Ploidy Controls the Success of Mutators and Nature of Mutations during Budding Yeast Evolution

SummaryBackgroundWe used the budding yeast Saccharomyces cerevisiae to ask how elevated mutation rates affect the evolution of asexual eukaryotic populations. Mismatch repair defective and nonmutator strains were competed during adaptation to four laboratory environments (rich medium, low glucose, high salt, and a nonfermentable carbon source).ResultsIn diploids, mutators have an advantage over nonmutators in all conditions, and mutators that win competitions are on average fitter than nonmutator winners. In contrast, haploid mutators have no advantage when competed against haploid nonmutators, and haploid mutator winners are less fit than nonmutator winners. The diploid mutator winners were all superior to their ancestors both in the condition they had adapted to, and in two of the other conditions. This phenotype was due to a mutation or class of mutations that confers a large growth advantage during the respiratory phase of yeast cultures that precedes stationary phase. This generalist mutation(s) was not selected in diploid nonmutator strains or in haploid strains, which adapt primarily by fixing specialist (condition-specific) mutations. In diploid mutators, such mutations also occur, and the majority accumulates after the fixation of the generalist mutation.ConclusionsWe conclude that the advantage of mutators depends on ploidy and that diploid mutators can give rise to beneficial mutations that are inaccessible to nonmutators and haploid mutators

Using Game of Thrones to teach neuroscience and neuropharmacology during lockdown

Peer reviewedPublisher PD

Psychological Therapy for People with Tinnitus:A Scoping Review of Treatment Components

BACKGROUND: Tinnitus is associated with depression and anxiety disorders, severely and adversely affecting the quality of life and functional health status for some people. With the dearth of clinical psychologists embedded in audiology services and the cessation of training for hearing therapists in the UK, it is left to audiologists to meet the psychological needs of many patients with tinnitus. However, there is no universally standardized training or manualized intervention specifically for audiologists across the whole UK public healthcare system and similar systems elsewhere across the world.OBJECTIVES: The primary aim of this scoping review was to catalog the components of psychological therapies for people with tinnitus, which have been used or tested by psychologists, so that they might inform the development of a standardized audiologist-delivered psychological intervention. Secondary aims of this article were to identify the types of psychological therapy for people with tinnitus, who were reported but not tested in any clinical trial, as well as the job roles of clinicians who delivered psychological therapy for people with tinnitus in the literature.DESIGN: The authors searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; Cochrane Central Register of Controlled Trials; PubMed; EMBASE; CINAHL; LILACS; KoreaMed; IndMed; PakMediNet; CAB Abstracts; Web of Science; BIOSIS Previews; ISRCTN; ClinicalTrials.gov; IC-TRP; and Google Scholar. In addition, the authors searched the gray literature including conference abstracts, dissertations, and editorials. No records were excluded on the basis of controls used, outcomes reached, timing, setting, or study design (except for reviews-of the search results. Records were included in which a psychological therapy intervention was reported to address adults (≤18 years) tinnitus-related distress. No restrictive criteria were placed upon the term tinnitus. Records were excluded in which the intervention included biofeedback, habituation, hypnosis, or relaxation as necessary parts of the treatment.RESULTS: A total of 5043 records were retrieved of which 64 were retained. Twenty-five themes of components that have been included within a psychological therapy were identified, including tinnitus education, psychoeducation, evaluation treatment rationale, treatment planning, problem-solving behavioral intervention, thought identification, thought challenging, worry time, emotions, social comparison, interpersonal skills, self-concept, lifestyle advice, acceptance and defusion, mindfulness, attention, relaxation, sleep, sound enrichment, comorbidity, treatment reflection, relapse prevention, and common therapeutic skills. The most frequently reported psychological therapies were cognitive behavioral therapy, tinnitus education, and internet-delivered cognitive behavioral therapy. No records reported that an audiologist delivered any of these psychological therapies in the context of an empirical trial in which their role was clearly delineated from that of other clinicians.CONCLUSIONS: Scoping review methodology does not attempt to appraise the quality of evidence or synthesize the included records. Further research should therefore determine the relative importance of these different components of psychological therapies from the perspective of the patient and the clinician.</p

Psychological therapy for people with tinnitus: a scoping review of treatment components

Background: Tinnitus is associated with depression and anxiety disor- ders, severely and adversely affecting the quality of life and functional health status for some people. With the dearth of clinical psychologists embedded in audiology services and the cessation of training for hearing therapists in the UK, it is left to audiologists to meet the psychological needs of many patients with tinnitus. However, there is no universally standardized training or manualized intervention specifically for audiolo- gists across the whole UK public healthcare system and similar systems elsewhere across the world. Objectives: The primary aim of this scoping review was to catalog the components of psychological therapies for people with tinnitus, which have been used or tested by psychologists, so that they might inform the development of a standardized audiologist-delivered psy- chological intervention. Secondary aims of this article were to identify the types of psychological therapy for people with tinnitus, who were reported but not tested in any clinical trial, as well as the job roles of clinicians who delivered psychological therapy for people with tinnitus in the literature. Design: The authors searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; Cochrane Central Register of Controlled Trials; PubMed; EMBASE; CINAHL; LILACS; KoreaMed; IndMed; PakMediNet; CAB Abstracts; Web of Science; BIOSIS Previews; ISRCTN; ClinicalTrials.gov; IC-TRP; and Google Scholar. In addition, the authors searched the gray literature including conference abstracts, disserta- tions, and editorials. No records were excluded on the basis of controls used, outcomes reached, timing, setting, or study design (except for reviews—of the search results. Records were included in which a psy- chological therapy intervention was reported to address adults (≤18 years) tinnitus-related distress. No restrictive criteria were placed upon the term tinnitus. Records were excluded in which the intervention included biofeedback, habituation, hypnosis, or relaxation as necessary parts of the treatment. Results: A total of 5043 records were retrieved of which 64 were retained. Twenty-five themes of components that have been included within a psychological therapy were identified, including tinnitus educa- tion, psychoeducation, evaluation treatment rationale, treatment plan- ning, problem-solving behavioral intervention, thought identification, thought challenging, worry time, emotions, social comparison, inter- personal skills, self-concept, lifestyle advice, acceptance and defusion, mindfulness, attention, relaxation, sleep, sound enrichment, comorbid- ity, treatment reflection, relapse prevention, and common therapeutic skills. The most frequently reported psychological therapies were cogni- tive behavioral therapy, tinnitus education, and internet-delivered cogni- tive behavioral therapy. No records reported that an audiologist delivered any of these psychological therapies in the context of an empirical trial in which their role was clearly delineated from that of other clinicians. Conclusions: Scoping review methodology does not attempt to appraise the quality of evidence or synthesize the included records. Further research should therefore determine the relative importance of these dif- ferent components of psychological therapies from the perspective of the patient and the clinician

Levitated Duct Fan (LDF) Aircraft Auxiliary Generator

This generator concept includes a novel stator and rotor architecture made from composite material with blades attached to the outer rotating shell of a ducted fan drum rotor, a non-contact support system between the stator and rotor using magnetic fields to provide levitation, and an integrated electromagnetic generation system. The magnetic suspension between the rotor and the stator suspends and supports the rotor within the stator housing using permanent magnets attached to the outer circumference of the drum rotor and passive levitation coils in the stator shell. The magnets are arranged in a Halbach array configuration

Cellular and molecular pathogenesis of Salmonid alphavirus 1 in Atlantic salmon Salmo salar L

Salmonid alphaviruses (SAV) are a group of viruses that have recently emerged as a serious threat to the salmonid aquaculture industry in Europe. Over recent years, diseases caused by SAV have severely hampered the Scottish, Irish and Norwegian Atlantic salmon industry, and are considered to be among the major economically important viral diseases affecting the industry at present. Amongst the six subtypes characterised so far, Salmonid alphavirus 1 (SAV1) causes severe pathology in the heart, pancreas and the skeletal muscle of Atlantic salmon leading to death and growth retardation in the affected fish. The biochemical characteristics of the virus and the sequential pathology of the diseases caused by SAV have been described; however the mechanisms responsible for causing the disease and the host defence mechanisms against the virus are poorly defined. This thesis therefore examined the pathogenesis of SAV infection at the cellular and molecular level in vivo in salmon and in vitro in salmonid cells, with a special emphasis on host immune defence mechanisms against the virus. SAV was first isolated from Chinook salmon embryo-214 (CHSE-214) cells in 1995 in Ireland. Several cell lines have since been used to grow the virus. In the present study, three established salmonid cell lines, Chum salmon heart -1 (CHH-1), CHSE-214 and Salmon head kidney -1 (SHK-1) were evaluated for their ability to support the isolation of SAV-1 from infected fish tissue, with CHH-1 cells giving the fastest cytopathic effect (CPE) during primary isolation. The CPE appeared as localised cell-rounding on CHH-1 and CHSE-214 cells, although in SHK-1 cells, the cells were seen to slough off the monolayer relatively later than with the other two cell lines during the infection. The host response to SAV infection was evaluated by experimentally infecting Atlantic salmon parr using a cell culture-adapted virus isolate. A quantitative reverse transcription polymerase chain reaction (qRT-PCR) was developed to examine the virus load in the fish, from which it was found that the highest viral RNA copy number was detected at 5 day post infection (d.p.i), of the 90 day experimental infection period. Characteristic pathological lesions were only seen in the pancreas and the heart but not in the skeletal muscles of the infected fish. A gene expression study using qRT-PCR revealed the rapid induction of interferon (INF) and INF-associated genes in the head kidney of the infected fish compared to the control fish. The Mx protein was found to be highly expressed in the heart and the mucous membranes of infected fish by immunohistochemistry. Interestingly, the pathological changes that were seen occurred some time after the peak expression of genes associated with the INF-1-pathway. When the host-virus interaction of Atlantic salmon infected with SAV was examined using a microarray, a potent first line defence response was observed, together with the signatures of early activation of the adaptive immune response during the initial stages of the infection. Genes associated with transcription, translation and lipid metabolism were significantly differentially expressed in virus infected fish compared to control fish. A large array of antiviral genes was significantly expressed, amongst which were some of the genes also described in mammalian alphavirus infections. Genes associated with apoptosis and anti-apoptosis were also seen to be differentially regulated showing the complexity of the host-virus interaction. Collectively, all of these findings suggest that a non-specific antiviral immune response takes place providing rapid immune protection during the early stages of SAV infection in salmon. In the study on morphogenesis of SAV in salmonid cells using electron microscopy (EM), a rapid internalization of virus into the cells and generation of replication complexes using the secretory pathway of the cell, similar to mammalian alphavirus replication was observed. The mature viruses were released through surface projections, acquiring envelopes from the host cell membrane. From the ultrastructural studies of the salmonid cells infected with SAV, a progressive chromatin marginalisation and condensation could be seen, leading to cellular fragmentation, forming membrane bound apoptotic bodies, characteristic of progressive apoptosis. The activation of caspase-3 in the cytoplasm and genomic DNA damage were also seen in the infected fish cells, indicating that apoptosis is the main cause of cell death during SAV infection. The results of this study have increased our knowledge and understanding of the cellular and molecular mechanisms involved in the pathogenesis of SAV infection, emphasising the importance of the first line defence mechanisms against SAV infection in salmon. This has given an interesting insight into the host mechanisms used to combat the virus during infection, and will undoubtedly be useful for designing new vaccines and management strategies for prevention and control of this important diseaseEThOS - Electronic Theses Online ServiceCommonwealth Scholarship CommissionGBUnited Kingdo

A psychologically informed, audiologist-delivered, manualised intervention for tinnitus:protocol for a randomised controlled feasibility trial (Tin Man study)

Background: Chronic tinnitus is a common incurable condition often associated with depression, anxiety, insomnia and reduced quality of life. Within National Health Service (NHS) audiology in the United Kingdom (UK), no standard protocol currently exists for the treatment of tinnitus. Counselling is only available in less than half of audiology departments, and there is no agreed standard for what constitutes tinnitus counselling. There is substantial evidence from systematic reviews for the clinical benefit of cognitive behaviour therapy (CBT) for tinnitus delivered by clinical psychologists or psychiatrists, but no studies have sufficiently evidenced the NHS model of tinnitus care where management is increasingly being delivered by audiology professionals. In a pilot randomised controlled trial (RCT), this study aims to evaluate the feasibility of comparing a psychologically informed guidance manual developed to support audiologist management of tinnitus with usual treatment. Methods/design: Phase 1 consisted of three development stages: (1) a scoping review to generate a comprehensive set of tinnitus counselling components, (2) a Delphi survey involving expert patients (n = 18) and clinicians (n = 21) to establish consensus on the essential core attributes of tinnitus counselling, and (3) incorporation of these elements into a manualised care protocol. In phase 2, following training in a dedicated workshop, the manualised intervention will be delivered by three experienced audiologists across three different sites. Patients (n = 30) will be randomly allocated to receive either (1) psychologically informed management from an audiologist trained to deliver the manualised intervention or (2) treatment as usual (TAU) from an audiologist who has not received this training. Quantitative outcome measures will be administered at baseline, discharge and 6-month follow-up. Qualitative interviews with participating patients and clinicians will be conducted to gather perspectives on the feasibility and acceptability of the manualised intervention. Discussion: The feasibility of proceeding to a definitive RCT will be assessed via compliance with the manual, willingness to be randomised, number of eligible participants, rate of recruitment, retention and collection of quantitative outcome measures. This research offers an important first step to an evidence-based, standardised and accessible approach to tinnitus care

A psychologically informed, audiologist-delivered, manualised intervention for tinnitus:protocol for a randomised controlled feasibility trial (Tin Man study)

Background: Chronic tinnitus is a common incurable condition often associated with depression, anxiety, insomnia and reduced quality of life. Within National Health Service (NHS) audiology in the United Kingdom (UK), no standard protocol currently exists for the treatment of tinnitus. Counselling is only available in less than half of audiology departments, and there is no agreed standard for what constitutes tinnitus counselling. There is substantial evidence from systematic reviews for the clinical benefit of cognitive behaviour therapy (CBT) for tinnitus delivered by clinical psychologists or psychiatrists, but no studies have sufficiently evidenced the NHS model of tinnitus care where management is increasingly being delivered by audiology professionals. In a pilot randomised controlled trial (RCT), this study aims to evaluate the feasibility of comparing a psychologically informed guidance manual developed to support audiologist management of tinnitus with usual treatment. Methods/design: Phase 1 consisted of three development stages: (1) a scoping review to generate a comprehensive set of tinnitus counselling components, (2) a Delphi survey involving expert patients (n = 18) and clinicians (n = 21) to establish consensus on the essential core attributes of tinnitus counselling, and (3) incorporation of these elements into a manualised care protocol. In phase 2, following training in a dedicated workshop, the manualised intervention will be delivered by three experienced audiologists across three different sites. Patients (n = 30) will be randomly allocated to receive either (1) psychologically informed management from an audiologist trained to deliver the manualised intervention or (2) treatment as usual (TAU) from an audiologist who has not received this training. Quantitative outcome measures will be administered at baseline, discharge and 6-month follow-up. Qualitative interviews with participating patients and clinicians will be conducted to gather perspectives on the feasibility and acceptability of the manualised intervention. Discussion: The feasibility of proceeding to a definitive RCT will be assessed via compliance with the manual, willingness to be randomised, number of eligible participants, rate of recruitment, retention and collection of quantitative outcome measures. This research offers an important first step to an evidence-based, standardised and accessible approach to tinnitus care

Examination of Fluconazole-Induced Alopecia in an Animal Model and Human Cohort.

Fluconazole-induced alopecia is a significant problem for patients receiving long-term therapy. We evaluated the hair cycle changes of fluconazole in a rat model and investigated potential molecular mechanisms. Plasma and tissue levels of retinoic acid were not found to be causal. Human patients with alopecia attributed to fluconazole also underwent detailed assessment and in both our murine model and human cohort fluconazole induced telogen effluvium. Future work further examining the mechanism of fluconazole-induced alopecia should be undertaken