This is a protocol for a randomised trial, the findings of which will contribute information about the optimal time of birth for women with an uncomplicated multiple pregnancy at and beyond 37 weeks gestation.</p> <p>Clinical Trial Registration</p> <p>Current Controlled Trials ISRCTN15761056</p