Formation and Function of the Rbl2p-beta-Tubulin Complex

The yeast protein Rbl2p suppresses the deleterious effects of excess beta-tubulin as efficiently as does alpha-tubulin. Both in vivo and in vitro, Rbl2p forms a complex with beta-tubulin that does not contain alpha-tubulin, thus defining a second pool of beta-tubulin in the cell. Formation of the complex depends upon the conformation of beta-tubulin. Newly synthesized beta-tubulin can bind to Rbl2p before it binds to alpha-tubulin. Rbl2p can also bind beta-tubulin from the alpha/beta-tubulin heterodimer, apparently by competing with alpha-tubulin. The Rbl2p-beta-tubulin complex has a half-life of ~2.5 h and is less stable than the alpha/beta-tubulin heterodimer. The results of our experiments explain both how excess Rbl2p can rescue cells overexpressing beta-tubulin and how it can be deleterious in a wild-type background. They also suggest that the Rbl2p-beta-tubulin complex is part of a cellular mechanism for regulating the levels and dimerization of tubulin chains

Rbl2p, a yeast protein that binds to β-tubulin and participates in microtubule function in vivo

AbstractGenetic configurations resulting in high ratios of β-tubulin to α-tubulin are toxic in S. cerevisiae, causing microtubule disassembly and cell death. We identified three non-tubulin yeast genes that, when overexpressed, rescue cells from excess β-tubulin. One, RBL2, rescues β-tubulin lethality as efficiently as does α-tubulin. Rbl2p binds to β-tubulin in vivo. Deficiencies or excesses of either RbI2p or α-tubulin affect microtubule-dependent functions in a parallel fashion. RbI2p has functional homology with murine cofactor A, a protein important for in vitro assays of β-tubulin folding. The results suggest that RbI2p participates in microtubule morphogenesis but not in the assembled polymer

Analysis of microtububule morphogenesis in vivo

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 1996.Includes bibliographical references (leaves 78-79).by Julie Elizabeth Archer.Ph.D

The effect of increased channel interaction on speech perception with cochlear implants.

Cochlear implants (CIs) are neuroprostheses that partially restore hearing for people with severe-to-profound hearing loss. While CIs can provide good speech perception in quiet listening situations for many, they fail to do so in environments with interfering sounds for most listeners. Previous research suggests that this is due to detrimental interaction effects between CI electrode channels, limiting their function to convey frequency-specific information, but evidence is still scarce. In this study, an experimental manipulation called spectral blurring was used to increase channel interaction in CI listeners using Advanced Bionics devices with HiFocus 1J and MS electrode arrays to directly investigate its causal effect on speech perception. Instead of using a single electrode per channel as in standard CI processing, spectral blurring used up to 6 electrodes per channel simultaneously to increase the overlap between adjacent frequency channels as would occur in cases with severe channel interaction. Results demonstrated that this manipulation significantly degraded CI speech perception in quiet by 15% and speech reception thresholds in babble noise by 5 dB when all channels were blurred by a factor of 6. Importantly, when channel interaction was increased just on a subset of electrodes, speech scores were mostly unaffected and were only significantly degraded when the 5 most apical channels were blurred. These apical channels convey information up to 1 kHz at the apical end of the electrode array and are typically located at angular insertion depths of about 250 up to 500°. These results confirm and extend earlier findings indicating that CI speech perception may not benefit from deactivating individual channels along the array and that efforts should instead be directed towards reducing channel interaction per se and in particular for the most-apical electrodes. Hereby, causal methods such as spectral blurring could be used in future research to control channel interaction effects within listeners for evaluating compensation strategies

An exploration of the impact of science stratification in the English school curriculum: the relationship between 'Double' and 'Triple' Science pathways and pupils' further study of science

Supply of students to ‘the science pipeline’ remains an important imperative for economic policy, and for individual life chances. In England, Science courses from age 14–16 have been divided into ‘Double’ and (extended) ‘Triple’ Science. This article draws on data from 6,053 students to investigate the effects of science course designation on progress to further science study and qualifications, as well as exploring the representation of students according to variables such as gender, ethnicity and social background. It finds that the study of Triple Science at age 16 is associated with future science study. Holding other variables constant, including attainment, those students that took Triple rather than Double Science are significantly more likely to pursue A Level Science (post 16/age 16–18), and to study Science at degree level. Hence Triple Science is significantly associated with an increase in undergraduate participation in science; however, for Double Science (the majority route), the likelihood of future participation is significantly diminished. The findings are analysed in relation to efficacy and social justice, arguing for further research to distil the explanation for these trends, and for reflection on access to Triple Science

The effect of increased channel interaction on speech perception with cochlear implants.

Cochlear implants (CIs) are neuroprostheses that partially restore hearing for people with severe-to-profound hearing loss. While CIs can provide good speech perception in quiet listening situations for many, they fail to do so in environments with interfering sounds for most listeners. Previous research suggests that this is due to detrimental interaction effects between CI electrode channels, limiting their function to convey frequency-specific information, but evidence is still scarce. In this study, an experimental manipulation called spectral blurring was used to increase channel interaction in CI listeners using Advanced Bionics devices with HiFocus 1J and MS electrode arrays to directly investigate its causal effect on speech perception. Instead of using a single electrode per channel as in standard CI processing, spectral blurring used up to 6 electrodes per channel simultaneously to increase the overlap between adjacent frequency channels as would occur in cases with severe channel interaction. Results demonstrated that this manipulation significantly degraded CI speech perception in quiet by 15% and speech reception thresholds in babble noise by 5 dB when all channels were blurred by a factor of 6. Importantly, when channel interaction was increased just on a subset of electrodes, speech scores were mostly unaffected and were only significantly degraded when the 5 most apical channels were blurred. These apical channels convey information up to 1 kHz at the apical end of the electrode array and are typically located at angular insertion depths of about 250 up to 500°. These results confirm and extend earlier findings indicating that CI speech perception may not benefit from deactivating individual channels along the array and that efforts should instead be directed towards reducing channel interaction per se and in particular for the most-apical electrodes. Hereby, causal methods such as spectral blurring could be used in future research to control channel interaction effects within listeners for evaluating compensation strategies

Genes of the serotonergic and dopaminergic pathways and their interaction affect the expression of Behavioural and Psychological Symptoms in Dementia (BPSD).

Although there is evidence for the involvement of genes of serotonergic and dopaminergic systems in the manifestation of the Behavioural and Psychological Symptoms in Dementia (BPSD), genetic association studies are contradictory. We used 1008 probable AD patients from the UK and applied a Multiple Indicators Multiple Causes (MIMIC) approach to investigate the effect of 11 polymorphisms in the serotonergic and dopaminergic systems, on four behavioural sub-phenotypes, namely "psychosis"," moods", "agitation" and "behavioural dyscontrol", as well as on 12 NPI items. Significant findings included the association of DRD1 A48G with "psychosis" (p=0.037), the association of DAT1 VNTR with "agitation" (p=0.006) and the association of DRD4 with "moods" sub-phenotype (p=0.008). In addition, associations were identified between DRD1 A48G and DAT1 VNTR with aberrant motor behaviour (AMB) symptoms (p=0.001 and p=0.015 respectively), between DRD4 and sleep disturbances (p=0.018) and between 5HTTLPR and apathy (p=0.033). Finally, significant interactions were observed between COMT Val158Met and 5HTTLPR with "psychosis" (p=0.026), between HTTLPR and STin2 with "psychosis" (p=0.005), between DAT1 3'UTR VNTR and COMT Val158Met with "agitation" (p=0.0001) and between DAT1 3'UTR VNTR and 5HTTLPR with the "moods" factor (p=0.0027). The complexity of the interrelations between genetic variation, behavioural symptoms and clinical variables was efficiently captured by this MIMIC model

Oral estradiol/micronized progesterone may be associated with lower risk of venous thromboembolism compared with conjugated equine estrogens/medroxyprogesterone acetate in real-world practice.

OBJECTIVES The Women's Health Initiative study reported an increased risk of venous thromboembolism among menopausal women treated with conjugated equine estrogens/medroxyprogesterone acetate (CEE/MPA) versus placebo. Newer hormone therapies may have a lower venous thromboembolism risk. The study compared the risk of venous thromboembolism between women treated with the combined oral product 17β-estradiol/micronized progesterone (E2/P4) and those treated with oral CEE/MPA regimens. STUDY DESIGN In a retrospective longitudinal study using real-world claims data from April 2019 to June 2021, women aged 40 years or more treated with oral E2/P4 or oral CEE/MPA who did not have a venous thromboembolism diagnosis before first dispensing claim of CEE/MPA or E2/P4 identified on or after May 1st 2019 (index date) were observed for 6 months or more after the index date. Oral E2/P4 and oral CEE/MPA had been prescribed by the treating physician in real-world practice and were observed through pharmacy dispensing records. MAIN OUTCOME MEASURES Venous thromboembolism risk was compared between women receiving oral E2/P4 versus oral CEE/MPA. RESULTS The study included 36,061 women treated with oral E2/P4 or oral CEE/MPA. In the analyses weighted by the inverse probability of treatment for control of potential confounding factors, the incidence of venous thromboembolism was significantly lower for oral E2/P4 compared with oral CEE/MPA (37/10,000 women-years for oral E2/P4 vs 53/10,000 women-years for oral CEE/MPA; incidence rate ratio 0.70, 95 % confidence interval: 0.53-0.92). CONCLUSIONS Real-world evidence suggests that the risk of venous thromboembolism is significantly lower among women treated with oral E2/P4 compared with oral CEE/MPA

ASPIRES3 Summary Report: Engineering

In this report, we share evidence from the ASPIRES research project, a fourteen-year, mixed methods investigation of the factors shaping young people’s trajectories in, through and out of STEM education (science, technology, engineering and mathematics), with a particular focus on access to STEM degrees. The study collected survey data from over 47,000 young people and conducted over 760 qualitative interviews with a longitudinal sample, which tracked 50 young people (and their parents/ carers) between the ages of 10 and 22. The project also conducted secondary analyses of UK National Statistics and Higher Education Statistics Agency (HESA) data sets on England domiciled students, aged 18 to 24. This report focuses on analyses of survey data collected at age 21/22 and longitudinal interviews conducted from age 10 to 22, to shed light on the factors shaping STEM trajectories, particularly at degree level

ASPIRES3 Summary Report: Mathematics

In this report, we share evidence from the ASPIRES research project, a fourteen-year, mixed methods investigation of the factors shaping young people’s trajectories in, through and out of STEM education (science, technology, engineering and mathematics), with a particular focus on access to STEM degrees. The study collected survey data from over 47,000 young people and conducted over 760 qualitative interviews with a longitudinal sample, which tracked 50 young people (and their parents/ carers) between the ages of 10 and 22. The project also conducted secondary analyses of UK National Statistics and Higher Education Statistics Agency (HESA) data sets on England domiciled students, aged 18 to 24. This report focuses on analyses of survey data collected at age 21/22 and longitudinal interviews conducted from age 10 to 22, to shed light on the factors shaping STEM trajectories, particularly at degree level