The F-box protein Cdc4/Fbxw7 is a novel regulator of neural crest development in Xenopus laevis.

BACKGROUND: The neural crest is a unique population of cells that arise in the vertebrate ectoderm at the neural plate border after which they migrate extensively throughout the embryo, giving rise to a wide range of derivatives. A number of proteins involved in neural crest development have dynamic expression patterns, and it is becoming clear that ubiquitin-mediated protein degradation is partly responsible for this. RESULTS: Here we demonstrate a novel role for the F-box protein Cdc4/Fbxw7 in neural crest development. Two isoforms of Xenopus laevis Cdc4 were identified, and designated xCdc4alpha and xCdc4beta. These are highly conserved with vertebrate Cdc4 orthologs, and the Xenopus proteins are functionally equivalent in terms of their ability to degrade Cyclin E, an established vertebrate Cdc4 target. Blocking xCdc4 function specifically inhibited neural crest development at an early stage, prior to expression of c-Myc, Snail2 and Snail. CONCLUSIONS: We demonstrate that Cdc4, an ubiquitin E3 ligase subunit previously identified as targeting primarily cell cycle regulators for proteolysis, has additional roles in control of formation of the neural crest. Hence, we identify Cdc4 as a protein with separable but complementary functions in control of cell proliferation and differentiation

The effect of a randomized 12-week soy drink intervention on everyday mood in postmenopausal women

Objective: Dietary soy may improve menopausal symptoms, and subsequently mediate mood. This novel study examines various doses of dietary soy drink on everyday mood stability and variability in postmenopausal women. Methods: Community-dwelling women (n = 101), within 7 years postmenopause, consumed daily either a low (10 mg, n = 35), medium (35 mg, n = 37), or high (60 mg, n = 29) dose of isoflavones, for 12 weeks. Menopausal symptoms and repeated measures of everyday mood (positive [PA] and negative [NA] affect) (assessed at four time points per day for 4 consecutive days, using The Positive and Negative Affect Schedule) were completed at baseline and follow-up. Results: The dietary soy intervention had no effect on everyday mood stability (for PA [F{2,70} = 0.95, P = 0.390] and NA [F{2,70} = 0.72, P = 0.489]) or variability (for PA [F{2,70} = 0.21, P = 0.807] and for NA [F{2,70} = 0.15, P = 0.864]), or on menopausal symptoms (for vasomotor [F{2,89} = 2.83, P = 0.064], psychological [F{2,88} = 0.63, P = 0.535], somatic [F{2,89} = 0.32, P = 0.729], and total menopausal symptoms [F{2,86} = 0.79, P = 0.458]). There were between-group differences with the medium dose reporting higher PA (low, mean 24.2, SD 6; and medium, mean 29.7, SD 6) and the low dose reporting higher NA (P = 0. 048) (low, mean 11.6, SD 2; and high, mean 10.6, SD 1) in mood scores. Psychological (baseline M = 18 and follow-up M = 16.5) and vasomotor (baseline M = 4.2 and follow-up M = 3.6) scores declined from baseline to follow-up for the overall sample. Conclusions: Soy isoflavones had no effect on mood at any of the doses tested. Future research should focus on the menopause transition from peri to postmenopause as there may be a window of vulnerability, with fluctuating hormones and increased symptoms which may affect mood

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Micro ring-disk electrode probes for scanning electrochemical microscopy

Abstract The construction and characterisation of ring-disk (RD) microelectrodes suitable for use in scanning electrochemical microscopy (SECM) is reported. Such RD electrodes are proposed as probes for novel generator-collector SECM experiments. In this case, the interaction of both the reactants and products with the substrate under investigation can be followed simultaneously from a single approach curve to the substrate. Examples of such approach curves to conducting and insulating substrates are given to demonstrate the potential of this new mode of SECM operation.