The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence

Funding: This work was funded by the European Research Council [http://erc.europa.eu/], AJPB (STRIFE Advanced Grant; C-2009-AdG-249793). The work was also supported by: the Wellcome Trust [www.wellcome.ac.uk], AJPB (080088, 097377); the UK Biotechnology and Biological Research Council [www.bbsrc.ac.uk], AJPB (BB/F00513X/1, BB/K017365/1); the CNPq-Brazil [http://cnpq.br], GMA (Science without Borders fellowship 202976/2014-9); and the National Centre for the Replacement, Refinement and Reduction of Animals in Research [www.nc3rs.org.uk], DMM (NC/K000306/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments We thank Dr. Elizabeth Johnson (Mycology Reference Laboratory, Bristol) for providing strains, and the Aberdeen Proteomics facility for the biotyping of S. cerevisiae clinical isolates, and to Euroscarf for providing S. cerevisiae strains and plasmids. We are grateful to our Microscopy Facility in the Institute of Medical Sciences for their expert help with the electron microscopy, and to our friends in the Aberdeen Fungal Group for insightful discussions.Peer reviewedPublisher PD

To respond or not to respond - a personal perspective of intestinal tolerance

For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research

Heart failure diagnosis in primary health care: clinical characteristics of problematic patients. A clinical judgement analysis study

BACKGROUND: Early detection of chronic heart failure has become increasingly important since the introduction of effective treatment. However, clinical diagnosis of heart failure is known to be difficult, especially in mild cases or early in the course of the disease. The purpose of this study is to analyse how patient characteristics contribute to difficulties in diagnosing systolic heart failure. METHODS: Design: A Clinical Judgement Analysis study of 40 case vignettes based on authentic patients, including relevant clinical data except echocardiography. Setting: Primary health care and two cardiology outpatient clinics in Stockholm. Subjects: 70 participants with different types of clinical experience; 27 specialists in general practice, 22 cardiologists, and 21 medical students. Main outcome measures: The assessed probability of heart failure for each case vignette, and the disagreement between the participants. The number of clinical variables (cues) indicative of heart failure in the case vignettes. RESULTS: The ten case vignettes with the least diverging assessments more often had increased relative cardiac volume and atrial fibrillation. No further specific clinical patterns could be found in subgroups of the case vignettes. The ten case vignettes with the most diverging assessments were those with an intermediate number of clinical variables. The case vignettes with the least diverging assessments more often represented patients with cardiac enlargement and atrial fibrillation. CONCLUSION: Diagnosing mild heart failure is difficult, as these patients are not easy to characterise. In our study, a larger number of positive cues resulted in more diagnostic conformity among the participants, and the most important information was cardiac enlargement. The importance of more objective diagnostic methods in diagnosing suspected cases of heart failure should be emphasised

Systematic review of the use of honey as a wound dressing

OBJECTIVE: To investigate topical honey in superficial burns and wounds though a systematic review of randomised controlled trials. DATA SOURCES: Cochrane Library, MEDLINE, EMBASE, PubMed, reference lists and databases were used to seek randomised controlled trials. Seven randomised trials involved superficial burns, partial thickness burns, moderate to severe burns that included full thickness injury, and infected postoperative wounds. REVIEW METHODS: Studies were randomised trials using honey, published papers, with a comparator. Main outcomes were relative benefit and number-needed-to-treat to prevent an outcome relating to wound healing time or infection rate. RESULTS: One study in infected postoperative wounds compared honey with antiseptics plus systemic antibiotics. The number needed to treat with honey for good wound healing compared with antiseptic was 2.9 (95% confidence interval 1.7 to 9.7). Five studies in patients with partial thickness or superficial burns involved less than 40% of the body surface. Comparators were polyurethane film, amniotic membrane, potato peel and silver sulphadiazine. The number needed to treat for seven days with honey to produce one patient with a healed burn was 2.6 (2.1 to 3.4) compared with any other treatment and 2.7 (2.0 to 4.1) compared with potato and amniotic membrane. For some or all outcomes honey was superior to all these treatments. Time for healing was significantly shorter for honey than all these treatments. The quality of studies was low. CONCLUSION: Confidence in a conclusion that honey is a useful treatment for superficial wounds or burns is low. There is biological plausibility

Conservative treatment of a comminuted cervical fracture in a racehorse

The 'classical' or 'Hangman' neck fracture involves the odontoid peg (process) of the second cervical vertebra (C2), and is described as an axial, dens or odontoid peg fracture in both the veterinary and human literature. Possible surgical treatment in both foals and adult horses requires a technique that allows decompression, anatomical alignment and stabilisation of the odontoid fracture. A limited number of surgical cases in foals have been reported in literature, but never in an adult horse. A mature Irish Thoroughbred racehorse was diagnosed with a type 2a odontoid peg fracture. Clinical signs included reluctance to move the head and neck, a left hind limb lameness and a neurological status of grade 2. The horse was treated conservatively and raced successfully five months after the diagnosed injury

Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides

As the concentrations of highly consumed nutrients, particularly glucose, are generally lower in tumours than in normal tissues1,2, cancer cells must adapt their metabolism to the tumour microenvironment. A better understanding of these adaptations might reveal cancer cell liabilities that can be exploited for therapeutic benefit. Here, we developed a continuous flow culture apparatus (Nutrostat) for maintaining proliferating cells in low nutrient media for long periods of time and used it to undertake competitive proliferation assays on a pooled collection of barcoded cancer cell lines cultured in low glucose conditions. Sensitivity to low glucose varies amongst cell lines, and an RNAi screen pinpointed mitochondrial oxidative phosphorylation (OXPHOS) as the major pathway required for optimal proliferation in low glucose. We found that cell lines most sensitive to low glucose are defective in the upregulation of OXPHOS normally caused by glucose limitation as a result of either mtDNA mutations in Complex I genes or impaired glucose utilization. These defects predict sensitivity to biguanides, anti-diabetic drugs that inhibit OXPHOS3,4, when cancer cells are grown in low glucose or as tumour xenografts. Remarkably, the biguanide sensitivity of cancer cells with mtDNA mutations was reversed by ectopic expression of yeast NDI1, a ubiquinone oxidoreductase that allows bypass of Complex I function5. Thus, we conclude that mtDNA mutations and impaired glucose utilization are potential biomarkers for identifying tumours with increased sensitivity to OXPHOS inhibitors

An ongoing process: A qualitative study of how the alcohol-dependent free themselves of addiction through progressive abstinence

<p>Abstract</p> <p>Background</p> <p>Most people being treated for alcoholism are unable to successfully quit drinking within their treatment programs. In few cases do we know the full picture of how abstinence is achieved in Taiwan. We tracked processes of abstinence in alcohol-dependency disorders, based on study evidence and results. This research explores the process of recovery from the viewpoint of the alcohol-dependent.</p> <p>Methods</p> <p>Semi-structured interviews were conducted in two different settings, using purpose sampling, during 2003-2004. The data were analyzed using content analysis. Participants were 32 adults, purposefully selected from an Alcoholics Anonymous group and a psychiatric hospital in North Taiwan.</p> <p>Results</p> <p>We found that the abstinence process is an ongoing process, in which the alcohol-dependent free themselves of addiction progressively. This process never ends or resolves in complete recovery. We have identified three stages in the struggle against alcoholism: the Indulgence, Ambivalence and Attempt (IAA) cycle, in which the sufferer is trapped in a cycle of attempting to give up and failing; the Turning Point, in which a Personal Nadir is reached, and the Ongoing Process of abstinence, in which a constant effort is made to remain sober through willpower and with the help of support groups. We also discuss Influencing Factors that can derail abstinence attempts, pushing the sufferer back into the IAA cycle.</p> <p>Conclusion</p> <p>This study provides important points of reference for alcohol and drug service workers and community healthcare professionals in Taiwan, casting light on the abstinence process and providing a basis for intervention or rehabilitation services.</p

Maize x Teosinte Hybrid Cobs Do Not Prevent Crop Gene Introgression

Maize x Teosinte Hybrid Cobs Do Not Prevent Crop Gene Introgression. Whether introgression from crops to wild relatives can occur is an important component of transgene risk assessment. In the case of maize, which co-occurs with its wild relative teosinte in Mexico, the possibility of introgression has been controversial. Maize is cross-compatible with teosinte, and spontaneous hybridization is known to occur. Some scientists have hypothesized that the maize x teosinte cob infructescence will prevent progeny dispersal, thus preventing introgression. Motivated by a prior study where we found maize x teosinte hybrid fruits naturally dispersed under field conditions, we tested whether hybrid cobs hold their fruits as tightly as maize cobs. We found the force required to detach hybrid fruits was substantially and significantly less than that for maize. Consequently, we expect that introgression of transgenes from maize into teosinte in Mexico should occur largely unimpeded by the hybrid cob.La mazorca o elote híbrido de maíz x teocintle no impide la introgresión de genes transgénicos provenientes del cultivo. La introgresión entre el maíz cultivado y el maíz silvestre, o teocintle, es un componente importante en la evaluación ambiental relacionada con los riesgos de la introducción de genes transgénicos. La posibilidad de introgresión entre el maíz domesticado y el teocintle ha sido un tema controversial, en particular en México, donde maíz y teocintle coexisten. El maíz es compatible con el teocintle y la hibridización espontánea ocurre entre ellos. Algunos científicos han planteado como hipótesis que al cruzar el maíz con teocintle, la estructura interna de la infrutescencia que sujeta los frutos conocida como la mazorca de maíz o el elote, impide la dispersión de la progenie evitando que la introgresión ocurra. Los resultados de un estudio previo evidencian la dispersión de los frutos híbridos del maíz x teocintle en condiciones naturales. Motivados por estos resultados, hemos decidido investigar si la mazorca o el elote de las infrutescencias del híbrido sujetan los frutos con una fuerza comparable o mayor a la del maíz. Nuestras mediciones implican que la fuerza necesaria para liberar los frutos híbridos son substancial y significativamente menores que aquellas necesarias para desprender los frutos del maíz. Como conclusión sugerimos que en México, la mazorca o el elote no representan una barrera que impida la introgresión de los genes transgénicos del maíz al teocintle