Cryo-EM structure of a helicase loading intermediate containing ORC-Cdc6-Cdt1-MCM2-7 bound to DNA

In eukaryotes, the Cdt1-bound replicative helicase core MCM2-7 is loaded onto DNA by the ORC-Cdc6 ATPase to form a prereplicative complex (pre-RC) with an MCM2-7 double hexamer encircling DNA. Using purified components in the presence of ATP-γS, we have captured in vitro an intermediate in pre-RC assembly that contains a complex between the ORC-Cdc6 and Cdt1-MCM2-7 heteroheptamers called the OCCM. Cryo-EM studies of this 14-subunit complex reveal that the two separate heptameric complexes are engaged extensively, with the ORC-Cdc6 N-terminal AAA+ domains latching onto the C-terminal AAA+ motor domains of the MCM2-7 hexamer. The conformation of ORC-Cdc6 undergoes a concerted change into a right-handed spiral with helical symmetry that is identical to that of the DNA double helix. The resulting ORC-Cdc6 helicase loader shows a notable structural similarity to the replication factor C clamp loader, suggesting a conserved mechanism of action

Pregnant women\u27s alcohol consumption : the predictive utility of intention to drink and prepregnancy drinking behaviour

Objective: This study had two aims: (1) to examine pregnant women\u27s alcohol consumption across time from prepregnancy until childbirth and (2) to explore whether prepregnancy drinking and intention to drink predict prenatal alcohol consumption while controlling for relevant demographic variables.Methods: At 17&ndash;21 weeks, 248 pregnant women completed questions about demographics, intention to drink alcohol during the subsequent pregnancy, and retrospective measures of prepregnancy and early pregnancy consumption. After this time, calendars were sent fortnightly assessing daily alcohol consumption until birth.Results: For women who drank both prepregnancy and postpregnancy confirmation, average fortnight alcohol consumption in the first weeks of pregnancy was lower than during prepregnancy, and consumption continued to decrease between gestational weeks 1 and 8, particularly following pregnancy confirmation, after which it remained relatively stable. When predicting whether women drank in late pregnancy, intention accounted for unique variance after controlling for income and prepregnancy drinking. For women who drank after pregnancy confirmation, prepregnancy drinking quantity significantly predicted intention to drink, which in turn predicted fortnight alcohol consumption in later pregnancy, after controlling for prepregnancy drinking and income.Conclusions: Findings highlight the need to measure alcohol consumption at multiple time points across pregnancy, the need for educating and supporting women to reduce consumption when planning pregnancies, and the usefulness of intention to drink as a predictor of drinking during pregnancy.<br /

Considering the Case for Biodiversity Cycles: Reexamining the Evidence for Periodicity in the Fossil Record

Medvedev and Melott (2007) have suggested that periodicity in fossil biodiversity may be induced by cosmic rays which vary as the Solar System oscillates normal to the galactic disk. We re-examine the evidence for a 62 million year (Myr) periodicity in biodiversity throughout the Phanerozoic history of animal life reported by Rohde & Mueller (2005), as well as related questions of periodicity in origination and extinction. We find that the signal is robust against variations in methods of analysis, and is based on fluctuations in the Paleozoic and a substantial part of the Mesozoic. Examination of origination and extinction is somewhat ambiguous, with results depending upon procedure. Origination and extinction intensity as defined by RM may be affected by an artifact at 27 Myr in the duration of stratigraphic intervals. Nevertheless, when a procedure free of this artifact is implemented, the 27 Myr periodicity appears in origination, suggesting that the artifact may ultimately be based on a signal in the data. A 62 Myr feature appears in extinction, when this same procedure is used. We conclude that evidence for a periodicity at 62 Myr is robust, and evidence for periodicity at approximately 27 Myr is also present, albeit more ambiguous.Comment: Minor modifications to reflect final published versio

The what and where of adding channel noise to the Hodgkin-Huxley equations

One of the most celebrated successes in computational biology is the Hodgkin-Huxley framework for modeling electrically active cells. This framework, expressed through a set of differential equations, synthesizes the impact of ionic currents on a cell's voltage -- and the highly nonlinear impact of that voltage back on the currents themselves -- into the rapid push and pull of the action potential. Latter studies confirmed that these cellular dynamics are orchestrated by individual ion channels, whose conformational changes regulate the conductance of each ionic current. Thus, kinetic equations familiar from physical chemistry are the natural setting for describing conductances; for small-to-moderate numbers of channels, these will predict fluctuations in conductances and stochasticity in the resulting action potentials. At first glance, the kinetic equations provide a far more complex (and higher-dimensional) description than the original Hodgkin-Huxley equations. This has prompted more than a decade of efforts to capture channel fluctuations with noise terms added to the Hodgkin-Huxley equations. Many of these approaches, while intuitively appealing, produce quantitative errors when compared to kinetic equations; others, as only very recently demonstrated, are both accurate and relatively simple. We review what works, what doesn't, and why, seeking to build a bridge to well-established results for the deterministic Hodgkin-Huxley equations. As such, we hope that this review will speed emerging studies of how channel noise modulates electrophysiological dynamics and function. We supply user-friendly Matlab simulation code of these stochastic versions of the Hodgkin-Huxley equations on the ModelDB website (accession number 138950) and http://www.amath.washington.edu/~etsb/tutorials.html.Comment: 14 pages, 3 figures, review articl

Can Reproductive Health Voucher Programs Improve Quality of Postnatal Care? A Quasi-Experimental Evaluation of Kenya’s Safe Motherhood Voucher Scheme

This study tests the group-level causal relationship between the expansion of Kenya’s Safe Motherhood voucher program and changes in quality of postnatal care (PNC) provided at voucher-contracted facilities. We compare facilities accredited since program inception in 2006 (phase I) and facilities accredited since 2010-2011 (phase II) relative to comparable non-voucher facilities. PNC quality is assessed using observed clinical content processes, as well as client-reported outcome measures. Two-tailed unpaired t-tests are used to identify differences in mean process quality scores and client-reported outcome measures, comparing changes between intervention and comparison groups at the 2010 and 2012 data collection periods. Difference-in-differences analysis is used to estimate the reproductive health (RH) voucher program’s causal effect on quality of care by exploiting group-level differences between voucher-accredited and non-accredited facilities in 2010 and 2012. Participation in the voucher scheme since 2006 significantly improves overall quality of postnatal care by 39% (p=0.02), where quality is defined as the observable processes or components of service provision that occur during a PNC consultation. Program participation since phase I is estimated to improve the quality of observed maternal postnatal care by 86% (p=0.02), with the largest quality improvements in counselling on family planning methods (IRR 5.0; p=0.01) and return to fertility (IRR 2.6; p=0.01). Despite improvements in maternal aspects of PNC, we find a high proportion of mothers who seek PNC are not being checked by any provider after delivery. Additional strategies will be necessary to standardize provision of packaged postnatal interventions to both mother and new-born. This study addresses an important gap in the existing RH literature by using a strong evaluation design to assess RH voucher program effectiveness on quality improvement

Dynamics of localization in a waveguide

This is a review of the dynamics of wave propagation through a disordered N-mode waveguide in the localized regime. The basic quantities considered are the Wigner-Smith and single-mode delay times, plus the time-dependent power spectrum of a reflected pulse. The long-time dynamics is dominated by resonant transmission over length scales much larger than the localization length. The corresponding distribution of the Wigner-Smith delay times is the Laguerre ensemble of random-matrix theory. In the power spectrum the resonances show up as a 1/t^2 tail after N^2 scattering times. In the distribution of single-mode delay times the resonances introduce a dynamic coherent backscattering effect, that provides a way to distinguish localization from absorption.Comment: 18 pages including 8 figures; minor correction

Subthreshold depression as a risk indicator for major depressive disorder: a systematic review of prospective studies.

Objective: In order to examine whether the incidence of major depressive disorder (MDD) is increased in subjects with subthreshold depression, or sD (clinically relevant depressive symptoms, without meeting criteria for a full-blown MDD), we conducted a review of prospective studies examining the incidence of MDD in subjects with sD. Method: A systematic literature search was conducted. For all studies, the relative risk of developing MDD was calculated, based on person-years. Results: Twenty studies (23 comparisons) were found, based on community samples, general medical patients and high-risk subjects. Most comparisons showed that subjects with sD had a consistently larger chance of developing MDD. The studies differed considerably in the definition of sD, the recency (occurrence of the last sD) and the in-/ exclusion of lifetime MDD. Conclusion: The incidence of MDD in subjects with sD is larger than in subjects without sD. Otherwise, the concept of sD is too broad to be used. In future studies, some consensus should be reached regarding the definition of sD

Memory development: implications for adults recalling childhood experiences in the courtroom

Adults frequently provide compelling, detailed accounts of early childhood experiences in the courtroom. Judges and jurors are asked to decide guilt or innocence based solely on these decades-old memories using 'common sense' notions about memory. However, these notions are not in agreement with findings from neuroscientific and behavioural studies of memory development. Without expert guidance, judges and jurors may have difficulty in properly adjudicating the weight of memory evidence in cases involving adult recollections of childhood experiences

Organizational factors and depression management in community-based primary care settings

Abstract Background Evidence-based quality improvement models for depression have not been fully implemented in routine primary care settings. To date, few studies have examined the organizational factors associated with depression management in real-world primary care practice. To successfully implement quality improvement models for depression, there must be a better understanding of the relevant organizational structure and processes of the primary care setting. The objective of this study is to describe these organizational features of routine primary care practice, and the organization of depression care, using survey questions derived from an evidence-based framework. Methods We used this framework to implement a survey of 27 practices comprised of 49 unique offices within a large primary care practice network in western Pennsylvania. Survey questions addressed practice structure (e.g., human resources, leadership, information technology (IT) infrastructure, and external incentives) and process features (e.g., staff performance, degree of integrated depression care, and IT performance). Results The results of our survey demonstrated substantial variation across the practice network of organizational factors pertinent to implementation of evidence-based depression management. Notably, quality improvement capability and IT infrastructure were widespread, but specific application to depression care differed between practices, as did coordination and communication tasks surrounding depression treatment. Conclusions The primary care practices in the network that we surveyed are at differing stages in their organization and implementation of evidence-based depression management. Practical surveys such as this may serve to better direct implementation of these quality improvement strategies for depression by improving understanding of the organizational barriers and facilitators that exist within both practices and practice networks. In addition, survey information can inform efforts of individual primary care practices in customizing intervention strategies to improve depression management.http://deepblue.lib.umich.edu/bitstream/2027.42/78269/1/1748-5908-4-84.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78269/2/1748-5908-4-84-S1.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78269/3/1748-5908-4-84.pdfPeer Reviewe