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

Increases in obstetric interventions and changes in gestational age distributions of U.S. births

Objective: To examine how changes in induction of labor (IOL) and cesarean deliveries between 1990 and 2017 affected gestational age distributions of births in the United States. Materials and Methods: Singleton first births were drawn from the National Vital Statistics System Birth Data for years 1990–2017. Separate analytic samples were created (1) by maternal race/ethnicity (Hispanic, non-Hispanic Black, non-Hispanic Asian, and non-Hispanic white), (2) by maternal age (15–19, 20–24, 25–29, 30–34, 35–39, 40–49), (3) by U.S. states, and (4) for women at low risk for obstetric interventions (e.g., age 20–34, no hypertension, no diabetes, no tobacco use). Gestational age was measured in weeks, and obstetric intervention status was measured as: (1) no IOL, vaginal delivery; (2) no IOL, cesarean delivery; and (3) IOL, all deliveries. The joint probabilities of birth at each gestational week by obstetric intervention status for years 1990–1991, 1998–1999, 2007–2008, and 2016–2017 were estimated. Results: Between 1990 and 2017, the percent of singleton first births occurring between 37 and 39 weeks of gestation increased from 38.5% to 49.5%. The changes were driven by increases in IOL and a shift in the use of cesarean deliveries toward earlier gestations. The changes were observed among all racial/ethnic groups and all maternal ages, and across all U.S. states. The same changes were also observed among U.S. women at low risk for interventions. Conclusion: Changes in gestational age distributions of U.S. births and their underlying causes are likely national-level phenomena and do not appear to be responding to increases in maternal risk for interventions

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

Differences in determinants: racialized obstetric care and increases in U.S. state labor induction rates

Induction of labor (IOL) rates in the United States have nearly tripled since 1990. We examine official U.S. birth records to document increases in states’ IOL rates among pregnancies to Black, Latina, and White women. We test if the increases are associated with changes in demographic characteristics and risk factors among states’ racial-ethnic childbearing populations. Among pregnancies to White women, increases in state IOL rates are strongly associated with changes in risk factors among White childbearing populations. However, the rising IOL rates among pregnancies to Black and Latina women are not due to changing factors in their own populations but are instead driven by changing factors among states’ White childbearing populations. The results suggest systemic racism may be shaping U.S. obstetric care whereby care is not “centered at the margins” but is instead responsive to characteristics in states’ White populations

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