Coordination of Replication-Coupled Protein Destruction and Origin Licensing Control During Cell Cycle Transitions

Timely ubiquitin-mediated protein degradation is fundamental to cell cycle control, but the precise degradation order at each cell cycle phase transition is still unclear. In this work, we investigated the degradation order of targets of a single human E3 ubiquitin ligase important for S-phase proteolysis, known as CRL4Cdt2. We showed that in both synchronized cells and asynchronously proliferating cells, CRL4Cdt2-mediated degradation of the cell cycle proteins Cdt1, p21, and PR-Set7 occurs in a consistent order during both the G1/S transition and during DNA repair synthesis. We additionally showed that these different rates of degradation are determined by the CRL4Cdt2 targeting motif called a PCNA interacting peptide (PIP) degron, which allows for substrate binding to DNA-bound proliferating cell nuclear antigen (PCNA) and recognition by CRL4Cdt2. Manipulating the degradation order such that p21 was degraded prematurely promoted stalled replication in mid-S phase and sensitivity to replication arrest. Collectively, these results establish for the first time that ordered degradation at the G1/S transition, facilitated by the CRL4Cdt2 E3 ligase, is important to avoid replication stress and genome instability. Another process that is tightly controlled at cell cycle transitions is replication origin licensing, in which replication initiation sites, or origins, are rendered competent for replication by the DNA loading of the replicative helicase, the Mini-Chromosome Maintenance (MCM) complex. Through the collective action of ORC, Cdc6, and Cdt1 proteins, MCM complexes are loaded onto DNA exclusively in G1 phase in an inactive form, and become activated by protein kinases during S phase. MCM loading is strictly inhibited beyond the G1/S transition and during cellular quiescence (G0 phase), although at the time of this study, mechanisms contributing to this licensing block specifically during G0 phase were poorly understood. To identify novel protein mediators of quiescence establishment and maintenance, we performed a mass spectrometry screen designed to identify differential MCM binding partners in quiescent vs. proliferating cells. We prioritized several novel MCM interactions uncovered from this initial screen for further validation experiments, including three with previously characterized roles in the control of cell proliferation/quiescence: Sam68 (KHDRBS1), Nme1, and Host Cell Factor C1 (HCFC1). Future work will be needed to improve the initial screening approach and to establish a role for these new MCM interactions in cell cycle control and/or MCM loading regulation.Doctor of Philosoph

Many Low Income Women In Texas Do Not Get the Effective Contraception They Want After Giving Birth

Population Research Cente

Care Works: Come Home for Care

Essential to executing the mission and vision of an academic medical center (AMC) is attracting and retaining the highest quality employees. As demonstrated by VCU’s commitment to the Great Place Initiative, the University has recognized that employees in today’s highly competitive environment demand competitive salary and benefit packages. Research has shown that access to high quality, on-site healthcare services provides significant benefits to both employees and employers, such as increased productivity and reduced wellness costs[1]. Yet, a query of de-identified patient records indicated that only a small percentage of VCU employees (~18%) utilized the health services provided by VCU Health System in 2016. VCU’s peer-institutions, other distinguished AMCs, and industry employers have implemented a variety of programs such as concierge services, expedited appointments, on-campus clinics, and lower copays to remain competitive and responsive to their employees. In light of the depth of these programs, Team CareWorks completed a comparative review of health and wellness related employee-specific benefits to determine how VCU might enhance its benefits through initiatives such as on-site medical clinics, prioritized appointments, telehealth, and on-site pharmacies. Informed by the comparative analysis, Team CareWorks will provide recommendations that VCU can use to: capitalize on the integrated relationship with VCU Health to enrich the health and wellness of its outstanding assets (the employees); and provide enhanced benefits to employees by making VCU Health more easily accessible and more appealing as a Medical Home. [1]Berry, Leonard, Ann M. Mirabito, & William B. Baun. “What\u27s the Hard Return on Employee Wellness Programs?” (2010). Harvard Business Review, December 2010.. Available at SSRN: https://ssrn.com/abstract=206487

Wireless energy behaviour monitoring (Wi-be) for office buildings

This paper presents a study on reduction of energy consumption in buildings through behaviour change informed by wireless monitoring systems for energy, environmental conditions and people positions. A key part to the Wi-Be system is the ability to accurately attribute energy usage behaviour to individuals, so they can be targeted with specific feedback tailored to their preferences. The use of wireless technologies for indoor positioning was investigated to ascertain the difficulties in deployment and potential benefits. The research to date has demonstrated the effectiveness of highly disaggregated personal-level data for developing insights into people’s energy behaviour and identifying significant energy saving opportunities (up to 77% in specific areas). Behavioural research addressed social issues such as privacy, which could affect the deployment of the system. Radio-frequency research into less intrusive technologies indicates that received-signal-strength-indicator-based systems should be able to detect the presence of a human body, though further work would be needed in both social and engineering areas

Age-related biological features of germ cell tumors.

Germ cell tumors (GCTs) are rare but clinically and pathologically diverse tumors that occur in an extensive range of age groups, from children to older adults and which include both seminomatous and nonseminomatous tumors. Current clinical management for both male and female teenagers and young adults (TYAs) with GCTs remains inconsistent, alternating between pediatric and adult multidisciplinary oncology teams, based on locally defined age cutoffs. Therefore, we reviewed available literature to determine the biological similarities and differences between GCTs in young children (0-12 years), TYAs (13-24 years), and older adults (>24 years). GCTs arising in pediatric and adult populations in general showed marked molecular biological differences within identical histological subtypes, whereas there was a distinct paucity of available data for GCTs in the TYA population. These findings highlight that clinical management based simply on chronological age may be inappropriate for TYA and suggests that the optimal future management of GCTs should consider specific molecular biological factors in addition to clinical parameters in the context of patient-specific age group rather than medical specialty.This is the accepted manuscript. The final version is available at http://onlinelibrary.wiley.com/doi/10.1002/gcc.22131/abstract

Post-Synapse Model Cell for Synaptic Glutamate Receptor (GluR)-Based Biosensing: Strategy and Engineering to Maximize Ligand-Gated Ion-Flux Achieving High Signal-to-Noise Ratio

Peer reviewe

Smoking and quit attempts during pregnancy and postpartum: a longitudinal UK cohort.

OBJECTIVES: Pregnancy motivates women to try stopping smoking, but little is known about timing of their quit attempts and how quitting intentions change during pregnancy and postpartum. Using longitudinal data, this study aimed to document women's smoking and quitting behaviour throughout pregnancy and after delivery. DESIGN: Longitudinal cohort survey with questionnaires at baseline (8-26 weeks' gestation), late pregnancy (34-36 weeks) and 3 months after delivery. SETTING: Two maternity hospitals in one National Health Service hospital trust, Nottingham, England. PARTICIPANTS: 850 pregnant women, aged 16 years or over, who were current smokers or had smoked in the 3 months before pregnancy, were recruited between August 2011 and August 2012. OUTCOME MEASURES: Self-reported smoking behaviour, quit attempts and quitting intentions. RESULTS: Smoking rates, adjusting for non-response at follow-up, were 57.4% (95% CI 54.1 to 60.7) at baseline, 59.1% (95% CI 54.9 to 63.4) in late pregnancy and 67.1% (95% CI 62.7 to 71.5) 3 months postpartum. At baseline, 272 of 488 current smokers had tried to quit since becoming pregnant (55.7%, 95% CI 51.3 to 60.1); 51.3% (95% CI 44.7 to 58.0) tried quitting between baseline and late pregnancy and 27.4% (95% CI 21.7 to 33.2) after childbirth. The percentage who intended to quit within the next month fell as pregnancy progressed, from 40.4% (95% CI 36.1 to 44.8) at baseline to 29.7% (95% CI 23.8 to 35.6) in late pregnancy and 14.2% (95% CI 10.0 to 18.3) postpartum. Postpartum relapse was lower among women who quit in the 3 months before pregnancy (17.8%, 95% CI 6.1 to 29.4) than those who stopped between baseline and late pregnancy (42.9%, 95% CI 24.6 to 61.3). CONCLUSIONS: Many pregnant smokers make quit attempts throughout pregnancy and postpartum, but intention to quit decreases over time; there is no evidence that smoking rates fall during gestation

Longitudinal cohort survey of women's smoking behaviour and attitudes in pregnancy: study methods and baseline data.

OBJECTIVES: To report the methods used to assemble a contemporary pregnancy cohort for investigating influences on smoking behaviour before, during and after pregnancy and to report characteristics of women recruited. DESIGN: Longitudinal cohort survey. SETTING: Two maternity hospitals, Nottingham, England. PARTICIPANTS: 3265 women who attended antenatal ultrasound scan clinics were offered cohort enrolment; those who were 8-26 weeks pregnant and were currently smoking or had recently stopped smoking were eligible. Cohort enrollment took place between August 2011 and August 2012. PRIMARY AND SECONDARY OUTCOME MEASURES: Prevalence of smoking at cohort entry and at two follow-up time points (34-36 weeks gestation and 3 months postnatally); response rate, participants' sociodemographic characteristics. RESULTS: 1101 (33.7%, 95% CI 32.1% to 35.4%) women were eligible for inclusion in the cohort, and of these 850 (77.2%, 95% CI 74.6% to 79.6%) were recruited. Within the cohort, 57.4% (N=488, 95% CI 54.1% to 60.7%) reported to be current smokers. Current smokers were significantly younger than ex-smokers (p<0.05), more likely to have no formal qualifications and to not be in current paid employment compared to recent ex-smokers (p<0.001). CONCLUSIONS: This contemporary cohort, which seeks very detailed information on smoking in pregnancy and its determinants, includes women with comparable sociodemographic characteristics to those in other UK cross-sectional studies and cohorts. This suggests that future analyses using this cohort and aimed at understanding smoking behaviour in pregnancy may produce findings that are broadly generalisable