The deafness ( dn ) and Beethoven ( Bth ) mutant mice are models for profound congenital deafness (DFNB7/B11) and progressive hearing loss (DFNA36), respectively,
caused by recessive and dominant ...mutations of transmembrane cochlear-expressed gene 1 ( TMC1 ), which encodes a transmembrane protein of unknown function. In the mouse cochlea Tmc1 is expressed in both outer (OHCs) and inner (IHCs) hair cells from early stages of development. Immature hair cells of mutant
mice seem normal in appearance and biophysical properties. From around P8 for OHCs and P12 for IHCs, mutants fail to acquire
( dn / dn ) or show reduced expression ( Bth / Bth and, to a lesser extent Bth /+) of the K + currents which contribute to their normal functional maturation (the BK-type current I K,f in IHCs, and the delayed rectifier I K,n in both cell types). Moreover, the exocytotic machinery in mutant IHCs does not develop normally as judged by the persistence
of immature features of the Ca 2 + current and exocytosis into adulthood. Mutant mice exhibited progressive hair cell damage and loss. The compound action potential
(CAP) thresholds of Bth /+ mice were raised and correlated with the degree of hair cell loss. Homozygous mutants ( dn / dn and Bth / Bth ) never showed CAP responses, even at ages where many hair cells were still present in the apex of the cochlea, suggesting
their hair cells never function normally. We propose that Tmc1 is involved in trafficking of molecules to the plasma membrane
or serves as an intracellular regulatory signal for differentiation of immature hair cells into fully functional auditory
receptors.
Retinitis pigmentosa (RP) represents the most common mendelian degenerative retinopathy of man, involving death of rod photoreceptors, cone cell degeneration, retinal vessel attenuation and ...pigmentary deposits. The patient experiences night blindness, usually followed by progressive loss of visual field. Genetic linkage between an autosomal dominant RP locus and rhodopsin, the photoreactive pigment of the rod cells, led to the identification of mutations within the rhodopsin gene in both dominant and recessive forms of RP. To better understand the functional and structural role of rhodopsin in the normal retina and in the pathogenesis of retinal disease, we generated mice carrying a targeted disruption of the rhodopsin gene. Rho-/- mice do not elaborate rod outer segments, losing their photoreceptors over 3 months. There is no rod ERG response in 8-week-old animals. Rho+/- animals retain the majority of their photoreceptors although the inner and outer segments of these cells display some structural disorganization, the outer segments becoming shorter in older mice. These animals should provide a useful genetic background on which to express other mutant opsin transgenes, as well as a model to assess the therapeutic potential of re-introducing functional rhodopsin genes into degenerating retinal tissues.
Although recent progress in identifying genes involved in deafness has been remarkable, the genetic basis of progressive hearing loss (or age-related hearing loss) is poorly understood because of the ...extreme difficulty in studying such a late-onset, complex disease in human populations. Several inbred strains of mice such as 129P1/ReJ, C57BL/6J, DBA/2J, and BALB/cByJ have been reported to exhibit age-related hearing loss and provide valuable models for human nonsyndromic progressive deafness. In this article we show that 101/H mice also exhibit progressive deafness with early onset. Linkage analysis of F(2) populations derived from crosses between the 101/H and the MAI/Pas and MBT/Pas wild-derived mice suggested at least two major quantitative trait loci (QTLs) that influence progressive hearing loss. A first QTL, designated Phl1, was mapped with a maximum LOD score of 6.7 to the centromeric region of Chromosome 17, where no deafness-related QTL has been mapped so far. A second QTL, designated Phl2, mapped to Chromosome 10 and exhibited a maximum LOD score of 5.3. The map position of Phl2 near the well-known QTL of age-related hearing loss (Ahl) suggested the possibility of allelism, although the Ahl mutation itself did not segregate in these crosses. Finally, we found some evidence of epistatic interaction between Phl1 and Phl2.
Otitis media is the most common cause of hearing impairment in children and is primarily characterized by inflammation of the middle ear mucosa. Yet nothing is known of the underlying genetic ...pathways predisposing to otitis media in the human population. Increasingly, large-scale mouse mutagenesis programs have undertaken systematic and genome-wide efforts to recover large numbers of novel mutations affecting a diverse array of phenotypic areas involved with genetic disease including deafness. As part of the UK mutagenesis program, we have identified a novel deaf mouse mutant, Jeff (Jf). Jeff maps to the distal region of mouse chromosome 17 and presents with fluid and pus in the middle ear cavity. Jeff mutants are 21% smaller than wild-type littermates, have a mild craniofacial abnormality, and have elevated hearing thresholds. Middle ear epithelia of Jeff mice show evidence of a chronic proliferative otitis media. The Jeff mutant should prove valuable in elucidating the underlying genetic pathways predisposing to otitis media.
Strictosidine synthase (STR) is a key enzyme in the biosynthesis of terpenoid indole alkaloids. This class of secondary metabolites harbours several pharmaceutically important compounds used, among ...other applications, in cancer treatment. Terpenoid indole alkaloid biosynthesis and expression of biosynthetic genes including Str1 is induced by fungal elicitors. To identify elicitor-responsive regulatory promoter elements and trans-acting factors, the single-copy Str1 gene was isolated from the subtropical plant species Catharanthus roseus (Madagascar periwinkle). Str1 upstream sequences conferred elicitor-responsive expression to the beta-glucuronidase (gusA) reporter gene in transgenic tobacco plants. Main enhancer sequences within the Str1 promoter region studied were shown to be located between -339 and -145. This region and two other regions of the promoter bound the tobacco nuclear protein factor GT-1. A G-box located around position -105 bound nuclear and cloned G-box-binding factors (GBFs). A mutation that knocked out GBF binding had no measurable effect on expression, which indicates that the G-box is not essential for the elicitor responsiveness of the Str1 promoter. No obvious homologies with promoter elements identified in other elicitor-responsive genes were observed, suggesting that the Strl gene may depend on novel regulatory mechanisms.
People with multiple sclerosis have problems with memory and attention. The effectiveness of cognitive rehabilitation has not been established.
The objectives were to assess the clinical ...effectiveness and cost-effectiveness of a cognitive rehabilitation programme for people with multiple sclerosis.
This was a multicentre, randomised controlled trial in which participants were randomised in a ratio of 6 : 5 to receive cognitive rehabilitation plus usual care or usual care alone. Participants were assessed at 6 and 12 months after randomisation.
The trial was set in hospital neurology clinics and community services.
Participants were people with multiple sclerosis who had cognitive problems, were aged 18-69 years, could travel to attend group sessions and gave informed consent.
The intervention was a group cognitive rehabilitation programme delivered weekly by an assistant psychologist to between four and six participants for 10 weeks.
The primary outcome was the Multiple Sclerosis Impact Scale - Psychological subscale at 12 months. Secondary outcomes included results from the Everyday Memory Questionnaire, the 30-Item General Health Questionnaire, the EuroQol-5 Dimensions, five-level version and a service use questionnaire from participants, and the Everyday Memory Questionnaire - relative version and the Modified Carer Strain Index from a relative or friend of the participant.
Of the 449 participants randomised, 245 were allocated to cognitive rehabilitation (intervention group) and 204 were allocated to usual care (control group). Of these, 214 in the intervention group and 173 in the control group were included in the primary analysis. There was no clinically important difference in the Multiple Sclerosis Impact Scale - Psychological subscale score between the two groups at the 12-month follow-up (adjusted difference in means -0.6, 95% confidence interval -1.5 to 0.3;
= 0.20). There were no important differences between the groups in relation to cognitive abilities, fatigue, employment, or carer strain at follow-up. However, there were differences, although small, between the groups in the Multiple Sclerosis Impact Scale - Psychological subscale score at 6 months (adjusted difference in means -0.9, 95% confidence interval -1.7 to -0.1;
= 0.03) and in everyday memory on the Everyday Memory Questionnaire as reported by participants at 6 (adjusted difference in means -5.3, 95% confidence interval -8.7 to -1.9) and 12 months (adjusted difference in means -4.4, 95% confidence interval -7.8 to -0.9) and by relatives at 6 (adjusted difference in means -5.4, 95% confidence interval -9.1 to -1.7) and 12 months (adjusted difference in means -5.5, 95% confidence interval -9.6 to -1.5) in favour of the cognitive rehabilitation group. There were also differences in mood on the 30-Item General Health Questionnaire at 6 (adjusted difference in means -3.4, 95% confidence interval -5.9 to -0.8) and 12 months (adjusted difference in means -3.4, 95% confidence interval -6.2 to -0.6) in favour of the cognitive rehabilitation group. A qualitative analysis indicated perceived benefits of the intervention. There was no evidence of a difference in costs (adjusted difference in means -£574.93, 95% confidence interval -£1878.93 to £729.07) or quality-adjusted life-year gain (adjusted difference in means 0.00, 95% confidence interval -0.02 to 0.02). No safety concerns were raised and no deaths were reported.
The trial included a sample of participants who had relatively severe cognitive problems in daily life. The trial was not powered to perform subgroup analyses. Participants could not be blinded to treatment allocation.
This cognitive rehabilitation programme had no long-term benefits on quality of life for people with multiple sclerosis.
Future research should evaluate the selection of those who may benefit from cognitive rehabilitation.
Current Controlled Trials ISRCTN09697576.
This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in
; Vol. 24, No. 4. See the National Institute for Health Research Journals Library website for further project information.
Objective:
To assess the clinical and cost-effectiveness of cognitive rehabilitation for attention and memory problems in people with multiple sclerosis.
Design:
Multicentre, pragmatic, randomized ...controlled trial.
Setting:
Community
Participants:
People with multiple sclerosis aged 18–69 years, who reported cognitive problems in daily life and had cognitive problems on standardized assessment.
Interventions:
A group cognitive rehabilitation programme delivered in 10 weekly sessions in comparison with usual care.
Main measures:
The primary outcome was the Multiple Sclerosis Impact Scale Psychological subscale at 12 months after randomization. Secondary outcomes included measures of everyday memory problems, mood, fatigue, cognitive abilities and employment at 6 and 12 months after randomization.
Results:
In all, 245 participants were allocated to cognitive rehabilitation and 204 to usual care. Mean Multiple Sclerosis Impact Scale Psychological at 12 months was 22.2 (SD = 6.1) for cognitive rehabilitation and 23.4 (SD = 6.0) for usual care group; adjusted difference −0.6, 95% confidence interval (CI) = −1.5 to 0.3, P = 0.20. No differences were observed in cognitive abilities, fatigue or employment. There were small differences in favour of cognitive rehabilitation for the Multiple Sclerosis Impact Scale Psychological at 6 months and everyday memory and mood at 6 and 12 months. There was no evidence of an effect on costs (−£808; 95% CI = −£2248 to £632) or on quality-adjusted life year gain (0.00; 95% CI = −0.01 to 0.02).
Conclusion:
This rehabilitation programme had no long-term benefits on the impact of multiple sclerosis on quality of life, but there was some evidence of an effect on everyday memory problems and mood.
As the human genome project approaches completion, the challenge for mammalian geneticists is to develop approaches for the systematic determination of mammalian gene function. Mouse mutagenesis will ...be a key element of studies of gene function. Phenotype-driven approaches using the chemical mutagen ethylnitrosourea (ENU) represent a potentially efficient route for the generation of large numbers of mutant mice that can be screened for novel phenotypes. The advantage of this approach is that, in assessing gene function, no a priori assumptions are made about the genes involved in any pathway. Phenotype-driven mutagenesis is thus an effective method for the identification of novel genes and pathways. We have undertaken a genome-wide, phenotype-driven screen for dominant mutations in the mouse. We generated and screened over 26,000 mice, and recovered some 500 new mouse mutants. Our work, along with the programme reported in the accompanying paper, has led to a substantial increase in the mouse mutant resource and represents a first step towards systematic studies of gene function in mammalian genetics.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
This thesis project seeks to answer the question of how visual rhetoric put forward in social media content by pro-life and pro-choice organizations may persuade their audiences’ perspective on ...abortion. Using Sonja Foss’s guidelines for analysis of visual rhetoric, I analyze 24 selected examples of Facebook content posted by two pro-life organizations (Human Coalition and Feminists for Life) and two pro-choice organizations (Planned Parenthood Action and NARAL Pro-Choice America) in 2017. My analysis found that the visual rhetoric posted by both organizations on social media can and does function as a form of visual metonymy. Because of this, these visual strategies can stand in for more complex arguments in dramatic ways.
Despite recent progress in identifying genes underlying deafness, there are still relatively few mouse models of specific forms of human deafness. Here we describe the phenotype of the Beethoven ...(Bth) mouse mutant and a missense mutation in Tmc1 (transmembrane cochlear-expressed gene 1). Progressive hearing loss (DFNA36) and profound congenital deafness (DFNB7/B11) are caused by dominant and recessive mutations of the human ortholog, TMC1 (ref. 1), for which Bth and deafness (dn) are mouse models, respectively.
PDF
