A novel role for the CBF3 kinetochore–scaffold complex in regulating septin dynamics and cytokinesis

In budding yeast, the kinetochore scaffold complex centromere binding factor 3 (CBF3) is required to form kinetochores on centromere DNA and to allow proper chromosome segregation. We have previously shown that SKP1 and SGT1 balance the assembly and turnover of CBF3 complexes, a cycle that we suggest is independent of its role in chromosome segregation (Rodrigo-Brenni, M.C., S. Thomas, D.C. Bouck, and K.B. Kaplan. 2004. Mol. Biol. Cell. 15:3366–3378). We provide evidence that this cycle contributes to a second, kinetochore-independent function of CBF3. In this study, we show that inhibiting the assembly of CBF3 causes disorganized septins and defects in cell polarity that give rise to cytokinesis failures. Specifically, we show that septin ring separation and disassembly is delayed in anaphase, suggesting that CBF3 regulates septin dynamics. Only mutations that affect the CBF3 cycle, and not mutants in outer kinetochore subunits, cause defects in septins. These results demonstrate a novel role for CBF3 in regulating cytokinesis, a role that is reminiscent of passenger proteins. Consistent with this possibility, we find that CBF3 interacts with Bir1p, the homologue of the passenger protein Survivin. Mutants in Bir1p similarly affect septin organization, leading us to propose that CBF3 and Bir1p act as passenger proteins to coordinate chromosome segregation with cytokinesis

Non-contrast renal magnetic resonance imaging to assess perfusion and corticomedullary differentiation in health and chronic kidney disease

AIMS Arterial spin labelling (ASL) MRI measures perfusion without administration of contrast agent. While ASL has been validated in animals and healthy volunteers (HVs), application to chronic kidney disease (CKD) has been limited. We investigated the utility of ASL MRI in patients with CKD. METHODS We studied renal perfusion in 24 HVs and 17 patients with CKD (age 22-77 years, 40% male) using ASL MRI at 3.0T. Kidney function was determined using estimated glomerular filtration rate (eGFR). T1 relaxation time was measured using modified look-locker inversion and xFB02;ow-sensitive alternating inversion recovery true-fast imaging and steady precession was performed to measure cortical and whole kidney perfusion. RESULTS T1 was higher in CKD within cortex and whole kidney, and there was association between T1 time and eGFR. No association was seen between kidney size and volume and either T1, or ASL perfusion. Perfusion was lower in CKD in cortex (136 ± 37 vs. 279 ± 69 ml/min/100 g; p < 0.001) and whole kidney (146 ± 24 vs. 221 ± 38 ml/min/100 g; p < 0.001). There was significant, negative, association between T1 longitudinal relaxation time and ASL perfusion in both the cortex (r = -0.75, p < 0.001) and whole kidney (r = -0.50, p < 0.001). There was correlation between eGFR and both cortical (r = 0.73, p < 0.01) and whole kidney (r = 0.69, p < 0.01) perfusion. CONCLUSIONS Significant differences in renal structure and function were demonstrated using ASL MRI. T1 may be representative of structural changes associated with CKD; however, further investigation is required into the pathological correlates of reduced ASL perfusion and increased T1 time in CKD

The Genetic Age: Who Owns the Genome?: A Symposium on Intellectual Property and the Human Genome, 2 J. Marshall Rev. Intell. Prop. L. 6 (2002)

A Symposium on Intellectual Property Co-Sponsored by The Woodrow Wilson Center. Featuring the remarks of Scott A. Brown, J.D.; Q. Todd Dickinson, J.D.; Stephen P.A. Fodor, Ph.D.; Justin Gillis; Hon. Lee H. Hamilton; Eric S. Lander, Ph.D.; and Pilar Ossorio, Ph.D., J.D

Sofosbuvir and Ribavirin Therapy for Children Aged 3 to <12 Years With Hepatitis C Virus Genotype 2 or 3 Infection.

Currently, the only approved hepatitis C virus (HCV) treatment for children aged <12 years is pegylated interferon plus ribavirin. In an open-label study, we evaluated the safety and efficacy of sofosbuvir plus ribavirin for 12 weeks in children aged 3 to <12 years chronically infected with genotype 2 or for 24 weeks in patients with genotype 3. Patients aged 3 to <6 years weighing <17 kg received sofosbuvir 150 mg, and patients aged 3 to <6 years weighing ≥17 kg and all patients aged 6 to <12 years received sofosbuvir 200 mg once daily. Intensive pharmacokinetic sampling conducted in each age group confirmed the appropriateness of sofosbuvir doses. For all patients, ribavirin dosing was determined by baseline weight (up to 1,400 mg/day, two divided doses). The primary efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Fifty-four patients were enrolled (41 aged 6 to <12 years and 13 aged 3 to <6 years). Most were treatment naïve (98%) and infected perinatally (94%). All but one patient achieved SVR12 (53/54, 98%; 95% confidence interval, 90%-100%). The patient who did not achieve SVR12 was a 4-year-old who discontinued treatment after 3 days because of "abnormal drug taste." The most commonly reported adverse events in patients aged 6 to <12 years were vomiting (32%) and headache (29%), and those in patients aged 3 to <6 years were vomiting (46%) and diarrhea (39%). One 3-year-old patient had a serious adverse event of accidental ribavirin overdose requiring hospitalization for monitoring; this patient completed treatment and achieved SVR12. Conclusion: Sofosbuvir plus ribavirin was well tolerated and highly effective in children aged 3 to <12 years with chronic HCV genotype 2 or 3 infection

A retrospective analysis investigating the effects of Telazol® and medetomidine on ejaculate characteristics in cheetahs (Acinonyx jubatus)

Zoo managed cheetahs provide an insurance population for wild cheetahs that are under threat of extinction from habitat loss, lack of prey, competition, pet trade and poaching for skin and bones. Assisted reproductive techniques including artificial insemination, in vitro fertilization, and embryo transfer augment natural breeding programs but rely on good quality semen for best results. It is understood that anesthesia can affect semen characteristics such as ejaculate volume, total sperm count, sperm motility, and incidence of urine contamination. Thus, the aim of this study was to conduct a retrospective analysis of 23 years of data to investigate sperm parameters of semen collected under anesthesia using medetomidine in combination with butorphanol and midazolam or Telazol® alone. Electroejaculation records (Medetomidine, Butorphanol, and Midazolam anesthetized n = 59 ejaculates, from 30 cheetahs, Telazol® anesthetized, n= 169 ejaculates, from 72 cheetahs) were evaluated for incidence of urine contamination. Electroejaculation records (Medetomidine, Butorphanol, and Midazolam anesthetized n = 21 ejaculates, from 17 cheetahs, Telazol® anesthetized, n = 143 ejaculates, from 63 cheetahs) were evaluated for total sperm count, total motility, ejaculate volume, and testicle size. Telazol® treated cheetahs had a numerically higher total sperm count (Median ± SD: 42.58 ± 77.8 × 106 spermatozoa) compared to those treated with medetomidine (Median ± SD: 31.2 ±44.58 × 106 spermatozoa), and a significantly (p < 0.05) higher sperm motility (Median ± SD: 70.0 ± 9.71%) compared to medetomidine (Median ± SD: 53.0 ± 16.41%) treated cheetahs. The findings of this study indicate that medetomidine anesthesia results in significantly lower sperm motility and Telazol® anesthesia results in a higher total sperm count and motility, thus resulting in higher quality ejaculate. This information can aid in the veterinary management of the species when involved in genome resource banking and assisted reproductive technologies

Consensus-based technical recommendations for clinical translation of renal T1 and T2 mapping MRI

To develop technical recommendations on the acquisition and post-processing of renal longitudinal (T1) and transverse (T2) relaxation time mapping. A multidisciplinary panel consisting of 18 experts in the field of renal T1 and T2 mapping participated in a consensus project, which was initiated by the European Cooperation in Science and Technology Action PARENCHIMA CA16103. Consensus recommendations were formulated using a two-step modified Delphi method. The first survey consisted of 56 items on T1 mapping, of which 4 reached the pre-defined consensus threshold of 75% or higher. The second survey was expanded to include both T1 and T2 mapping, and consisted of 54 items of which 32 reached consensus. Recommendations based were formulated on hardware, patient preparation, acquisition, analysis and reporting. Consensus-based technical recommendations for renal T1 and T2 mapping were formulated. However, there was considerable lack of consensus for renal T1 and particularly renal T2 mapping, to some extent surprising considering the long history of relaxometry in MRI, highlighting key knowledge gaps that require further work. This paper should be regarded as a first step in a long-term evidence-based iterative process towards ever increasing harmonization of scan protocols across sites, to ultimately facilitate clinical implementation

Cognitive and social functioning deficits after anti-N-methyl-D-aspartate receptor encephalitis: an exploratory case series

Background: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently described life-threatening autoimmune disorder associated with a characteristic multi-stage neuropsychiatric syndrome. Although it is known that the majority of patients experience neuropsychological disturbance post-treatment, some aspects of the cognitive profile remain unclear. Methods: This study sought to investigate patterns of cognitive functioning in a sample of anti-NMDAR encephalitis patients. Seven (6F:1M; mean age, 26.4 years; range, 16-37 years) treated patients completed a comprehensive set of neurocognitive and social functioning measures. Performance was analyzed using normative data (where available), and comparison with matched controls (10F:4M; mean age, 25.8 years; range, 16-38 years). Results: Individual cognitive profiles ranged from within normal limits to extensive dysfunction. Relative to controls, the patient group's performance was affected in the domains of verbal/ visual memory, working memory, attention, processing speed, executive functioning, and social cognition. The patient group also reported significantly higher levels of anxiety compared to controls. Conclusions: These results add to the accumulating evidence that neurocognitive deficits, consistent with the distribution and functions of the NMDAR system can persist during recovery from anti-NMDAR encephalitis. This is the first study to provide evidence of performance decrements on measures of social cognition, including some involving theory of mind

First Observation of PP-odd γ\gamma Asymmetry in Polarized Neutron Capture on Hydrogen

We report the first observation of the parity-violating 2.2 MeV gamma-ray asymmetry $A^{np}_\gamma$ in neutron-proton capture using polarized cold neutrons incident on a liquid parahydrogen target at the Spallation Neutron Source at Oak Ridge National Laboratory. $A^{np}_\gamma$ isolates the $\Delta I=1$, \mbox{$^{3}S_{1}\rightarrow {^{3}P_{1}}$} component of the weak nucleon-nucleon interaction, which is dominated by pion exchange and can be directly related to a single coupling constant in either the DDH meson exchange model or pionless EFT. We measured $A^{np}_\gamma = [-3.0 \pm 1.4 (stat) \pm 0.2 (sys)]\times 10^{-8}$, which implies a DDH weak $\pi NN$ coupling of $h_{\pi}^{1} = [2.6 \pm 1.2(stat) \pm 0.2(sys)] \times 10^{-7}$ and a pionless EFT constant of $C^{^{3}S_{1}\rightarrow ^{3}P_{1}}/C_{0}=[-7.4 \pm 3.5 (stat) \pm 0.5 (sys)] \times 10^{-11}$ MeV$^{-1}$. We describe the experiment, data analysis, systematic uncertainties, and the implications of the result.Comment: 6 pages, 5 figure

Fertility, Living Arrangements, Care and Mobility

There are four main interconnecting themes around which the contributions in this book are based. This introductory chapter aims to establish the broad context for the chapters that follow by discussing each of the themes. It does so by setting these themes within the overarching demographic challenge of the twenty-first century – demographic ageing. Each chapter is introduced in the context of the specific theme to which it primarily relates and there is a summary of the data sets used by the contributors to illustrate the wide range of cross-sectional and longitudinal data analysed

Glargine and degludec: solution behaviour of higher dose synthetic insulins

Single, double and triple doses of the synthetic insulins glargine and degludec currently used in patient therapy are characterised using macromolecular hydrodynamic techniques (dynamic light scattering and analytical ultracentrifugation) in an attempt to provide the basis for improved personalised insulin profiling in patients with diabetes. Using dynamic light scattering and sedimentation velocity in the analytical ultracentrifuge glargine was shown to be primarily dimeric under solvent conditions used in current formulations whereas degludec behaved as a dihexamer with evidence of further association of the hexamers (“multi-hexamerisation”). Further analysis by sedimentation equilibrium showed that degludec exhibited reversible interaction between mono- and-di-hexamer forms. Unlike glargine, degludec showed strong thermodynamic non-ideality, but this was suppressed by the addition of salt. With such large injectable doses of synthetic insulins remaining in the physiological system for extended periods of time, in some case 24–40 hours, double and triple dose insulins may impact adversely on personalised insulin profiling in patients with diabetes