Crystal structure of Hop2-Mnd1 and mechanistic insights into its role in meiotic recombination

In meiotic DNA recombination, the Hop2-Mnd1 complex promotes Dmc1-mediated single-stranded DNA (ssDNA) invasion into homologous chromosomes to form a synaptic complex by a yet-unclear mechanism. Here, the crystal structure of Hop2-Mnd1 reveals that it forms a curved rod-like structure consisting of three leucine zippers and two kinked junctions. One end of the rod is linked to two juxtaposed winged-helix domains, and the other end is capped by extra ?-helices to form a helical bundle-like structure. Deletion analysis shows that the helical bundle-like structure is sufficient for interacting with the Dmc1-ssDNA nucleofilament, and molecular modeling suggests that the curved rod could be accommodated into the helical groove of the nucleofilament. Remarkably, the winged-helix domains are juxtaposed at fixed relative orientation, and their binding to DNA is likely to perturb the base pairing according to molecular simulations. These findings allow us to propose a model explaining how Hop2-Mnd1 juxtaposes Dmc1-bound ssDNA with distorted recipient double-stranded DNA and thus facilitates strand invasion

Job Resources and Matching Active Coping Styles as Moderators of the Longitudinal Relation Between Job Demands and Job Strain

Background: Only in a few longitudinal studies it has been examined whether job resources should be matched to job demands to show stress-buffering effects of job resources (matching hypothesis), while there are no empirical studies in which the moderating effect of matching personal characteristics on the stress-buffering effect of job resources has been examined. Purpose: In this study, both the matching hypothesis and the moderating effect of matching active coping styles were examined with respect to the longitudinal relation between job demands, job resources, and job strain.Method: The study group consisted of 317 beginning teachers from Belgium. The two-wave survey data with a 1-year time lag were analyzed by means of structural equation modeling and multiple group analyses. Results: Data did not support the matching hypothesis. In addition, no support was found for the moderating effect of specific active coping styles, irrespective of the level of match. Conclusion: To show stress-buffering effects of job resources, it seems to make no difference whether or not specific types of job demands and job resources are matched, and whether or not individual differences in specific active coping styles are taken into account

Ultrasound-guided breast-sparing surgery to improve cosmetic outcomes and quality of life. A prospective multicentre randomised controlled clinical trial comparing ultrasound-guided surgery to traditional palpation-guided surgery (COBALT trial)

<p>Abstract</p> <p>Background</p> <p>Breast-conserving surgery for breast cancer was developed as a method to preserve healthy breast tissue, thereby improving cosmetic outcomes. Thus far, the primary aim of breast-conserving surgery has been the achievement of tumour-free resection margins and prevention of local recurrence, whereas the cosmetic outcome has been considered less important. Large studies have reported poor cosmetic outcomes in 20-40% of patients after breast-conserving surgery, with the volume of the resected breast tissue being the major determinant. There is clear evidence for the efficacy of ultrasonography in the resection of nonpalpable tumours. Surgical resection of palpable breast cancer is performed with guidance by intra-operative palpation. These palpation-guided excisions often result in an unnecessarily wide resection of adjacent healthy breast tissue, while the rate of tumour-involved resection margins is still high. It is hypothesised that the use of intra-operative ultrasonography in the excision of palpable breast cancer will improve the ability to spare healthy breast tissue while maintaining or even improving the oncological margin status. The aim of this study is to compare ultrasound-guided surgery for palpable tumours with the standard palpation-guided surgery in terms of the extent of healthy breast tissue resection, the percentage of tumour-free margins, cosmetic outcomes and quality of life.</p> <p>Methods/design</p> <p>In this prospective multicentre randomised controlled clinical trial, 120 women who have been diagnosed with palpable early-stage (T1-2N0-1) primary invasive breast cancer and deemed suitable for breast-conserving surgery will be randomised between ultrasound-guided surgery and palpation-guided surgery. With this sample size, an expected 20% reduction of resected breast tissue and an 18% difference in tumour-free margins can be detected with a power of 80%. Secondary endpoints include cosmetic outcomes and quality of life. The rationale, study design and planned analyses are described.</p> <p>Conclusion</p> <p>The COBALT trial is a prospective, multicentre, randomised controlled study to assess the efficacy of ultrasound-guided breast-conserving surgery in patients with palpable early-stage primary invasive breast cancer in terms of the sparing of breast tissue, oncological margin status, cosmetic outcomes and quality of life.</p> <p>Trial Registration Number</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2579">NTR2579</a></p

Alteration in P-glycoprotein Functionality Affects Intrabrain Distribution of Quinidine More Than Brain Entry—A Study in Rats Subjected to Status Epilepticus by Kainate

This study aimed to investigate the use of quinidine microdialysis to study potential changes in brain P-glycoprotein functionality after induction of status epilepticus (SE) by kainate. Rats were infused with 10 or 20 mg/kg quinidine over 30 min or 4 h. Plasma, brain extracellular fluid (brain ECF), and end-of-experiment total brain concentrations of quinidine were determined during 7 h after the start of the infusion. Effect of pretreatment with tariquidar (15 mg/kg, administered 30 min before the start of the quinidine infusion) on the brain distribution of quinidine was assessed. This approach was repeated in kainate-treated rats. Quinidine kinetics were analyzed with population modeling (NONMEM). The quinidine microdialysis assay clearly revealed differences in brain distribution upon changes in P-glycoprotein functionality by pre-administration of tariquidar, which resulted in a 7.2-fold increase in brain ECF and a 40-fold increase in total brain quinidine concentration. After kainate treatment alone, however, no difference in quinidine transport across the blood–brain barrier was found, but kainate-treated rats tended to have a lower total brain concentration but a higher brain ECF concentration of quinidine than saline-treated rats. This study did not provide evidence for the hypothesis that P-glycoprotein function at the blood–brain barrier is altered at 1 week after SE induction, but rather suggests that P-glycoprotein function might be altered at the brain parenchymal level

Local Difference Measures between Complex Networks for Dynamical System Model Evaluation

Acknowledgments We thank Reik V. Donner for inspiring suggestions that initialized the work presented herein. Jan H. Feldhoff is credited for providing us with the STARS simulation data and for his contributions to fruitful discussions. Comments by the anonymous reviewers are gratefully acknowledged as they led to substantial improvements of the manuscript.Peer reviewedPublisher PD

A Longitudinal Test of the Demand–Control Model Using Specific Job Demands and Specific Job Control

# The Author(s) 2010. This article is published with open access at Springerlink.com Background Supportive studies of the demand–control (DC) model were more likely to measure specific demands combined with a corresponding aspect of control. Purpose A longitudinal test of Karasek’s (Adm Sci Q. 24:285–308, 1) job strain hypothesis including specific measures of job demands and job control, and both selfreport and objectively recorded well-being. Method Job strain hypothesis was tested among 267 health care employees from a two-wave Dutch panel survey with a 2-year time lag. Results Significant demand/control interactions were found for mental and emotional demands, but not for physical demands. The association between job demands and job satisfaction was positive in case of high job control, whereas this association was negative in case of low job control. In addition, the relation between job demands and J. de Jonge (*

Workdays, in-between workdays and the weekend: a diary study on effort and recovery

Contains fulltext : 55892.pdf (publisher's version ) (Closed access)16 p

Investigating the Associations among Overtime Work, Health Behaviors, and Health: A Longitudinal Study among Full-time Employees

# The Author(s) 2010. This article is published with open access at Springerlink.com Background It has often been suggested that high levels of overtime lead to adverse health outcomes. One mechanism that may account for this association is that working overtime leads to elevated levels of stress, which could affect worker’s behavioral decisions or habits (such as smoking and lack of physical activity). In turn, this could lead to adverse health. Purpose The present study examined this reasoning in a prospective longitudinal design. Data from the prospective 2-year Study on Health at Work (N=649) were used to test our hypotheses. Methods Structural equation analysis was used to examine the relationships among overtime, beneficial (exercising, intake of fruit and vegetables) and risky (smoking and drinking) health behaviors, and health indicators (BMI and subjective health). Results Working overtime was longitudinally related with adverse subjective health, but not with body mass

Occupation and mental health in a national UK survey

This paper and the analyses it describes were funded by the Health and Safety Executive (HSE)