The role of gender in MPH graduates' salaries.

PubMed

Bradley, E H; White, W; Anderson, E; Mattocks, K; Pistell, A

2000-01-01

Several studies have demonstrated that workforce roles and salaries differ substantially between men and women in administrative positions within the health care industry. Recent studies of graduates with masters of business administration (MBA) and masters of health administration (MHA) degrees have indicated that women tend to experience lower salaries, given like responsibilities. However, the impact of gender on salary has been less studied among masters of public health (MPH) graduates in the health care field. Our objective was to assess the impact of gender on salary among MPH degree graduates. Using a cross-sectional survey of all graduates from the MPH program at Yale University between 1991-1997 (n = 201, response rate = 51%), we ascertained graduates' reported salary in the first job post-graduation and reported salary in their current position. Bivariate and multivariate analyses were used to assess the unadjusted and adjusted associations between gender and salary. Salaries in both the first job post-graduation and in the current job differed significantly by gender, with women earning less than men (p-values < .05). Moreover, these differences persisted after controlling for a set of human capital measures including pre-MPH work experience, age at graduation, years since graduation, area of specialization within the MPH degree, and type of work site (governmental or nonprofit versus for-profit). Unlike studies of MBA and MHA graduates, however, this study did not find evidence that the gender-related salary gap widened as the years since graduation increased, although the sample size did not allow comprehensive testing of this trend.

70 mph study : final report.

DOT National Transportation Integrated Search

2016-06-30

In July and August 2014, the Pennsylvania Department of Transportation (PennDOT) and Pennsylvania Turnpike Commission : (PTC) raised the posted speed limit on rural sections of Interstates 80, 380, and 76 from 65 to 70 mph. The purpose of this study ...

MPH program adaptability in a competitive marketplace: the case for continued assessment.

PubMed

Caron, Rosemary M; Tutko, Holly

2010-06-01

In the last several years, the number of Master of Public Health (MPH) programs has increased rapidly in the US. As such, MPH programs, particularly smaller-sized ones, need to critically examine how their programs are meeting the needs and preferences of local public health practitioners. To assist in this necessity, the University of New Hampshire conducted a comprehensive educational assessment of its effectiveness as a smaller-sized, accredited MPH program. The aim of the assessment was to review the MPH program from the perspective of all stakeholders and then to agree on changes that would contribute to the fulfillment of the program's mission, as well as improve program quality and reach. The program's stakeholders examined the following components: policy development and implementation; target audience; marketing strategies; marketplace position; delivery model; curriculum design; and continuing education. Though assessment activities explored a wide array of program attributes, target audience, curriculum design, and delivery strategy presented significant challenges and opportunities for our smaller MPH Program to remain competitive. The effort put forth into conducting an in-depth assessment of the core components of our program also allowed for a comparison to the increasing number of MPH programs developing regionally. Since public health practice is changing and the education of public health practitioners must be adaptable, we propose that a routine assessment of an institution's MPH program could not only meet this need but also assist with keeping smaller, unbranded MPH programs competitive in a burgeoning marketplace.

Grantee Spotlight: Katherine Briant, MPH, CHES

Cancer.gov

Katherine Briant, MPH, CHES, is Community Health Educator in NCI’s National Outreach Network links NCI-supported outreach and community education efforts and cancer health disparities research and training programs.

MPH-M, AODV-M and DSR-M Performance Evaluation under Jamming Attacks.

PubMed

Del-Valle-Soto, Carolina; Mex-Perera, Carlos; Monroy, Raul; Nolazco-Flores, Juan A

2017-07-05

In this work, we present the design of a mitigation scheme for jamming attacks integrated to the routing protocols MPH, AODV, and DSR. The resulting protocols are named MPH-M (Multi-Parent Hierarchical - Modified), AODV-M (Ad hoc On Demand Distance Vector - Modified), and DSR-M (Dynamic Source Routing - Modified). For the mitigation algorithm, if the detection algorithm running locally in each node produces a positive result then the node is isolated; second, the routing protocol adapts their paths avoiding the isolated nodes. We evaluated how jamming attacks affect different metrics for all these modified protocols. The metrics we employ to detect jamming attack are number of packet retransmissions, number of CSMA/CA (Carrier Sense Multiple Access with Collision Avoidance) retries while waiting for an idle channel and the energy wasted by the node. The metrics to evaluate the performance of the modified routing protocols are the throughput and resilience of the system and the energy used by the nodes. We evaluated all the modified protocols when the attacker position was set near, middle and far of the collector node. The results of our evaluation show that performance for MPH-M is much better than AODV-M and DSR-M. For example, the node energy for MPH-M is 138.13% better than AODV-M and 126.07% better than DSR-M. Moreover, we also find that MPH-M benefits much more of the mitigation scheme than AODV-M and DSR-M. For example, the node energy consumption is 34.61% lower for MPH-M and only 3.92% and 3.42% for AODV-M and DSR-M, respectively. On throughput, the MPH protocol presents a packet reception efficiency at the collector node of 16.4% on to AODV and DSR when there is no mitigation mechanism. Moreover, MPH-M has an efficiency greater than 7.7% with respect to AODV-M and DSR-M when there is a mitigation scheme. In addition, we have that with the mitigation mechanism AODV-M and DSR-M do not present noticeable modification. However, MPH-M improves its efficiency

MPH-M, AODV-M and DSR-M Performance Evaluation under Jamming Attacks

PubMed Central

Del-Valle-Soto, Carolina

2017-01-01

In this work, we present the design of a mitigation scheme for jamming attacks integrated to the routing protocols MPH, AODV, and DSR. The resulting protocols are named MPH-M (Multi-Parent Hierarchical - Modified), AODV-M (Ad hoc On Demand Distance Vector - Modified), and DSR-M (Dynamic Source Routing - Modified). For the mitigation algorithm, if the detection algorithm running locally in each node produces a positive result then the node is isolated; second, the routing protocol adapts their paths avoiding the isolated nodes. We evaluated how jamming attacks affect different metrics for all these modified protocols. The metrics we employ to detect jamming attack are number of packet retransmissions, number of CSMA/CA (Carrier Sense Multiple Access with Collision Avoidance) retries while waiting for an idle channel and the energy wasted by the node. The metrics to evaluate the performance of the modified routing protocols are the throughput and resilience of the system and the energy used by the nodes. We evaluated all the modified protocols when the attacker position was set near, middle and far of the collector node. The results of our evaluation show that performance for MPH-M is much better than AODV-M and DSR-M. For example, the node energy for MPH-M is 138.13% better than AODV-M and 126.07% better than DSR-M. Moreover, we also find that MPH-M benefits much more of the mitigation scheme than AODV-M and DSR-M. For example, the node energy consumption is 34.61% lower for MPH-M and only 3.92% and 3.42% for AODV-M and DSR-M, respectively. On throughput, the MPH protocol presents a packet reception efficiency at the collector node of 16.4% on to AODV and DSR when there is no mitigation mechanism. Moreover, MPH-M has an efficiency greater than 7.7% with respect to AODV-M and DSR-M when there is a mitigation scheme. In addition, we have that with the mitigation mechanism AODV-M and DSR-M do not present noticeable modification. However, MPH-M improves its efficiency

Structure and Function of the Macrolide Biosensor Protein, MphR(A), with and without Erythromycin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng, Jianting; Sagar, Vatsala; Smolinsky, Adam

2009-09-02

The regulatory protein MphR(A) has recently seen extensive use in synthetic biological applications, such as metabolite sensing and exogenous control of gene expression. This protein negatively regulates the expression of a macrolide 2{prime}-phosphotransferase I resistance gene (mphA) via binding to a 35-bp DNA operator upstream of the start codon and is de-repressed by the presence of erythromycin. Here, we present the refined crystal structure of the MphR(A) protein free of erythromycin and that of the MphR(A) protein with bound erythromycin at 2.00- and 1.76-{angstrom} resolutions, respectively. We also studied the DNA binding properties of the protein and identified mutants ofmore » MphR(A) that are defective in gene repression and ligand binding in a cell-based reporter assay. The combination of these two structures illustrates the molecular basis of erythromycin-induced gene expression and provides a framework for additional applied uses of this protein in the isolation and engineered biosynthesis of polyketide natural products.« less

Using business plan development as a capstone project for MPH programs in Canada: validation through the student perspective.

PubMed

Papadopoulos, Andrew; Britten, Nicole; Hatcher, Meghan; Rainville, Keira

2013-10-01

Master of Public Health (MPH) programs have been developed across Canada as a response to the need for adequately trained individuals to work in the public health sector. Educational institutions that deliver MPH programs have a responsibility to ensure that graduates of their program have the essential knowledge, skills and attitudes to begin a successful career in public health. The Public Health Agency of Canada has created the core competencies for public health to guide the development, delivery and evaluation of MPH programs. In Canada, a capstone project is the recommended method of evaluating the MPH graduate's ability to demonstrate proficiency in the public health core competencies. A business plan that develops the framework for a public health program is an ideal capstone project currently used in practice within the University of Guelph MPH program. This group assignment incorporates all 36 of the public health core competencies while providing students with a real-world public health experience, and should be considered for inclusion within MPH programs across Canada. Business planning provides students the opportunity to engage in practice-based learning, applying theoretical knowledge to practice. Further, the ability to develop realistic but financially feasible public health problems is an invaluable skill for MPH graduates. As the development of programs becomes more restricted and the continuation of other programs are under constant threat, the ability to develop a sound business plan is a required skill for individuals entering the public health sector, and will ensure students are able to maximize outcomes given tight fiscal budgets and limited resources.

Requirement of mismatch repair genes MSH2 and MSH3 in the RAD1-RAD10 pathway of mitotic recombination in Saccharomyces cerevisiae.

PubMed

Saparbaev, M; Prakash, L; Prakash, S

1996-03-01

The RAD1 and RAD10 genes of Saccharomyces cerevisiae are required for nucleotide excision repair and they also act in mitotic recombination. The Rad1-Rad10 complex has a single-stranded DNA endonuclease activity. Here, we show that the mismatch repair genes MSH2 and MSH3 function in mitotic recombination. For both his3 and his4 duplications, and for homologous integration of a linear DNA fragment into the genome, the msh3 delta mutation has an effect on recombination similar to that of the rad1 delta and rad10 delta mutations. The msh2 delta mutation also reduces the rate of recombination of the his3 duplication and lowers the incidence of homologous integration of a linear DNA fragment. Epistasis analyses indicate that MSH2 and MSH3 function in the RAD1-RAD10 recombination pathway, and studies presented here suggest an involvement of the RAD1-RAD10 pathway in reciprocal recombination. The possible roles of Msh2, Msh3, Rad1, and Rad10 proteins in genetic recombination are discussed. Coupling of mismatch binding proteins with the recombinational machinery could be important for ensuring genetic fidelity in the recombination process.

Cost-benefit analysis of the 55-mph speed limit

DOE Office of Scientific and Technical Information (OSTI.GOV)

Forester, T.H.; McNown, R.F.; Singell, L.D.

1984-01-01

This article presents the results of an empirical study which estimates the number of reduced fatalities as a result of the imposed 55-mph speed limit. Time series data for the US from 1952 to 1979 is employed in a regression model capturing the relation between fatalities, average speed, variability of speed, and the speed limit. Also discussed are the alternative approaches to valuing human life and the value of time. Provided is a series of benefit-cost ratios based on alternative measures of the benefits and costs from life saving. The paper concludes that the 55-mph speed limit is not costmore » efficient unless additional time on the highway is valued significantly below levels estimated in the best reasearch on the value of time. 12 references, 1 table.« less

Coordination success and interpersonal perceptions: matching versus mismatching.

PubMed

Abele, Susanne; Stasser, Garold

2008-09-01

Coordination is an essential part of social functioning. The authors distinguish 2 types of coordination: matching and mismatching. In matching, coordination is successful if parties choose the same action. In mismatching, coordination is successful if people choose different actions. In 3 studies, the authors investigated the downstream social consequences of tacit coordination for interpersonal perceptions. In all studies, participants repeatedly choose between 2 bets with equivalent expected values, and payoffs increased either when they choose the same bet or when they choose different bets. In the 1st 2 studies, coordination success increased the perceptions of interpersonal similarity and liking when matching was required but not when mismatching was required. The authors' interpretation is that matching responses and coordination success had countervailing effects in the mismatching task. Also, percentage of matched responses did not affect perceptions when coordination was not required (Experiment 2). In 4 person teams, a frequently matching partner was viewed more favorably (smarter, more similar to self, and more liked) than were other teammates, even when mismatching increased payoffs (Experiment 3).

Requirement of mismatch repair genes MSH2 and MSH3 in the RAD1-RAD10 pathway of mitotic recombination in Saccharomyces cerevisiae

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saparbaev, M.; Prakash, L.; Prakash, S.

1996-03-01

The RAD1 and RAD10 genes of Saccharomyces cerevisiae are required for nucleotide excision repair and they also act in mitotic recombination. The Rad1-Rad10 complex has a single-stranded DNA endonuclease activity. Here, we show that the mismatch repair genes MSH2 and MSH3 function in mitotic recombination. For both his3 and his4 duplications, and for homologous integration of a linear DNA fragment into the genome, the msh3-A mutation has an effect on recombination similar to that of the rad1{Delta} and rad10{Delta} mutations. The msh2{Delta} mutation also reduces the rate of recombination of the his3 duplication and lowers the incidence of homologous integrationmore » of a linear DNA fragment. Epistasis analyses indicate that MSH2 and MSH3 function in the RAD1-RAD10 recombination pathway, and studies presented here suggest an involvement of the RAM-RAD10 pathway in reciprocal recombination. The possible roles of Msh2, Msh3, Rad1, and Rad10 proteins in genetic recombination are discussed. Coupling of mismatch binding proteins with the recombinational machinery could be important for ensuring genetic fidelity in the recombination process. 59 refs., 2 figs., 7 tabs.« less

Ashley Felix, Ph.D., M.P.H.

Cancer.gov

NCI Cancer Prevention Fellowship Program (CPFP) alumna, Ashley Felix, Ph.D., M.P.H., details her transition from pre-med student to an epidemiologist who focuses on studying the causes and prevention of disease.

‘Why do an MPH?’ Motivations and intentions of physicians undertaking postgraduate public health training at the University of Cape Town

PubMed Central

Zweigenthal, Virginia E.M.; Marquez, Emma; London, Leslie

2016-01-01

Background Public health (PH) approaches underpin the management and transformation of health systems in low- and middle-income countries. Despite the Master of Public Health (MPH) rarely being a prerequisite for health service employment in South Africa, many physicians pursue MPH qualifications. Objectives This study identifies their motivations and career intentions and explored MPH programme strengths and gaps in under- and post-graduate PH training. Design A cross-sectional study using an online questionnaire was completed by physicians graduating with an MPH between 2000 and 2009 and those enrolled in the programme in 2010 at the University of Cape Town. Results Nearly a quarter of MPH students were physicians. Of the 65 contactable physicians, 48% responded. They were mid-career physicians who wished to obtain research training (55%), who wished to gain broader perspectives on health (32%), and who used the MPH to advance careers (90%) as researchers, policy-makers, or managers. The MPH widened professional opportunities, with 62% changing jobs. They believed that inadequate undergraduate exposure should be remedied by applying PH approaches to clinical problems in community settings, which would increase the attractiveness of postgraduate PH training. Conclusions The MPH allows physicians to transition from pure clinical to research, policy and/or management work, preparing them to innovate changes for effective health systems, responsive to the health needs of populations. Limited local job options and incentives are important constraining factors. Advocacy for positions requiring qualifications and benchmarking exit competencies of programmes nationally may promote enrolment. PMID:27741958

Raising the speed limit from 75 to 80mph on Utah rural interstates: Effects on vehicle speeds and speed variance.

PubMed

Hu, Wen

2017-06-01

In November 2010 and October 2013, Utah increased speed limits on sections of rural interstates from 75 to 80mph. Effects on vehicle speeds and speed variance were examined. Speeds were measured in May 2010 and May 2014 within the new 80mph zones, and at a nearby spillover site and at more distant control sites where speed limits remained 75mph. Log-linear regression models estimated percentage changes in speed variance and mean speeds for passenger vehicles and large trucks associated with the speed limit increase. Logistic regression models estimated effects on the probability of passenger vehicles exceeding 80, 85, or 90mph and large trucks exceeding 80mph. Within the 80mph zones and at the spillover location in 2014, mean passenger vehicle speeds were significantly higher (4.1% and 3.5%, respectively), as were the probabilities that passenger vehicles exceeded 80mph (122.3% and 88.5%, respectively), than would have been expected without the speed limit increase. Probabilities that passenger vehicles exceeded 85 and 90mph were non-significantly higher than expected within the 80mph zones. For large trucks, the mean speed and probability of exceeding 80mph were higher than expected within the 80mph zones. Only the increase in mean speed was significant. Raising the speed limit was associated with non-significant increases in speed variance. The study adds to the wealth of evidence that increasing speed limits leads to higher travel speeds and an increased probability of exceeding the new speed limit. Results moreover contradict the claim that increasing speed limits reduces speed variance. Although the estimated increases in mean vehicle speeds may appear modest, prior research suggests such increases would be associated with substantial increases in fatal or injury crashes. This should be considered by lawmakers considering increasing speed limits. Copyright © 2017 Elsevier Ltd and National Safety Council. All rights reserved.

Human mismatch repair protein hMutLα is required to repair short slipped-DNAs of trinucleotide repeats.

PubMed

Panigrahi, Gagan B; Slean, Meghan M; Simard, Jodie P; Pearson, Christopher E

2012-12-07

Mismatch repair (MMR) is required for proper maintenance of the genome by protecting against mutations. The mismatch repair system has also been implicated as a driver of certain mutations, including disease-associated trinucleotide repeat instability. We recently revealed a requirement of hMutSβ in the repair of short slip-outs containing a single CTG repeat unit (1). The involvement of other MMR proteins in short trinucleotide repeat slip-out repair is unknown. Here we show that hMutLα is required for the highly efficient in vitro repair of single CTG repeat slip-outs, to the same degree as hMutSβ. HEK293T cell extracts, deficient in hMLH1, are unable to process single-repeat slip-outs, but are functional when complemented with hMutLα. The MMR-deficient hMLH1 mutant, T117M, which has a point mutation proximal to the ATP-binding domain, is defective in slip-out repair, further supporting a requirement for hMLH1 in the processing of short slip-outs and possibly the involvement of hMHL1 ATPase activity. Extracts of hPMS2-deficient HEC-1-A cells, which express hMLH1, hMLH3, and hPMS1, are only functional when complemented with hMutLα, indicating that neither hMutLβ nor hMutLγ is sufficient to repair short slip-outs. The resolution of clustered short slip-outs, which are poorly repaired, was partially dependent upon a functional hMutLα. The joint involvement of hMutSβ and hMutLα suggests that repeat instability may be the result of aberrant outcomes of repair attempts.

Inficon Transpector MPH Mass Spectrometer Random Vibration Test Report

NASA Technical Reports Server (NTRS)

Santiago-Bond, Jo; Captain, Janine

2015-01-01

The purpose of this test report is to summarize results from the vibration testing of the INFICON Transpector MPH100M model Mass Spectrometer. It also identifies requirements satisfied, and procedures used in the test. As a payload of Resource Prospector, it is necessary to determine the survivability of the mass spectrometer to proto-qualification level random vibration. Changes in sensitivity of the mass spectrometer can be interpreted as a change in alignment of the instrument. The results of this test will be used to determine any necessary design changes as the team moves forward with flight design.

The Association Between Broad Antigen HLA Mismatches, Eplet HLA Mismatches and Acute Rejection After Kidney Transplantation.

PubMed

Do Nguyen, Hung Thanh; Wong, Germaine; Chapman, Jeremy R; McDonald, Stephen P; Coates, Patrick T; Watson, Narelle; Russ, Graeme R; D'Orsogna, Lloyd; Lim, Wai Hon

2016-12-01

Epitope matching, which evaluates mismatched amino acids within antigen-antibody interaction sites (eplets), may better predict acute rejection than broad antigen matching alone. We aimed to determine the association between eplet mismatches and acute rejection in kidney transplant recipients. The association between eplet mismatches, broad antigen mismatches and acute rejection was assessed using adjusted Cox proportional hazard regression. Model discrimination for acute rejection was evaluated using the area under receiver operating characteristic curves. Of the 3,499 kidney transplant recipients from 2006 to 2011, the average (SD) number of broad antigen and eplet mismatches were 3.4 (1.7) and 22.8 (12.2), respectively. Compared with 0 to 2 eplet mismatches, the adjusted hazard ratio (HR) for acute rejection among those with 20 or greater eplet mismatches was 2.16 (95% confidence interval [CI], 1.33-3.52; P = 0.001). The adjusted area under the curve for broad antigen mismatches was 0.58 (95% CI, 0.56-0.61), similar to that for eplet mismatches (HR, 0.59; 95% CI, 0.56-0.61; P = 0.365). In recipients who were considered as low immunological risk (0-2 broad antigen HLA-ABDR mismatch), those with 20 or greater eplet mismatches experienced an increased risk of rejection compared to those with less than 20 mismatches (adjusted HR, 1.85; 95% CI, 1.11-3.08; P = 0.019). Increasing number of eplet mismatches is associated with acute rejection in kidney transplant recipients. Consideration of eplet HLA mismatches may improve risk stratification for acute rejection in a selected group of kidney transplant candidates.

Charge transfer process at the Ag/MPH/TiO2 interface by SERS: alignment of the Fermi level.

PubMed

Zhang, Xiaolei; Sui, Huimin; Wang, Xiaolei; Su, Hongyang; Cheng, Weina; Wang, Xu; Zhao, Bing

2016-11-02

A nanoscale metal-molecule-semiconductor assembly (Ag/4-mercaptophenol/TiO 2 ) has been fabricated over Au nanoparticle (NP) films as a model to study the interfacial charge transfer (CT) effects involved in Ag/MPH/TiO 2 . Due to the interaction between Au NPs and Ag NPs, some distinct differences occur in the SERS spectra. We also measured the SERS of Ag/MPH (4-mercaptophenol), Ag/MPH/TiO 2 , and Au/Ag/MPH/TiO 2 assemblies at excitation wavelengths of 477, 514, 532, 633, and 785 nm. We found that the changes in the CT process, caused by the introduction of TiO 2 and Au, can be reflected in SERS. Then in combination with other detection methods, we proposed a possible CT process involved in the Ag/MPH, Ag/MPH/TiO 2 , and Au/Ag/MPH/TiO 2 assemblies. A Pt/Ag/MPH/TiO 2 assembly was also constructed to verify our proposed CT mechanism. This work not only provides more details about CT between metal-molecule-semiconductor interfaces but also aids in constructing nanoscale models to study interfacial problems with the SERS technique.

Impact of the 65 mph speed limit on Virginia's rural interstate highways, 1989-1992.

DOT National Transportation Integrated Search

1994-01-01

In April of 1987, Congress passed the Surface Transportation and Uniform Relocation Assistance Act (STURAA), which permitted states to raise their maximum speed limit on rural interstate highways to 65 mph. Virginia's 65 mph speed limit went into eff...

The impact of the 65 MPH speed limit on Virginia's rural interstate highways through 1990.

DOT National Transportation Integrated Search

1992-01-01

In April of 1987, Congress passed the Surface Transportation and Uniform Relocation Assistance Act (STURAA), which permitted states to raise their maximum speed limit on rural interstate highways (rural interstates) to 65 mph. Virginia's 65 mph speed...

The dual DVM/MPH degree at the University of Wisconsin--Madison: a uniquely interdisciplinary collaboration.

PubMed

Olsen, Christopher W; Remington, Patrick L

2008-01-01

The University of Wisconsin-Madison (UWM) launched a new Master of Public Health (MPH) degree program in 2005. This 42-credit MPH degree consists of 18 core and 14 elective course credits, two seminar credits, and eight field project/culminating experience credits. Unique strengths of the program include its strongly interdisciplinary philosophy, encompassing both health science (human medicine, veterinary medicine, pharmacy, nursing) and social science units on campus, and its emphasis on service learning through instructional and field project ties to the public-health community of the state and beyond. To date, the program has admitted 87 students, including full-time students as well as part-time students who continue to work in the health care and/or public-health sectors. The program is currently proceeding with the process for accreditation through the Council for Education in Public Health. In 2007, a formal dual DVM/MPH program was approved to allow students to integrate DVM and MPH training and complete both degrees in a total of five years. Nine MPH students over the first three years of admissions have been individuals affiliated with veterinary medicine (five DVM students and four post-graduate veterinarians).

Size mismatch in liver transplantation.

PubMed

Fukazawa, Kyota; Nishida, Seigo

2016-08-01

Size mismatch is an unique and inevitable but critical issue in live donor liver transplantation. Unmatched metabolic demand of recipient as well as physiologic mismatch aggravates the damage to liver graft, inevitably leading to graft failure on recipient. Also, an excessive resection of liver graft for better recipient outcome in live donor liver transplant may jeopardize the healthy donor well-being and even put donor life in danger. There is a fine balance between resected graft volume required to meet the recipient's metabolic demand and residual graft volume required for donor safety. The obvious clinical necessity of finding that balance has prompted a clinical need and promoted the improvement of knowledge and development of management strategies for size-mismatched transplants. The development of the size-matching methodology has significantly improved graft outcome and recipient survival in live donor liver transplants. On the other hand, the effect of size mismatch in cadaveric transplants has never been observed as being so pronounced. The importance of matching of the donor recipient size has been unrecognized in cadaveric liver transplant. In this review, we attempt to summarize the current most updated knowledge on the subject, particularly addressing the definition and complications of size-mismatched cadaveric liver transplant, as well as management strategies. © 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

Insights into resistance mechanism of the macrolide biosensor protein MphR(A) binding to macrolide antibiotic erythromycin by molecular dynamics simulation

NASA Astrophysics Data System (ADS)

Feng, Tingting; Zhang, Yanjun; Ding, Jing-Na; Fan, Song; Han, Ju-Guang

2015-12-01

Macrolide biosensor protein MphR(A) has been known as a key regulatory protein in metabolite sensing and genetic expression regulating. MphR(A) protein binds to macrolide antibiotic erythromycin (Ery) and releases the gene operon, thus activates expression of the mphA gene and initiates Ery resistance. The two mutant amino acid residues (V66L and V126L) might potentially disrupt Ery binding to MphR(A). In these studies, the binding of macrolide antibiotic Ery to wild type (Wt) MphR(A) and double mutant (V66L/V126L) MphR(A) are explored by molecular dynamics simulations. Compared to the Apo-MphR(A) protein and Wt-MphR(A)-Ery complex, many interesting effects owing to the double mutant (V66L/V126L) are discovered. In the case of Ery, Helix I which plays an important role in transcription shows itself a right-hand α helix in Wt-MphR(A)-Ery, whereas the activated helix is broken down in double mutant-V66L/V126L-MphR(A)-Ery. The calculated results exhibit that the double mutant V66L/V126L reduces the binding affinity of the V66L/V126L-MphR(A) to Ery, resulting in the block of Ery resistance. The binding free energy decomposition analysis reveals that the decrease of the binding affinity for the variant V66L/V126L-MphR(A)-Ery is mainly attributed to the gas phase electrostatic energies. The residue Leu66, Thr154, and Arg122 enhance the binding affinity of V66L/V126L-MphR(A) to Ery. The residues Tyr103 and His147 contributes mainly to binding energies in the Wt-MphR(A)-Ery complex, whereas the two residues have no contribution to the binding free energy inV66L/V126L-MphR(A)-Ery complex. Our study gives useful insights into the nature of amino acids mutation effect, the mechanism of blocking drug resistance at the atomic level and the characteristics in binding affinity for Ery to double mutant (V66L/V126L) MphR(A), which will contribute to the design of more effective macrolide antibiotics.

Passenger vehicles sustain huge damage in 5 Mph tests

DOT National Transportation Integrated Search

2000-04-15

Seventeen new cars, all 1999 and 2000 models, turned in mostly disappointing results in 5 mph crash tests conducted to assess how well the bumpers resist costly damage in the kinds of impacts that frequently occur in commuter traffic and parking lots...

Activation of Saccharomyces cerevisiae Mlh1-Pms1 Endonuclease in a Reconstituted Mismatch Repair System.

PubMed

Smith, Catherine E; Bowen, Nikki; Graham, William J; Goellner, Eva M; Srivatsan, Anjana; Kolodner, Richard D

2015-08-28

Previous studies reported the reconstitution of an Mlh1-Pms1-independent 5' nick-directed mismatch repair (MMR) reaction using Saccharomyces cerevisiae proteins. Here we describe the reconstitution of a mispair-dependent Mlh1-Pms1 endonuclease activation reaction requiring Msh2-Msh6 (or Msh2-Msh3), proliferating cell nuclear antigen (PCNA), and replication factor C (RFC) and a reconstituted Mlh1-Pms1-dependent 3' nick-directed MMR reaction requiring Msh2-Msh6 (or Msh2-Msh3), exonuclease 1 (Exo1), replication protein A (RPA), RFC, PCNA, and DNA polymerase δ. Both reactions required Mg(2+) and Mn(2+) for optimal activity. The MMR reaction also required two reaction stages in which the first stage required incubation of Mlh1-Pms1 with substrate DNA, with or without Msh2-Msh6 (or Msh2-Msh3), PCNA, and RFC but did not require nicking of the substrate, followed by a second stage in which other proteins were added. Analysis of different mutant proteins demonstrated that both reactions required a functional Mlh1-Pms1 endonuclease active site, as well as mispair recognition and Mlh1-Pms1 recruitment by Msh2-Msh6 but not sliding clamp formation. Mutant Mlh1-Pms1 and PCNA proteins that were defective for Exo1-independent but not Exo1-dependent MMR in vivo were partially defective in the Mlh1-Pms1 endonuclease and MMR reactions, suggesting that both reactions reflect the activation of Mlh1-Pms1 seen in Exo1-independent MMR in vivo. The availability of this reconstituted MMR reaction should now make it possible to better study both Exo1-independent and Exo1-dependent MMR. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Activation of Saccharomyces cerevisiae Mlh1-Pms1 Endonuclease in a Reconstituted Mismatch Repair System*

PubMed Central

Smith, Catherine E.; Bowen, Nikki; Graham, William J.; Goellner, Eva M.; Srivatsan, Anjana; Kolodner, Richard D.

2015-01-01

Previous studies reported the reconstitution of an Mlh1-Pms1-independent 5′ nick-directed mismatch repair (MMR) reaction using Saccharomyces cerevisiae proteins. Here we describe the reconstitution of a mispair-dependent Mlh1-Pms1 endonuclease activation reaction requiring Msh2-Msh6 (or Msh2-Msh3), proliferating cell nuclear antigen (PCNA), and replication factor C (RFC) and a reconstituted Mlh1-Pms1-dependent 3′ nick-directed MMR reaction requiring Msh2-Msh6 (or Msh2-Msh3), exonuclease 1 (Exo1), replication protein A (RPA), RFC, PCNA, and DNA polymerase δ. Both reactions required Mg2+ and Mn2+ for optimal activity. The MMR reaction also required two reaction stages in which the first stage required incubation of Mlh1-Pms1 with substrate DNA, with or without Msh2-Msh6 (or Msh2-Msh3), PCNA, and RFC but did not require nicking of the substrate, followed by a second stage in which other proteins were added. Analysis of different mutant proteins demonstrated that both reactions required a functional Mlh1-Pms1 endonuclease active site, as well as mispair recognition and Mlh1-Pms1 recruitment by Msh2-Msh6 but not sliding clamp formation. Mutant Mlh1-Pms1 and PCNA proteins that were defective for Exo1-independent but not Exo1-dependent MMR in vivo were partially defective in the Mlh1-Pms1 endonuclease and MMR reactions, suggesting that both reactions reflect the activation of Mlh1-Pms1 seen in Exo1-independent MMR in vivo. The availability of this reconstituted MMR reaction should now make it possible to better study both Exo1-independent and Exo1-dependent MMR. PMID:26170454

Acute Effects of MPH on the Parent-Teen Interactions of Adolescents With ADHD.

PubMed

Pelham, William E; Meichenbaum, David L; Smith, Bradley H; Sibley, Margaret H; Gnagy, Elizabeth M; Bukstein, Oscar

2017-01-01

This study explored the nature of interactions between adolescent males with ADHD and their mothers, and the effects of methylphenidate (MPH) on an analogue parent-teen interaction task. Twenty-five adolescent males with ADHD ( M = 13.6 years) and their mothers and 14 non-ADHD adolescent males ( M = 13.4 years) and their mothers completed ratings of perceived dyadic conflict. Behavioral observations of dyads during 10-min conflict-resolution tasks were also collected. The ADHD dyads completed these tasks twice, with adolescents receiving either 0.3 mg/kg MPH or placebo. Videotaped sessions were coded using the Parent-Adolescent Interaction Rating Scale. Following the conflict-resolution task, participants rated their perceived conflict and affect during the interaction. Findings indicated higher conflict in the ADHD dyads, and minimal MPH effects on parent-teen interactions during the analogue task. Results suggest that stimulant medication does not produce meaningful acute effects on parent-teen interactions.

65 mph speed limit : analysis of fatal accident injury severity

DOT National Transportation Integrated Search

1989-11-01

Several studies of the fatality experience in the 38 states that implemented a65 mph speed : limit on Rural Interstate highways in 1987 concluded that the higher speed limit has : caused fatalities to increase. This relationship between the speed lim...

Wastewater treatment models in teaching and training: the mismatch between education and requirements for jobs.

PubMed

Hug, Thomas; Benedetti, Lorenzo; Hall, Eric R; Johnson, Bruce R; Morgenroth, Eberhard; Nopens, Ingmar; Rieger, Leiv; Shaw, Andrew; Vanrolleghem, Peter A

2009-01-01

As mathematical modeling of wastewater treatment plants has become more common in research and consultancy, a mismatch between education and requirements for model-related jobs has developed. There seems to be a shortage of skilled people, both in terms of quantity and in quality. In order to address this problem, this paper provides a framework to outline different types of model-related jobs, assess the required skills for these jobs and characterize different types of education that modelers obtain "in school" as well as "on the job". It is important to consider that education of modelers does not mainly happen in university courses and that the variety of model related jobs goes far beyond use for process design by consulting companies. To resolve the mismatch, the current connection between requirements for different jobs and the various types of education has to be assessed for different geographical regions and professional environments. This allows the evaluation and improvement of important educational paths, considering quality assurance and future developments. Moreover, conclusions from a workshop involving practitioners and academics from North America and Europe are presented. The participants stressed the importance of non-technical skills and recommended strengthening the role of realistic modeling experience in university training. However, this paper suggests that all providers of modeling education and support, not only universities, but also software suppliers, professional associations and companies performing modeling tasks are called to assess and strengthen their role in training and support of professional modelers.

Hala Azzam, PhD, MPH | Division of Cancer Prevention

Cancer.gov

Dr. Hala Azzam is a Cancer Epidemiologist in the Cancer Prevention Fellowship Program (CPFP) in the Division of Cancer Prevention within the National Cancer Institute. She received her Bachelor's degree in molecular biology from Kings College London University, her PhD in anatomy and cell biology from Georgetown University Lombardi Cancer Center, and her MPH in epidemiology

Components of a Fanconi-like pathway control Pso2-independent DNA interstrand crosslink repair in yeast.

PubMed

Ward, Thomas A; Dudášová, Zuzana; Sarkar, Sovan; Bhide, Mangesh R; Vlasáková, Danuša; Chovanec, Miroslav; McHugh, Peter J

2012-01-01

Fanconi anemia (FA) is a devastating genetic disease, associated with genomic instability and defects in DNA interstrand cross-link (ICL) repair. The FA repair pathway is not thought to be conserved in budding yeast, and although the yeast Mph1 helicase is a putative homolog of human FANCM, yeast cells disrupted for MPH1 are not sensitive to ICLs. Here, we reveal a key role for Mph1 in ICL repair when the Pso2 exonuclease is inactivated. We find that the yeast FANCM ortholog Mph1 physically and functionally interacts with Mgm101, a protein previously implicated in mitochondrial DNA repair, and the MutSα mismatch repair factor (Msh2-Msh6). Co-disruption of MPH1, MGM101, MSH6, or MSH2 with PSO2 produces a lesion-specific increase in ICL sensitivity, the elevation of ICL-induced chromosomal rearrangements, and persistence of ICL-associated DNA double-strand breaks. We find that Mph1-Mgm101-MutSα directs the ICL-induced recruitment of Exo1 to chromatin, and we propose that Exo1 is an alternative 5'-3' exonuclease utilised for ICL repair in the absence of Pso2. Moreover, ICL-induced Rad51 chromatin loading is delayed when both Pso2 and components of the Mph1-Mgm101-MutSα and Exo1 pathway are inactivated, demonstrating that the homologous recombination stages of ICL repair are inhibited. Finally, the FANCJ- and FANCP-related factors Chl1 and Slx4, respectively, are also components of the genetic pathway controlled by Mph1-Mgm101-MutSα. Together this suggests that a prototypical FA-related ICL repair pathway operates in budding yeast, which acts redundantly with the pathway controlled by Pso2, and is required for the targeting of Exo1 to chromatin to execute ICL repair.

Binding of insertion/deletion DNA mismatches by the heterodimer of yeast mismatch repair proteins MSH2 and MSH3.

PubMed

Habraken, Y; Sung, P; Prakash, L; Prakash, S

1996-09-01

DNA-mismatch repair removes mismatches from the newly replicated DNA strand. In humans, mutations in the mismatch repair genes hMSH2, hMLH1, hPMS1 and hPMS2 result in hereditary non-polyposis colorectal cancer (HNPCC) [1-8]. The hMSH2 (MSH for MutS homologue) protein forms a complex with a 160 kDa protein, and this heterodimer, hMutSalpha, has high affinity for a G/T mismatch [9,10]. Cell lines in which the 160 kDa subunit of hMutSalpha is mutated are specifically defective in the repair of base-base and single-nucleotide insertion/deletion mismatches [9,11]. Genetic studies in S. cerevisiae have suggested that MSH2 functions with either MSH3 or MSH6 in mismatch repair, and, in the absence of the latter two genes, MSH2 is inactive [12,13]. MSH6 encodes the yeast counterpart of the 160 kDa subunit of hMutSalpha [12,13]. As in humans, yeast MSH6 forms a complex with MSH2, and the MSH2-MSH6 heterodimer binds a G/T mismatch [14]. Here, we find that MSH2 and MSH3 form another stable heterodimer, and we purify this heterodimer to near homogeneity. We show that MSH2-MSH3 has low affinity for a G/T mismatch but binds to insertion/deletion mismatches with high specificity, unlike MSH2-MSH6.

Dominant Mutations in S. cerevisiae PMS1 Identify the Mlh1-Pms1 Endonuclease Active Site and an Exonuclease 1-Independent Mismatch Repair Pathway

PubMed Central

Smith, Catherine E.; Mendillo, Marc L.; Bowen, Nikki; Hombauer, Hans; Campbell, Christopher S.; Desai, Arshad; Putnam, Christopher D.; Kolodner, Richard D.

2013-01-01

Lynch syndrome (hereditary nonpolypsis colorectal cancer or HNPCC) is a common cancer predisposition syndrome. Predisposition to cancer in this syndrome results from increased accumulation of mutations due to defective mismatch repair (MMR) caused by a mutation in one of the mismatch repair genes MLH1, MSH2, MSH6 or PMS2/scPMS1. To better understand the function of Mlh1-Pms1 in MMR, we used Saccharomyces cerevisiae to identify six pms1 mutations (pms1-G683E, pms1-C817R, pms1-C848S, pms1-H850R, pms1-H703A and pms1-E707A) that were weakly dominant in wild-type cells, which surprisingly caused a strong MMR defect when present on low copy plasmids in an exo1Δ mutant. Molecular modeling showed these mutations caused amino acid substitutions in the metal coordination pocket of the Pms1 endonuclease active site and biochemical studies showed that they inactivated the endonuclease activity. This model of Mlh1-Pms1 suggested that the Mlh1-FERC motif contributes to the endonuclease active site. Consistent with this, the mlh1-E767stp mutation caused both MMR and endonuclease defects similar to those caused by the dominant pms1 mutations whereas mutations affecting the predicted metal coordinating residue Mlh1-C769 had no effect. These studies establish that the Mlh1-Pms1 endonuclease is required for MMR in a previously uncharacterized Exo1-independent MMR pathway. PMID:24204293

Dominant mutations in S. cerevisiae PMS1 identify the Mlh1-Pms1 endonuclease active site and an exonuclease 1-independent mismatch repair pathway.

PubMed

Smith, Catherine E; Mendillo, Marc L; Bowen, Nikki; Hombauer, Hans; Campbell, Christopher S; Desai, Arshad; Putnam, Christopher D; Kolodner, Richard D

2013-10-01

Lynch syndrome (hereditary nonpolypsis colorectal cancer or HNPCC) is a common cancer predisposition syndrome. Predisposition to cancer in this syndrome results from increased accumulation of mutations due to defective mismatch repair (MMR) caused by a mutation in one of the mismatch repair genes MLH1, MSH2, MSH6 or PMS2/scPMS1. To better understand the function of Mlh1-Pms1 in MMR, we used Saccharomyces cerevisiae to identify six pms1 mutations (pms1-G683E, pms1-C817R, pms1-C848S, pms1-H850R, pms1-H703A and pms1-E707A) that were weakly dominant in wild-type cells, which surprisingly caused a strong MMR defect when present on low copy plasmids in an exo1Δ mutant. Molecular modeling showed these mutations caused amino acid substitutions in the metal coordination pocket of the Pms1 endonuclease active site and biochemical studies showed that they inactivated the endonuclease activity. This model of Mlh1-Pms1 suggested that the Mlh1-FERC motif contributes to the endonuclease active site. Consistent with this, the mlh1-E767stp mutation caused both MMR and endonuclease defects similar to those caused by the dominant pms1 mutations whereas mutations affecting the predicted metal coordinating residue Mlh1-C769 had no effect. These studies establish that the Mlh1-Pms1 endonuclease is required for MMR in a previously uncharacterized Exo1-independent MMR pathway.

A flexible approach to training veterinarians in public health: an overview and early assessment of the DVM/MPH dual-degree program at the University of Minnesota.

PubMed

Minicucci, Larissa A; Hanson, Kate A; Olson, Debra K; Hueston, William D

2008-01-01

As a result of the growing need for public-health veterinarians, novel educational programs are essential to train future public-health professionals. The University of Minnesota School of Public Health, in collaboration with the College of Veterinary Medicine, initiated a dual DVM/MPH program in 2002. This program provides flexibility by combining distance learning and on-campus courses offered through a summer public-health institute. MPH requirements are completed through core courses, elective courses in a focus area, and an MPH project and field experience. Currently, more than 100 students representing 13 veterinary schools are enrolled in the program. The majority of initial program graduates have pursued public-practice careers upon completion of the program. Strengths of the Minnesota program design include accessibility and an environment to support multidisciplinary training. Continued assessment of program graduates will allow for evaluation and adjustment of the program in the coming years.

HLA-DQ Mismatching and Kidney Transplant Outcomes.

PubMed

Leeaphorn, Napat; Pena, Jeremy Ryan A; Thamcharoen, Natanong; Khankin, Eliyahu V; Pavlakis, Martha; Cardarelli, Francesca

2018-05-07

Recent evidence suggests that HLA epitope-mismatching at HLA-DQ loci is associated with the development of anti-DQ donor-specific antibodies and adverse graft outcomes. However, the clinical significance of broad antigen HLA-DQ mismatching for graft outcomes is not well examined. Using the United Network Organ Sharing/the Organ Procurement and Transplantation Network (UNOS/OPTN) data, patients with primary kidney transplants performed between 2005 and 2014 were included. Patients were classified as having either zero HLA-DQ mismatches, or one or two HLA-DQ mismatches. Primary outcomes were death-censored graft survival and incidence of acute rejection. A total of 93,782 patients were included. Of these, 22,730 (24%) and 71,052 (76%) received zero and one or two HLA-DQ mismatched kidneys, respectively. After adjusting for variables including HLA-ABDR, HLA-DQ mismatching was associated with a higher risk of graft loss in living kidney donor recipients with an adjusted hazard ratio (HR) of 1.18 (95% confidence interval [95% CI], 1.07 to 1.30; P <0.01), but not in deceased kidney donor recipients (HR, 1.05; 95% CI, 0.98 to 1.12; P =0.18) ( P value for interaction <0.01). When taking cold ischemic time into account, HLA-DQ mismatching was associated with a higher risk of graft loss in deceased kidney donor recipients with cold ischemic time ≤17 hours (HR, 1.12; 95% CI, 1.02 to 1.27; P =0.002), but not in deceased kidney donor recipients with cold ischemic time >17 hours (HR, 0.97; 95% CI, 0.88 to 1.06; P =0.49) ( P value for interaction <0.01). Recipients with one or two HLA-DQ mismatched kidneys had a higher incidence of acute rejection at 1 year, with adjusted odds ratios of 1.13 (95% CI, 1.03 to 1.23; P <0.01) in deceased donor and 1.14 (95% CI, 1.03 to 1.27; P =0.02) in living donor kidney transplant recipients. Specific donor-DQ mismatches seemed to be associated with the risk of acute rejection and graft failure, whereas others did not. HLA-DQ mismatching is

Construction and characterization of mismatch-containing circular DNA molecules competent for assessment of nick-directed human mismatch repair in vitro.

PubMed

Larson, Erik D; Nickens, David; Drummond, James T

2002-02-01

The ability of cell-free extracts to correct DNA mismatches has been demonstrated in both prokaryotes and eukaryotes. Such an assay requires a template containing both a mismatch and a strand discrimination signal, and the multi-step construction process can be technically difficult. We have developed a three-step procedure for preparing DNA heteroduplexes containing a site-specific nick. The mismatch composition, sequence context, distance to the strand signal, and the means for assessing repair in each strand are adjustable features built into a synthetic oligonucleotide. Controlled ligation events involving three of the four DNA strands incorporate the oligonucleotide into a circular template and generate the repair-directing nick. Mismatch correction in either strand of a prototype G.T mismatch was achieved by placing a nick 10-40 bp away from the targeted base. This proximity of nick and mismatch represents a setting where repair has not been well characterized, but the presence of a nick was shown to be essential, as was the MSH2/MSH6 heterodimer, although low levels of repair occurred in extract defective in each protein. All repair events were inhibited by a peptide that interacts with proliferating cell nuclear antigen and inhibits both mismatch repair and long-patch replication.

Unrelated cord blood transplantation vs. related transplantation with HLA 1-antigen mismatch in the GVH direction.

PubMed

Kanda, Junya

2015-05-01

The donor selection superiority of HLA 1-antigen mismatched related donor versus unrelated cord blood (UCB) is an important issue for patients without an HLA-matched related or unrelated donor. Using Japanese registry data, we analyzed patients with leukemia and myelodysplastic syndrome who received transplantation using UCB or from a related donor with 1-antigen mismatch in the graft-versus-host (GVH) direction (RD/1AG-MM-GVH). Compared to the UCB group, neutrophil engraftment was significantly faster, and the incidences of acute and chronic GVHD were significantly higher in the RD/1AG-MM-GVH group. As a result, there was no significant difference in overall survival between transplantation using the RD/1AG-MM-GVH and UCB. However, the HLA-B-antigen mismatched group showed significantly inferior overall survival. The RD/1AG-MM-GVH group using anti-thymocyte globulin (ATG) showed neutrophil engraftment comparable to that of the non-ATG group and a GVHD incidence similar to that of the UCB group, which resulted in a better overall survival rate in the ATG than in the UCB group. In particular, the adverse effects of HLA-B mismatch were not observed in the ATG group. RD/1AGMM-GVH transplantation using ATG could potentially improve outcomes, and a prospective study of RD/1AGMM-GVH transplantation using low-dose ATG is currently ongoing.

Identification of a permissible HLA mismatch in hematopoietic stem cell transplantation

PubMed Central

Fernandez-Viña, Marcelo A.; Wang, Tao; Lee, Stephanie J.; Haagenson, Michael; Aljurf, Mahmoud; Askar, Medhat; Battiwalla, Minoo; Baxter-Lowe, Lee-Ann; Gajewski, James; Jakubowski, Ann A.; Marino, Susana; Oudshoorn, Machteld; Marsh, Steven G. E.; Petersdorf, Effie W.; Schultz, Kirk; Turner, E. Victoria; Waller, Edmund K.; Woolfrey, Ann; Umejiego, John; Spellman, Stephen R.; Setterholm, Michelle

2014-01-01

In subjects mismatched in the HLA alleles C*03:03/C*03:04 no allogeneic cytotoxic T-lymphocyte responses are detected in vitro. Hematopoietic stem cell transplantation (HSCT) with unrelated donors (UDs) showed no association between the HLA-C allele mismatches (CAMMs) and adverse outcomes; antigen mismatches at this and mismatches other HLA loci are deleterious. The absence of effect of the CAMM may have resulted from the predominance of the mismatch C*03:03/C*03:04. Patients with hematologic malignancies receiving UD HSCT matched in 8/8 and 7/8 HLA alleles were examined. Transplants mismatched in HLA-C antigens or mismatched in HLA-A, -B, or -DRB1 presented significant differences (P < .0001) in mortality (hazard ratio [HR] = 1.37, 1.30), disease-free survival (HR = 1.33, 1.27), treatment-related mortality (HR = 1.54, 1.54), and grade 3-4 acute graft-versus-host disease (HR = 1.49, 1.77) compared with the 8/8 group; transplants mismatched in other CAMMs had similar outcomes with HR ranging from 1.34 to 172 for these endpoints. The C*03:03/C*03:04 mismatched and the 8/8 matched groups had identical outcomes (HR ranging from 0.96-1.05). The previous finding that CAMMs do not associate with adverse outcomes is explained by the predominance (69%) of the mismatch C*03:03/03:04 in this group that is better tolerated than other HLA mismatches. PMID:24408320

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients

PubMed Central

Chapman, Jeremy R.; Coates, Patrick T.; Lewis, Joshua R.; Russ, Graeme R.; Watson, Narelle; Holdsworth, Rhonda; Wong, Germaine

2016-01-01

Background and objectives The current allocation algorithm for deceased donor kidney transplantation takes into consideration HLA mismatches at the ABDR loci but not HLA mismatches at other loci, including HLA-DQ. However, the independent effects of incompatibilities for the closely linked HLA-DQ antigens in the context of HLA-DR antigen matched and mismatched allografts are uncertain. We aimed to determine the effect of HLA-DQ mismatches on renal allograft outcomes. Design, setting, participants, & measurements Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the association between HLA-DQ mismatches and acute rejections in primary live and deceased donor kidney transplant recipients between 2004 and 2012 using adjusted Cox regression models. Results Of the 788 recipients followed for a median of 2.8 years (resulting in 2891 person-years), 321 (40.7%) and 467 (59.3%) received zero and one or two HLA-DQ mismatched kidneys, respectively. Compared with recipients who have received zero HLA-DQ mismatched kidneys, those who have received one or two HLA-DQ mismatched kidneys experienced greater numbers of any rejection (50 of 321 versus 117 of 467; P<0.01), late rejections (occurring >6 months post-transplant; 8 of 321 versus 27 of 467; P=0.03), and antibody-mediated rejections (AMRs; 12 of 321 versus 38 of 467; P=0.01). Compared with recipients of zero HLA-DQ mismatched kidneys, the adjusted hazard ratios for any and late rejections in recipients who had received one or two HLA-DQ mismatched kidneys were 1.54 (95% confidence interval [95% CI], 1.08 to 2.19) and 2.85 (95% CI, 1.05 to 7.75), respectively. HLA-DR was an effect modifier between HLA-DQ mismatches and AMR (P value for interaction =0.02), such that the association between HLA-DQ mismatches and AMR was statistically significant in those who have received one or two HLA-DR mismatched kidneys, with adjusted hazard ratio of 2.50 (95% CI, 1.05 to 5.94). Conclusions HLA

Examination of media coverage of increasing the speed limit to 65 mph

DOT National Transportation Integrated Search

1988-09-01

Heightened newspaper and television coverage of the proposed 65 mph limit may have encouraged increased travel speeds which in turn could have produced an increase in fatalities prior to passage of the national legislation. To pursue this further, NH...

Teaching Note--Educating Public Health Social Work Professionals: Results from an MSW/MPH Program Outcomes Study

ERIC Educational Resources Information Center

Ruth, Betty J.; Marshall, Jamie Wyatt; Velásquez, Esther E. M.; Bachman, Sara S.

2015-01-01

Dual-degree programs in public health and social work continue to proliferate, yet there has been little research on master's of social work (MSW)/master's of public health (MPH) graduates. The purpose of this study was to describe and better understand the self-reported professional experiences, identities, roles, and outcomes associated with 1…

Calculation of wind speeds required to damage or destroy buildings

NASA Astrophysics Data System (ADS)

Liu, Henry

Determination of wind speeds required to damage or destroy a building is important not only for the improvement of building design and construction but also for the estimation of wind speeds in tornadoes and other damaging storms. For instance, since 1973 the U.S. National Weather Service has been using the well-known Fujita scale (F scale) to estimate the maximum wind speeds of tornadoes [Fujita, 1981]. The F scale classifies tornadoes into 13 numbers, F-0 through F-12. The wind speed (maximum gust speed) associated with each F number is given in Table 1. Note that F-6 through F-12 are for wind speeds between 319 mi/hr (mph) and the sonic velocity (approximately 760 mph; 1 mph = 1.6 km/kr). However, since no tornadoes have been classified to exceed F-5, the F-6 through F-12 categories have no practical meaning [Fujita, 1981].

Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action.

PubMed

Zhang, Chun-Lei; Feng, Ze-Jun; Liu, Yue; Ji, Xiao-Hua; Peng, Ji-Yun; Zhang, Xue-Han; Zhen, Xue-Chu; Li, Bao-Ming

2012-01-01

Methylphenidate (MPH), commercially called Ritalin or Concerta, has been widely used as a drug for Attention Deficit Hyperactivity Disorder (ADHD). Noteworthily, growing numbers of young people using prescribed MPH improperly for pleasurable enhancement, take high risk of addiction. Thus, understanding the mechanism underlying high level of MPH action in the brain becomes an important goal nowadays. As a blocker of catecholamine transporters, its therapeutic effect is explained as being due to proper modulation of D1 and α2A receptor. Here we showed that higher dose of MPH facilitates NMDA-receptor mediated synaptic transmission via a catecholamine-independent mechanism, in layer V∼VI pyramidal cells of the rat medial prefrontal cortex (PFC). To indicate its postsynaptic action, we next found that MPH facilitates NMDA-induced current and such facilitation could be blocked by σ1 but not D1/5 and α2 receptor antagonists. And this MPH eliciting enhancement of NMDA-receptor activity involves PLC, PKC and IP3 receptor mediated intracellular Ca(2+) increase, but does not require PKA and extracellular Ca(2+) influx. Our additional pharmacological studies confirmed that higher dose of MPH increases locomotor activity via interacting with σ1 receptor. Together, the present study demonstrates for the first time that MPH facilitates NMDA-receptor mediated synaptic transmission via σ1 receptor, and such facilitation requires PLC/IP3/PKC signaling pathway. This novel mechanism possibly explains the underlying mechanism for MPH induced addictive potential and other psychiatric side effects.

Methylphenidate Enhances NMDA-Receptor Response in Medial Prefrontal Cortex via Sigma-1 Receptor: A Novel Mechanism for Methylphenidate Action

PubMed Central

Liu, Yue; Ji, Xiao-Hua; Peng, Ji-Yun; Zhang, Xue-Han; Zhen, Xue-Chu; Li, Bao-Ming

2012-01-01

Methylphenidate (MPH), commercially called Ritalin or Concerta, has been widely used as a drug for Attention Deficit Hyperactivity Disorder (ADHD). Noteworthily, growing numbers of young people using prescribed MPH improperly for pleasurable enhancement, take high risk of addiction. Thus, understanding the mechanism underlying high level of MPH action in the brain becomes an important goal nowadays. As a blocker of catecholamine transporters, its therapeutic effect is explained as being due to proper modulation of D1 and α2A receptor. Here we showed that higher dose of MPH facilitates NMDA-receptor mediated synaptic transmission via a catecholamine-independent mechanism, in layer V∼VI pyramidal cells of the rat medial prefrontal cortex (PFC). To indicate its postsynaptic action, we next found that MPH facilitates NMDA-induced current and such facilitation could be blocked by σ1 but not D1/5 and α2 receptor antagonists. And this MPH eliciting enhancement of NMDA-receptor activity involves PLC, PKC and IP3 receptor mediated intracellular Ca2+ increase, but does not require PKA and extracellular Ca2+ influx. Our additional pharmacological studies confirmed that higher dose of MPH increases locomotor activity via interacting with σ1 receptor. Together, the present study demonstrates for the first time that MPH facilitates NMDA-receptor mediated synaptic transmission via σ1 receptor, and such facilitation requires PLC/IP3/PKC signaling pathway. This novel mechanism possibly explains the underlying mechanism for MPH induced addictive potential and other psychiatric side effects. PMID:23284812

Mlh1-Mlh3, a Meiotic Crossover and DNA Mismatch Repair Factor, Is a Msh2-Msh3-stimulated Endonuclease*

PubMed Central

Rogacheva, Maria V.; Manhart, Carol M.; Chen, Cheng; Guarne, Alba; Surtees, Jennifer; Alani, Eric

2014-01-01

Crossing over between homologous chromosomes is initiated in meiotic prophase in most sexually reproducing organisms by the appearance of programmed double strand breaks throughout the genome. In Saccharomyces cerevisiae the double-strand breaks are resected to form three prime single-strand tails that primarily invade complementary sequences in unbroken homologs. These invasion intermediates are converted into double Holliday junctions and then resolved into crossovers that facilitate homolog segregation during Meiosis I. Work in yeast suggests that Msh4-Msh5 stabilizes invasion intermediates and double Holliday junctions, which are resolved into crossovers in steps requiring Sgs1 helicase, Exo1, and a putative endonuclease activity encoded by the DNA mismatch repair factor Mlh1-Mlh3. We purified Mlh1-Mlh3 and showed that it is a metal-dependent and Msh2-Msh3-stimulated endonuclease that makes single-strand breaks in supercoiled DNA. These observations support a direct role for an Mlh1-Mlh3 endonuclease activity in resolving recombination intermediates and in DNA mismatch repair. PMID:24403070

Mlh1-Mlh3, a meiotic crossover and DNA mismatch repair factor, is a Msh2-Msh3-stimulated endonuclease.

PubMed

Rogacheva, Maria V; Manhart, Carol M; Chen, Cheng; Guarne, Alba; Surtees, Jennifer; Alani, Eric

2014-02-28

Crossing over between homologous chromosomes is initiated in meiotic prophase in most sexually reproducing organisms by the appearance of programmed double strand breaks throughout the genome. In Saccharomyces cerevisiae the double-strand breaks are resected to form three prime single-strand tails that primarily invade complementary sequences in unbroken homologs. These invasion intermediates are converted into double Holliday junctions and then resolved into crossovers that facilitate homolog segregation during Meiosis I. Work in yeast suggests that Msh4-Msh5 stabilizes invasion intermediates and double Holliday junctions, which are resolved into crossovers in steps requiring Sgs1 helicase, Exo1, and a putative endonuclease activity encoded by the DNA mismatch repair factor Mlh1-Mlh3. We purified Mlh1-Mlh3 and showed that it is a metal-dependent and Msh2-Msh3-stimulated endonuclease that makes single-strand breaks in supercoiled DNA. These observations support a direct role for an Mlh1-Mlh3 endonuclease activity in resolving recombination intermediates and in DNA mismatch repair.

BatMis: a fast algorithm for k-mismatch mapping.

PubMed

Tennakoon, Chandana; Purbojati, Rikky W; Sung, Wing-Kin

2012-08-15

Second-generation sequencing (SGS) generates millions of reads that need to be aligned to a reference genome allowing errors. Although current aligners can efficiently map reads allowing a small number of mismatches, they are not well suited for handling a large number of mismatches. The efficiency of aligners can be improved using various heuristics, but the sensitivity and accuracy of the alignments are sacrificed. In this article, we introduce Basic Alignment tool for Mismatches (BatMis)--an efficient method to align short reads to a reference allowing k mismatches. BatMis is a Burrows-Wheeler transformation based aligner that uses a seed and extend approach, and it is an exact method. Benchmark tests show that BatMis performs better than competing aligners in solving the k-mismatch problem. Furthermore, it can compete favorably even when compared with the heuristic modes of the other aligners. BatMis is a useful alternative for applications where fast k-mismatch mappings, unique mappings or multiple mappings of SGS data are required. BatMis is written in C/C++ and is freely available from http://code.google.com/p/batmis/

Estrogen enhances mismatch repair by induction of MLH1 expression via estrogen receptor-β

PubMed Central

Lu, Jun-Yu; Jin, Peng; Gao, Wei; Wang, De-Zhi; Sheng, Jian-Qiu

2017-01-01

Epidemiological data demonstrated that hormone replace treatment has protective effect against colorectal cancer (CRC). Our previous studies showed that this effect may be associated with DNA mismatch repair. This study aims to investigate the mechanism of estrogen induction of MLH1, and whether colorectal tumor proliferation can be inhibited through induction of MLH1 by estrogen signal pathway. Human CRC cell lines were used to examine the regulation of MLH1 expression by over-expression and depletion of estrogen receptor-α (ERα) and estrogen receptor-β (ERβ), under the treatment with 17β-estradiol or β-Estradiol 6-(O-carboxy-methyl)oxime:BSA, followed by a real-time Q-PCR and Western blotting analysis. Luciferase reporter and chromatin immunoprecipitation assays were used to identify the estrogen response elements in the proximal promoter of MLH1 gene. Then, the influence of estrogen-induced MLH1 on CRC tumor growth were determined in vitro and in vivo. We found that mismatch repair ability and microsatellite stability of cells were enhanced by estrogen via induction of MLH1 expression, which was mediated by ERβ, through a transcriptional activation process. Furthermore, we identified that ERβ exerted an inhibitory effect on CRC tumor proliferation in vitro and in vivo, combined with 5-FU, through up-regulation of MLH1 expression. Finally, we concluded that estrogen enhances mismatch repair ability and tumor inhibition effect in vitro and in vivo, via induction of MLH1 expression mediated by ERβ. PMID:28404976

Estrogen enhances mismatch repair by induction of MLH1 expression via estrogen receptor-β.

PubMed

Lu, Jun-Yu; Jin, Peng; Gao, Wei; Wang, De-Zhi; Sheng, Jian-Qiu

2017-06-13

Epidemiological data demonstrated that hormone replace treatment has protective effect against colorectal cancer (CRC). Our previous studies showed that this effect may be associated with DNA mismatch repair. This study aims to investigate the mechanism of estrogen induction of MLH1, and whether colorectal tumor proliferation can be inhibited through induction of MLH1 by estrogen signal pathway. Human CRC cell lines were used to examine the regulation of MLH1 expression by over-expression and depletion of estrogen receptor-α (ERα) and estrogen receptor-β (ERβ), under the treatment with 17β-estradiol or β-Estradiol 6-(O-carboxy-methyl)oxime:BSA, followed by a real-time Q-PCR and Western blotting analysis. Luciferase reporter and chromatin immunoprecipitation assays were used to identify the estrogen response elements in the proximal promoter of MLH1 gene. Then, the influence of estrogen-induced MLH1 on CRC tumor growth were determined in vitro and in vivo. We found that mismatch repair ability and microsatellite stability of cells were enhanced by estrogen via induction of MLH1 expression, which was mediated by ERβ, through a transcriptional activation process. Furthermore, we identified that ERβ exerted an inhibitory effect on CRC tumor proliferation in vitro and in vivo, combined with 5-FU, through up-regulation of MLH1 expression. Finally, we concluded that estrogen enhances mismatch repair ability and tumor inhibition effect in vitro and in vivo, via induction of MLH1 expression mediated by ERβ.

Patient-prosthesis mismatch in aortic valve replacement: really tolerable?

PubMed

Fuster, Rafael García; Montero Argudo, José A; Albarova, Oscar Gil; Sos, Fernando Hornero; López, Sergio Cánovas; Codoñer, María Bueno; Buendía Miñano, José A; Albarran, Ignacio Rodríguez

2005-03-01

Several studies have demonstrated favorable results despite patient-prosthesis mismatch after aortic valve replacement with the use of third generation prostheses. Our aim was to determine whether this mismatch is always tolerable. A clinical-echocardiographic study has been performed in 339 consecutive patients who underwent aortic valve replacement because of aortic stenosis. In-hospital outcome and left ventricular mass index regression (1st month-1st year) were analyzed in the presence or absence of mismatch (indexed effective orifice area < or =0.85cm(2)/m(2)). The influence of high degrees of preoperative left ventricular mass on in-hospital mortality has also been evaluated. Left ventricular mass index was considered increased if the calculated value was over the superior quartile of the frequency distribution of all the values observed in both sexes. Mismatch was found in 38% of the patients. In the absence of mismatch, the absolute mass regression was proportional to the preoperative left ventricular mass. This regression was higher in patients with increased left ventricular mass indexed (vs not increased): -38.0+/-7.8 vs -8.8+/-4.7g/m(2), p<0.01 (1st month) and -67.7+/-16.9vs -23.5+/-6.7g/m(2), p<0.05 (1st year). Mass regression was impaired in the presence of mismatch, particularly, in patients with previously increased left ventricular mass: -8.2+/-11.6 vs -5.6+/-6.3g/m(2) (p=0.83) and -24.6+/-12.6 vs -11.7+/-10.5g/m(2) (p=0.54). This worse regression was reflected on a 100% incidence of residual hypertrophy at follow-up (1st month-1st year). In the presence of mismatch, increased ventricular mass was associated with higher mortality: 14.7% vs 2.1% (p<0.01). In the absence of mismatch, ventricular mass was not associated with mortality: 4.1 vs 2.5% (p=0.55). In patients with severe ventricular hypertrophy it may be important to elude patient-prosthesis mismatch to avoid a significant increase in mortality and improve ventricular mass regression

Analysis of in vivo correction of defined mismatches in the DNA mismatch repair mutants msh2, msh3 and msh6 of Saccharomyces cerevisiae.

PubMed

Lühr, B; Scheller, J; Meyer, P; Kramer, W

1998-02-01

We have analysed the correction of defined mismatches in wild-type and msh2, msh3, msh6 and msh3 msh6 mutants of Saccharomyces cerevisiae in two different yeast strain backgrounds by transformation with plasmid heteroduplex DNA constructs. Ten different base/base mismatches, two single-nucleotide loops and a 38-nucleotide loop were tested. Repair of all types of mismatches was severely impaired in msh2 and msh3 msh6 mutants. In msh6 mutants, repair efficiency of most base/base mismatches was reduced to a similar extent as in msh3 msh6 double mutants. G/T and A/C mismatches, however, displayed residual repair in msh6 mutants in one strain background, implying a role for Msh3p in recognition of base/base mismatches. Furthermore, the efficiency of repair of base/base mismatches was considerably reduced in msh3 mutants in one strain background, indicating a requirement for MSH3 for fully efficient mismatch correction. Also the efficiency of repair of the 38-nucleotide loop was reduced in msh3 mutants, and to a lesser extent in msh6 mutants. The single-nucleotide loop with an unpaired A was less efficiently repaired in msh3 mutants and that with an unpaired T was less efficiently corrected in msh6 mutants, indicating non-redundant functions for the two proteins in the recognition of single-nucleotide loops.

Neurotrophin 3 genotype and emotional adverse effects of osmotic-release oral system methylphenidate (OROS-MPH) in children with attention-deficit/hyperactivity disorder.

PubMed

Park, Subin; Kim, Bung-Nyun; Kim, Jae-Won; Shin, Min-Sup; Cho, Soo-Churl; Kim, Ji-Hoon; Son, Jung-Woo; Shin, Yun-Mi; Chung, Un-Sun; Han, Doug-Hyun

2014-03-01

Neurotrophin 3 (NTF3) has been studied in relation to the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) and mood disorders as well as psychostimulant action. We hypothesized that the risk of an emotional side effect to methylphenidate (MPH) treatment may be associated with NTF3 genotypes. Ninety-six medication-naïve children with ADHD (mean age 8.70, standard deviation 1.41 years, 79 males) were genotyped and treated with MPH. At baseline, which was prior to MPH treatment, and after two weeks of medication, investigators asked children and their parents or caregivers about adverse events using a symptom rating scale. ADHD subjects with the A/A genotype at the NTF3 rs6332 polymorphism showed the highest 'Emotionality' and 'Over-focus/euphoria' factor scores, followed by those with the G/A genotype and those with the G/G genotype (p=0.042 and p=0.045, respectively). ADHD subjects with the A/A genotype at the NTF3 rs6332 polymorphism showed the highest 'Proneness to crying' and 'Nail biting' item scores, followed by those with the G/A genotype and those with the G/G genotype (p=0.047 and p=0.017, respectively). These data provide preliminary evidence that genetic variation in the NTF3 gene is related to susceptibility to emotional side effects in response to MPH treatment in Korean children with ADHD.

Unaccusative Mismatches in Japanese.

ERIC Educational Resources Information Center

Tsujimura, Natsuko

Two instances of unaccusative verb mismatches in Japanese are examined. An unaccusative mismatch is the situation in which a different accusative diagnostic singles out different classes of intransitive verbs within and across languages. One type of unaccusative mismatch has to do with group C verbs, or verbs of manner with protagonist control.…

Educational Mismatch between Graduates' Possessed Skills and Market Demands in Pakistan

ERIC Educational Resources Information Center

Uzair-ul-Hassan, Muhammad; Noreen, Zahida

2013-01-01

Educational mismatch in skills that graduates possess and market requires creates barriers for organizations as well as for job seekers. The study was conducted to find out the educational mismatch between graduates possessed skills and market demands. Convenient sampling was carried out and data were collected from 200 graduates of economics…

Artificial mismatch hybridization

DOEpatents

Guo, Zhen; Smith, Lloyd M.

1998-01-01

An improved nucleic acid hybridization process is provided which employs a modified oligonucleotide and improves the ability to discriminate a control nucleic acid target from a variant nucleic acid target containing a sequence variation. The modified probe contains at least one artificial mismatch relative to the control nucleic acid target in addition to any mismatch(es) arising from the sequence variation. The invention has direct and advantageous application to numerous existing hybridization methods, including, applications that employ, for example, the Polymerase Chain Reaction, allele-specific nucleic acid sequencing methods, and diagnostic hybridization methods.

Snowshoe hares display limited phenotypic plasticity to mismatch in seasonal camouflage

USGS Publications Warehouse

Zimova, Marketa; Mills, L. Scott; Lukacs, Paul M.; Mitchell, Michael S.

2014-01-01

As duration of snow cover decreases owing to climate change, species undergoing seasonal colour moults can become colour mismatched with their background. The immediate adaptive solution to this mismatch is phenotypic plasticity, either in phenology of seasonal colour moults or in behaviours that reduce mismatch or its consequences. We observed nearly 200 snowshoe hares across a wide range of snow conditions and two study sites in Montana, USA, and found minimal plasticity in response to mismatch between coat colour and background. We found that moult phenology varied between study sites, likely due to differences in photoperiod and climate, but was largely fixed within study sites with only minimal plasticity to snow conditions during the spring white-to-brown moult. We also found no evidence that hares modify their behaviour in response to colour mismatch. Hiding and fleeing behaviours and resting spot preference of hares were more affected by variables related to season, site and concealment by vegetation, than by colour mismatch. We conclude that plasticity in moult phenology and behaviours in snowshoe hares is insufficient for adaptation to camouflage mismatch, suggesting that any future adaptation to climate change will require natural selection on moult phenology or behaviour.

HLA Association with hematopoietic stem cell transplantation outcome: the number of mismatches at HLA-A, -B, -C, -DRB1, or -DQB1 is strongly associated with overall survival.

PubMed

Loiseau, Pascale; Busson, Marc; Balere, Marie-Lorraine; Dormoy, Anne; Bignon, Jean-Denis; Gagne, Katia; Gebuhrer, Lucette; Dubois, Valérie; Jollet, Isabelle; Bois, Monique; Perrier, Pascale; Masson, Dominique; Moine, Agnès; Absi, Léna; Reviron, Denis; Lepage, Virginia; Tamouza, Ryad; Toubert, Antoine; Marry, Evelyne; Chir, Zina; Jouet, Jean-Pierre; Blaise, Didier; Charron, Dominique; Raffoux, Colette

2007-08-01

HLA matching between the donor and recipient improves the success of unrelated hematopoietic stem cell transplantation (HSCT). Because many patients in need of an unrelated transplant have only donors with mismatch, information is needed to evaluate the limits of HLA mismatching. We examined the association of survival, acute graft-versus-host disease (aGVHD) and relapse with HLA-A, -B, -C, -DRB, -DQB1, and -DPB1 mismatching in 334 patients coming from 12 French transplant centers and who received a non-T cell-depleted bone marrow graft from an unrelated donor. All patients were prepared with the use of myeloablative conditioning regimens. Our analyses demonstrate negative effects of HLA mismatching for either HLA-A, -B, -C, -DRB1, or -DQB1 loci on survival. Multivariate Cox analyses showed that a single mismatch was associated with a significant decrement in survival (P=.046, hazard ratio [HR]=1.41, confidence interval [CI] 95% 1.1-1.98). The presence of multiple mismatches was worse for survival (P=.003, HR=1.91, CI 95% 1.26-2.91) and severe aGVHD (grade III-IV) (P=.002, HR=2.51, CI95% 1.41-4.46). The cumulative incidences of aGVHD and relapse in those HLA-A, -B, -C, -DRB1, and -DQB1 identical pairs with 2, 1, or 0 DPB1 incompatibilities were 63%, 50%, and 51%, and 12%, 27%, and 20%, respectively, but these differences were not statistically significant. Similar differences of aGVHD and relapse, but not statistically significant, were observed in those HLA-A, -B, -C, -DRB1, and -DQB1 identical pairs with DPB1 disparities classified into permissive or nonpermissive mismatches according to Zino's classification based on a hierarchy of the immunogenicity of the HLA-DP molecules. "Missing killer cell immunoglobulin-like receptor (KIR) ligand" evaluated on the presence of HLA-C1, -C2, and Bw4 groups in the recipients was not associated with aGVHD, survival, and relapse in this cohort of non-T cell-depleted HSCT.

Mismatch cleavage by single-strand specific nucleases

PubMed Central

Till, Bradley J.; Burtner, Chris; Comai, Luca; Henikoff, Steven

2004-01-01

We have investigated the ability of single-strand specific (sss) nucleases from different sources to cleave single base pair mismatches in heteroduplex DNA templates used for mutation and single-nucleotide polymorphism analysis. The TILLING (Targeting Induced Local Lesions IN Genomes) mismatch cleavage protocol was used with the LI-COR gel detection system to assay cleavage of amplified heteroduplexes derived from a variety of induced mutations and naturally occurring polymorphisms. We found that purified nucleases derived from celery (CEL I), mung bean sprouts and Aspergillus (S1) were able to specifically cleave nearly all single base pair mismatches tested. Optimal nicking of heteroduplexes for mismatch detection was achieved using higher pH, temperature and divalent cation conditions than are routinely used for digestion of single-stranded DNA. Surprisingly, crude plant extracts performed as well as the highly purified preparations for this application. These observations suggest that diverse members of the S1 family of sss nucleases act similarly in cleaving non-specifically at bulges in heteroduplexes, and single-base mismatches are the least accessible because they present the smallest single-stranded region for enzyme binding. We conclude that a variety of sss nucleases and extracts can be effectively used for high-throughput mutation and polymorphism discovery. PMID:15141034

HLA Mismatching Strategies for Solid Organ Transplantation – A Balancing Act

PubMed Central

Zachary, Andrea A.; Leffell, Mary S.

2016-01-01

HLA matching provides numerous benefits in organ transplantation including better graft function, fewer rejection episodes, longer graft survival, and the possibility of reduced immunosuppression. Mismatches are attended by more frequent rejection episodes that require increased immunosuppression that, in turn, can increase the risk of infection and malignancy. HLA mismatches also incur the risk of sensitization, which can reduce the opportunity and increase waiting time for a subsequent transplant. However, other factors such as donor age, donor type, and immunosuppression protocol, can affect the benefit derived from matching. Furthermore, finding a well-matched donor may not be possible for all patients and usually prolongs waiting time. Strategies to optimize transplantation for patients without a well-matched donor should take into account the immunologic barrier represented by different mismatches: what are the least immunogenic mismatches considering the patient’s HLA phenotype; should repeated mismatches be avoided; is the patient sensitized to HLA and, if so, what are the strengths of the patient’s antibodies? This information can then be used to define the HLA type of an immunologically optimal donor and the probability of such a donor occurring. A probability that is considered to be too low may require expanding the donor population through paired donation or modifying what is acceptable, which may require employing treatment to overcome immunologic barriers such as increased immunosuppression or desensitization. Thus, transplantation must strike a balance between the risk associated with waiting for the optimal donor and the risk associated with a less than optimal donor. PMID:28003816

The Influence of Pelvic Incidence and Lumbar Lordosis Mismatch on Development of Symptomatic Adjacent Level Disease Following Single-Level Transforaminal Lumbar Interbody Fusion.

PubMed

Tempel, Zachary J; Gandhoke, Gurpreet S; Bolinger, Bryan D; Khattar, Nicolas K; Parry, Philip V; Chang, Yue-Fang; Okonkwo, David O; Kanter, Adam S

2017-06-01

Annual incidence of symptomatic adjacent level disease (ALD) following lumbar fusion surgery ranges from 0.6% to 3.9% per year. Sagittal malalignment may contribute to the development of ALD. To describe the relationship between pelvic incidence-lumbar lordosis (PI-LL) mismatch and the development of symptomatic ALD requiring revision surgery following single-level transforaminal lumbar interbody fusion for degenerative lumbar spondylosis and/or low-grade spondylolisthesis. All patients who underwent a single-level transforaminal lumbar interbody fusion at either L4/5 or L5/S1 between July 2006 and December 2012 were analyzed for pre- and postoperative spinopelvic parameters. Using univariate and logistic regression analysis, we compared the spinopelvic parameters of those patients who required revision surgery against those patients who did not develop symptomatic ALD. We calculated the predictive value of PI-LL mismatch. One hundred fifty-nine patients met the inclusion criteria. The results noted that, for a 1° increase in PI-LL mismatch (preop and postop), the odds of developing ALD requiring surgery increased by 1.3 and 1.4 fold, respectively, which were statistically significant increases. Based on our analysis, a PI-LL mismatch of >11° had a positive predictive value of 75% for the development of symptomatic ALD requiring revision surgery. A high PI-LL mismatch is strongly associated with the development of symptomatic ALD requiring revision lumbar spine surgery. The development of ALD may represent a global disease process as opposed to a focal condition. Spine surgeons may wish to consider assessment of spinopelvic parameters in the evaluation of degenerative lumbar spine pathology. Copyright © 2017 by the Congress of Neurological Surgeons

Replication infidelity via a mismatch with Watson–Crick geometry

PubMed Central

Bebenek, Katarzyna; Pedersen, Lars C.; Kunkel, Thomas A.

2011-01-01

In describing the DNA double helix, Watson and Crick suggested that “spontaneous mutation may be due to a base occasionally occurring in one of its less likely tautomeric forms.” Indeed, among many mispairing possibilities, either tautomerization or ionization of bases might allow a DNA polymerase to insert a mismatch with correct Watson–Crick geometry. However, despite substantial progress in understanding the structural basis of error prevention during polymerization, no DNA polymerase has yet been shown to form a natural base–base mismatch with Watson–Crick-like geometry. Here we provide such evidence, in the form of a crystal structure of a human DNA polymerase λ variant poised to misinsert dGTP opposite a template T. All atoms needed for catalysis are present at the active site and in positions that overlay with those for a correct base pair. The mismatch has Watson–Crick geometry consistent with a tautomeric or ionized base pair, with the pH dependence of misinsertion consistent with the latter. The results support the original idea that a base substitution can originate from a mismatch having Watson–Crick geometry, and they suggest a common catalytic mechanism for inserting a correct and an incorrect nucleotide. A second structure indicates that after misinsertion, the now primer-terminal G•T mismatch is also poised for catalysis but in the wobble conformation seen in other studies, indicating the dynamic nature of the pathway required to create a mismatch in fully duplex DNA. PMID:21233421

Replication infidelity via a mismatch with Watson-Crick geometry.

PubMed

Bebenek, Katarzyna; Pedersen, Lars C; Kunkel, Thomas A

2011-02-01

In describing the DNA double helix, Watson and Crick suggested that "spontaneous mutation may be due to a base occasionally occurring in one of its less likely tautomeric forms." Indeed, among many mispairing possibilities, either tautomerization or ionization of bases might allow a DNA polymerase to insert a mismatch with correct Watson-Crick geometry. However, despite substantial progress in understanding the structural basis of error prevention during polymerization, no DNA polymerase has yet been shown to form a natural base-base mismatch with Watson-Crick-like geometry. Here we provide such evidence, in the form of a crystal structure of a human DNA polymerase λ variant poised to misinsert dGTP opposite a template T. All atoms needed for catalysis are present at the active site and in positions that overlay with those for a correct base pair. The mismatch has Watson-Crick geometry consistent with a tautomeric or ionized base pair, with the pH dependence of misinsertion consistent with the latter. The results support the original idea that a base substitution can originate from a mismatch having Watson-Crick geometry, and they suggest a common catalytic mechanism for inserting a correct and an incorrect nucleotide. A second structure indicates that after misinsertion, the now primer-terminal G • T mismatch is also poised for catalysis but in the wobble conformation seen in other studies, indicating the dynamic nature of the pathway required to create a mismatch in fully duplex DNA.

Related transplantation with HLA-1 Ag mismatch in the GVH direction and HLA-8/8 allele-matched unrelated transplantation: a nationwide retrospective study.

PubMed

Kanda, Junya; Saji, Hiroh; Fukuda, Takahiro; Kobayashi, Takeshi; Miyamura, Koichi; Eto, Tetsuya; Kurokawa, Mineo; Kanamori, Heiwa; Mori, Takehiko; Hidaka, Michihiro; Iwato, Koji; Yoshida, Takashi; Sakamaki, Hisashi; Tanaka, Junji; Kawa, Keisei; Morishima, Yasuo; Suzuki, Ritsuro; Atsuta, Yoshiko; Kanda, Yoshinobu

2012-03-08

To clarify which is preferable, a related donor with an HLA-1 Ag mismatch at the HLA-A, HLA-B, or HLA-DR loci in the graft-versus-host (GVH) direction (RD/1AG-MM-GVH) or an HLA 8/8-allele (HLA-A, HLA-B, HLA-C, and HLA-DRB1)-matched unrelated donor (8/8-MUD), we evaluated 779 patients with acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome who received a T cell-replete graft from an RD/1AG-MM-GVH or 8/8-MUD. The use of an RD/1AG-MM-GVH donor was significantly associated with a higher overall mortality rate than the use of an 8/8-MUD in a multivariate analysis (hazard ratio, 1.49; P < .001), and this impact was statistically significant only in patients with standard-risk diseases (P = .001). Among patients with standard-risk diseases who received transplantation from an RD/1AG-MM-GVH donor, the presence of an HLA-B Ag mismatch was significantly associated with a lower overall survival rate than an HLA-DR Ag mismatch because of an increased risk of treatment-related mortality. The HLA-C Ag mismatch or multiple allelic mismatches were frequently observed in the HLA-B Ag-mismatched group, and were possibly associated with the poor outcome. In conclusion, an 8/8-MUD should be prioritized over an RD/1AG-MM-GVH donor during donor selection. In particular, an HLA-B Ag mismatch in the GVH direction has an adverse effect on overall survival and treatment-related mortality in patients with standard-risk diseases.

Analysis of the functional domains of the mismatch repair homologue Msh1p and its role in mitochondrial genome maintenance.

PubMed

Mookerjee, Shona A; Lyon, Hiram D; Sia, Elaine A

2005-02-01

Mitochondrial DNA (mtDNA) repair occurs in all eukaryotic organisms and is essential for the maintenance of mitochondrial function. Evidence from both humans and yeast suggests that mismatch repair is one of the pathways that functions in overall mtDNA stability. In the mitochondria of the yeast Saccharomyces cerevisiae, the presence of a homologue to the bacterial MutS mismatch repair protein, MSH1, has long been known to be essential for mitochondrial function. The mechanisms for which it is essential are unclear, however. Here, we analyze the effects of two point mutations, msh1-F105A and msh1-G776D, both predicted to be defective in mismatch repair; and we show that they are both able to maintain partial mitochondrial function. Moreover, there are significant differences in the severity of mitochondrial disruption between the two mutants that suggest multiple roles for Msh1p in addition to mismatch repair. Our overall findings suggest that these additional predicted functions of Msh1p, including recombination surveillance and heteroduplex rejection, may be primarily responsible for its essential role in mtDNA stability.

Educational Mismatch and Self-Employment

ERIC Educational Resources Information Center

Bender, Keith A.; Roche, Kristen

2013-01-01

Previous research on educational mismatch concentrates on estimating its labor market consequences but with a focus on wage and salary workers. This paper examines the far less studied influence of mismatch on the self-employed. Using a sample of workers in science and engineering fields, results show larger earnings penalties for mismatch among…

Thermodynamic characterization of tandem mismatches found in naturally occurring RNA

PubMed Central

Christiansen, Martha E.; Znosko, Brent M.

2009-01-01

Although all sequence symmetric tandem mismatches and some sequence asymmetric tandem mismatches have been thermodynamically characterized and a model has been proposed to predict the stability of previously unmeasured sequence asymmetric tandem mismatches [Christiansen,M.E. and Znosko,B.M. (2008) Biochemistry, 47, 4329–4336], experimental thermodynamic data for frequently occurring tandem mismatches is lacking. Since experimental data is preferred over a predictive model, the thermodynamic parameters for 25 frequently occurring tandem mismatches were determined. These new experimental values, on average, are 1.0 kcal/mol different from the values predicted for these mismatches using the previous model. The data for the sequence asymmetric tandem mismatches reported here were then combined with the data for 72 sequence asymmetric tandem mismatches that were published previously, and the parameters used to predict the thermodynamics of previously unmeasured sequence asymmetric tandem mismatches were updated. The average absolute difference between the measured values and the values predicted using these updated parameters is 0.5 kcal/mol. This updated model improves the prediction for tandem mismatches that were predicted rather poorly by the previous model. This new experimental data and updated predictive model allow for more accurate calculations of the free energy of RNA duplexes containing tandem mismatches, and, furthermore, should allow for improved prediction of secondary structure from sequence. PMID:19509311

MHC-mismatched mixed chimerism restores peripheral tolerance of noncross-reactive autoreactive T cells in NOD mice

PubMed Central

Zhang, Mingfeng; Racine, Jeremy J.; Lin, Qing; Liu, Yuqing; Tang, Shanshan; Qin, Qi; Qi, Tong; Riggs, Arthur D.; Zeng, Defu

2018-01-01

Autoimmune type 1 diabetes (T1D) and other autoimmune diseases are associated with particular MHC haplotypes and expansion of autoreactive T cells. Induction of MHC-mismatched but not -matched mixed chimerism by hematopoietic cell transplantation effectively reverses autoimmunity in diabetic nonobese diabetic (NOD) mice, even those with established diabetes. As expected, MHC-mismatched mixed chimerism mediates deletion in the thymus of host-type autoreactive T cells that have T-cell receptor (TCR) recognizing (cross-reacting with) donor-type antigen presenting cells (APCs), which have come to reside in the thymus. However, how MHC-mismatched mixed chimerism tolerizes host autoreactive T cells that recognize only self-MHC–peptide complexes remains unknown. Here, using NOD.Rag1−/−.BDC2.5 or NOD.Rag1−/−.BDC12-4.1 mice that have only noncross-reactive transgenic autoreactive T cells, we show that induction of MHC-mismatched but not -matched mixed chimerism restores immune tolerance of peripheral noncross-reactive autoreactive T cells. MHC-mismatched mixed chimerism results in increased percentages of both donor- and host-type Foxp3+ Treg cells and up-regulated expression of programmed death-ligand 1 (PD-L1) by host-type plasmacytoid dendritic cells (pDCs). Furthermore, adoptive transfer experiments showed that engraftment of donor-type dendritic cells (DCs) and expansion of donor-type Treg cells are required for tolerizing the noncross-reactive autoreactive T cells in the periphery, which are in association with up-regulation of host-type DC expression of PD-L1 and increased percentage of host-type Treg cells. Thus, induction of MHC-mismatched mixed chimerism may establish a peripheral tolerogenic DC and Treg network that actively tolerizes autoreactive T cells, even those with no TCR recognition of the donor APCs. PMID:29463744

The structural impact of DNA mismatches

PubMed Central

Rossetti, Giulia; Dans, Pablo D.; Gomez-Pinto, Irene; Ivani, Ivan; Gonzalez, Carlos; Orozco, Modesto

2015-01-01

The structure and dynamics of all the transversion and transition mismatches in three different DNA environments have been characterized by molecular dynamics simulations and NMR spectroscopy. We found that the presence of mismatches produced significant local structural alterations, especially in the case of purine transversions. Mismatched pairs often show promiscuous hydrogen bonding patterns, which interchange among each other in the nanosecond time scale. This therefore defines flexible base pairs, where breathing is frequent, and where distortions in helical parameters are strong, resulting in significant alterations in groove dimension. Even if the DNA structure is plastic enough to absorb the structural impact of the mismatch, local structural changes can be propagated far from the mismatch site, following the expected through-backbone and a previously unknown through-space mechanism. The structural changes related to the presence of mismatches help to understand the different susceptibility of mismatches to the action of repairing proteins. PMID:25820425

The impact of the 65 mph speed limit on Virginia's rural interstate highways through 1989.

DOT National Transportation Integrated Search

1990-01-01

In April 1987, Congress passed the Surface Transportation and Uniform Relocation Assistance Act (STURAA) which permitted states to raise their maximum speed limit on rural interstate highways (rural interstates) to 65 mph. Since then, 40 states, incl...

University Graduates' Skills Mismatches in Central Asia: Employers' Perspectives from Post-Soviet Tajikistan

ERIC Educational Resources Information Center

Jonbekova, Dilrabo

2015-01-01

This paper examines employers' perspectives about university graduates' skills and preparation for employment in post-Soviet Tajikistan. It explores the mismatch between the skills university graduates acquire and the skills required in the job market, and addresses some of the underlying reasons for the perceived skills mismatch. Thematic…

45 MPH 6,000-Pound and 10,000-Pound Rough Terrain Fork Lift Truck Feasibility Study.

DTIC Science & Technology

1986-06-24

Airport Post Office Box 66911 Chicago, IL 60666 NPN Security Classification of This Page REPORT DOCUMENTATION PAGE la . Report Security Classification...HOP Unausended Duadin., 20 - I: - 1 1.8 Inch RMS Road 14 la -3 * Clam C (0.93 Inch RMS) Rod w 12 10 10 Per~cent 9 P 7 U. 3 Percent 3 2 0 20 40 SPM...elm 10 67- * * 3 o *" - .2 0 20 40 W (mph) 4/2/ SOJA Figure 75. Rear Wheel Hop on Four Road Surfaces (10K RTFLT Unsuspended Baseline) " Page 93 Adding

On the MAC/network/energy performance evaluation of Wireless Sensor Networks: Contrasting MPH, AODV, DSR and ZTR routing protocols.

PubMed

Del-Valle-Soto, Carolina; Mex-Perera, Carlos; Orozco-Lugo, Aldo; Lara, Mauricio; Galván-Tejada, Giselle M; Olmedo, Oscar

2014-12-02

Wireless Sensor Networks deliver valuable information for long periods, then it is desirable to have optimum performance, reduced delays, low overhead, and reliable delivery of information. In this work, proposed metrics that influence energy consumption are used for a performance comparison among our proposed routing protocol, called Multi-Parent Hierarchical (MPH), the well-known protocols for sensor networks, Ad hoc On-Demand Distance Vector (AODV), Dynamic Source Routing (DSR), and Zigbee Tree Routing (ZTR), all of them working with the IEEE 802.15.4 MAC layer. Results show how some communication metrics affect performance, throughput, reliability and energy consumption. It can be concluded that MPH is an efficient protocol since it reaches the best performance against the other three protocols under evaluation, such as 19.3% reduction of packet retransmissions, 26.9% decrease of overhead, and 41.2% improvement on the capacity of the protocol for recovering the topology from failures with respect to AODV protocol. We implemented and tested MPH in a real network of 99 nodes during ten days and analyzed parameters as number of hops, connectivity and delay, in order to validate our Sensors 2014, 14 22812 simulator and obtain reliable results. Moreover, an energy model of CC2530 chip is proposed and used for simulations of the four aforementioned protocols, showing that MPH has 15.9% reduction of energy consumption with respect to AODV, 13.7% versus DSR, and 5% against ZTR.

Family Medicine or Primary Care Residency Selection: Effects of Family Medicine Interest Groups, MD/MPH Dual Degrees, and Rural Medical Education.

PubMed

Wei McIntosh, Elizabeth; Morley, Christopher P

2016-05-01

If medical schools are to produce primary care physicians (family medicine, pediatrics, or general internal medicine), they must provide educational experiences that enable medical students to maintain existing or form new interests in such careers. This study examined three mechanisms for doing so, at one medical school: participation as an officer in a family medicine interest group (FMIG), completion of a dual medical/public health (MD/MPH) degree program, and participation in a rural medical education (RMED) clinical track. Specialty Match data for students who graduated from the study institution between 2006 and 2015 were included as dependent variables in bivariate analysis (c2) and logistic regression models, examining FMIG, MD/MPH, and RMED participation as independent predictors of specialty choice (family medicine yes/no, or any primary care (PC) yes/no), controlling for student demographic data. In bivariate c2 analyses, FMIG officership did not significantly predict matching with family medicine or any PC; RMED and MD/MPH education were significant predictors of both family medicine and PC. Binary logistic regression analyses replicated the bivariate findings, controlling for student demographics. Dual MD/MPH and rural medical education had stronger effects in producing primary care physicians than participation in a FMIG as an officer, at one institution. Further study at multiple institutions is warranted.

Innovating in health care management education: development of an accelerated MBA and MPH degree program at Yale.

PubMed

Pettigrew, Melinda M; Forman, Howard P; Pistell, Anne F; Nembhard, Ingrid M

2015-03-01

Increasingly, there is recognition of the need for individuals with expertise in both management and public health to help health care organizations deliver high-quality and cost-effective care. The Yale School of Public Health and Yale School of Management began offering an accelerated Master of Business Administration (MBA) and Master of Public Health (MPH) joint degree program in the summer of 2014. This new program enables students to earn MBA and MPH degrees simultaneously from 2 fully accredited schools in 22 months. Students will graduate with the knowledge and skills needed to become innovative leaders of health care organizations. We discuss the rationale for the program, the developmental process, the curriculum, benefits of the program, and potential challenges.

Effect of HLA mismatch on acute graft-versus-host disease.

PubMed

Kanda, Junya

2013-09-01

HLA matching between donors and recipients is the most important factor associated with acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation. With improvements in GVHD prophylaxis and supportive care, transplantations from HLA mismatched donors are performed increasingly frequently, drawing greater attention to the effects of HLA mismatch. In related transplantation, HLA 1-antigen mismatch at the HLA-A, HLA-B, and HLA-DR loci is considered acceptable, but the incidence of severe acute GVHD under standard prophylaxis is higher than that for matched related and unrelated transplantation, highlighting the need for a modification of GVHD prophylaxis. Development of new GVHD prophylaxes has now made HLA 2-3-antigen mismatched related transplantation feasible, and has almost overcome the HLA barrier. In unrelated bone marrow or peripheral blood stem cell transplantation, donors matched for HLA-A, HLA-B, HLA-C, and HLA-DRB1 alleles are the most preferable. The impact of allele or antigen mismatch has been evaluated in a number of studies, but the results of these have not been consistent, partly due to differences in race and HLA distribution. The effects of HLA mismatch may differ depending on the year of transplantation and the form of GVHD prophylaxis administered. In cord blood transplantation, successful transplantation can be achieved with up to two HLA mismatches. In children, compared to the use of HLA mismatched units, the use of HLA-matched units is associated with a lower risk of acute GVHD and mortality, while in adults HLA mismatches may have a lower impact on outcome. Thus, the effect of HLA matching should be evaluated separately for different stem cell sources.

DNA Mismatch Binding and Antiproliferative Activity of Rhodium Metalloinsertors

PubMed Central

Ernst, Russell J.; Song, Hang; Barton, Jacqueline K.

2009-01-01

Deficiencies in mismatch repair (MMR) are associated with carcinogenesis. Rhodium metalloinsertors bind to DNA base mismatches with high specificity and inhibit cellular proliferation preferentially in MMR-deficient cells versus MMR-proficient cells. A family of chrysenequinone diimine complexes of rhodium with varying ancillary ligands that serve as DNA metalloinsertors has been synthesized, and both DNA mismatch binding affinities and antiproliferative activities against the human colorectal carcinoma cell lines HCT116N and HCT116O, an isogenic model system for MMR deficiency, have been determined. DNA photocleavage experiments reveal that all complexes bind to the mismatch sites with high specificities; DNA binding affinities to oligonucleotides containing single base CA and CC mismatches, obtained through photocleavage titration or competition, vary from 104 to 108 M−1 for the series of complexes. Significantly, binding affinities are found to be inversely related to ancillary ligand size and directly related to differential inhibition of the HCT116 cell lines. The observed trend in binding affinity is consistent with the metalloinsertion mode where the complex binds from the minor groove with ejection of mismatched base pairs. The correlation between binding affinity and targeting of the MMR-deficient cell line suggests that rhodium metalloinsertors exert their selective biological effects on MMR-deficient cells through mismatch binding in vivo. PMID:19175313

Materials at 200 mph: Making NASCAR Faster and Safer

NASA Astrophysics Data System (ADS)

Leslie-Pelecky, Diandra

2008-03-01

You cannot win a NASCAR race without understanding science.ootnotetextDiandra Leslie-Pelecky, The Physics of NASCAR (Dutton, New York City, 2008). Materials play important roles in improving performance, as well as ensuring safety. On the performance side, NASCAR limits the materials race car scientists and engineers can use to limit ownership costs. `Exotic metals' are not allowed, so controlling microstructure and nanostructure are important tools. Compacted Graphite Iron, a cast iron in which magnesium additions produce interlocking microscale graphite reinforcements, makes engine blocks stronger and lighter. NASCAR's new car design employs a composite called Tegris^TM that has 70 percent of the strength of carbon fiber composites at about 10 percent of the cost. The most important role of materials in racing is safety. Drivers wear firesuits made of polymers that carbonize (providing thermal protection) and expand (reducing oxygen access) when heated. Catalytic materials originally developed for space-based CO2 lasers filter air for drivers during races. Although materials help cars go fast, they also help cars slow down safely---important because the kinetic energy of a race car going 180 mph is nine times greater than that of a passenger car going 60 mph. Energy-absorbing foams in the cars and on the tracks control energy dissipation during accidents. To say that most NASCAR fans (and there are estimated to be 75 million of them) are passionate about their sport is an understatement. NASCAR fans understand that science and engineering are integral to keeping their drivers safe and helping their teams win. Their passion for racing gives us a great opportunity to share our passion for science with them. NASCAR^ is a registered trademark of the National Association for Stock Car Auto Racing, Inc. Tegris^TM is a trademark of Milliken & Company.

DNA mismatch-specific targeting and hypersensitivity of mismatch-repair-deficient cells to bulky rhodium(III) intercalators

PubMed Central

Hart, Jonathan R.; Glebov, Oleg; Ernst, Russell J.; Kirsch, Ilan R.; Barton, Jacqueline K.

2006-01-01

Mismatch repair (MMR) is critical to maintaining the integrity of the genome, and deficiencies in MMR are correlated with cancerous transformations. Bulky rhodium intercalators target DNA base mismatches with high specificity. Here we describe the application of bulky rhodium intercalators to inhibit cellular proliferation differentially in MMR-deficient cells compared with cells that are MMR-proficient. Preferential inhibition by the rhodium complexes associated with MMR deficiency is seen both in a human colon cancer cell line and in normal mouse fibroblast cells; the inhibition of cellular proliferation depends strictly on the MMR deficiency of the cell. Furthermore, our assay of cellular proliferation is found to correlate with DNA mismatch targeting by the bulky metallointercalators. It is the Δ-isomer that is active both in targeting base mismatches and in inhibiting DNA synthesis. Additionally, the rhodium intercalators promote strand cleavage at the mismatch site with photoactivation, and we observe that the cellular response is enhanced with photoactivation. Targeting DNA mismatches may therefore provide a cell-selective strategy for chemotherapeutic design. PMID:17030786

A rhodium(III) complex for high-affinity DNA base-pair mismatch recognition

PubMed Central

Junicke, Henrik; Hart, Jonathan R.; Kisko, Jennifer; Glebov, Oleg; Kirsch, Ilan R.; Barton, Jacqueline K.

2003-01-01

A rhodium(III) complex, rac-[Rh(bpy)2phzi]3+ (bpy, 2,2′-bipyridine; phzi, benzo[a]phenazine-5,6-quinone diimine) has been designed as a sterically demanding intercalator targeted to destabilized mismatched sites in double-helical DNA. The complex is readily synthesized by condensation of the phenazine quinone with the corresponding diammine complex. Upon photoactivation, the complex promotes direct strand scission at single-base mismatch sites within the DNA duplex. As with the parent mismatch-specific reagent, [Rh(bpy)2(chrysi)]3+ [chrysene-5,6-quinone diimine (chrysi)], mismatch selectivity depends on the helix destabilization associated with mispairing. Unlike the parent chrysi complex, the phzi analogue binds and cleaves with high affinity and efficiency. The specific binding constants for CA, CC, and CT mismatches within a 31-mer oligonucleotide duplex are 0.3, 1, and 6 × 107 M−1, respectively; site-specific photocleavage is evident at nanomolar concentrations. Moreover, the specificity, defined as the ratio in binding affinities for mispaired vs. well paired sites, is maintained. The increase in affinity is attributed to greater stability in the mismatched site associated with stacking by the heterocyclic aromatic ligand. The high-affinity complex is also applied in the differential cleavage of DNA obtained from cell lines deficient in mismatch repair vs. those proficient in mismatch repair. Agreement is found between photocleavage by the mismatch-specific probes and deficiency in mismatch repair. This mismatch-specific targeting, therefore, offers a potential strategy for new chemotherapeutic design. PMID:12610209

The effectiveness of the 55 MPH national maximum speed limit as a life saving benefit

DOT National Transportation Integrated Search

1980-10-01

The report contains an analysis of the life saving benefits resulting from the 55 mph NMSL from 1974-1979. Monthly fatality data from 1970-1979 was used in a time series model to arrive at the estimated safety benefits (lives saved). The time series ...

Entanglement verification with detection efficiency mismatch

NASA Astrophysics Data System (ADS)

Zhang, Yanbao; Lütkenhaus, Norbert

Entanglement is a necessary condition for secure quantum key distribution (QKD). When there is an efficiency mismatch between various detectors used in the QKD system, it is still an open problem how to verify entanglement. Here we present a method to address this problem, given that the detection efficiency mismatch is characterized and known. The method works without assuming an upper bound on the number of photons going to each threshold detector. Our results suggest that the efficiency mismatch affects the ability to verify entanglement: the larger the efficiency mismatch is, the smaller the set of entangled states that can be verified becomes. When there is no mismatch, our method can verify entanglement even if the method based on squashing maps [PRL 101, 093601 (2008)] fails.

Innovating in Health Care Management Education: Development of an Accelerated MBA and MPH Degree Program at Yale

PubMed Central

Forman, Howard P.; Pistell, Anne F.; Nembhard, Ingrid M.

2015-01-01

Increasingly, there is recognition of the need for individuals with expertise in both management and public health to help health care organizations deliver high-quality and cost-effective care. The Yale School of Public Health and Yale School of Management began offering an accelerated Master of Business Administration (MBA) and Master of Public Health (MPH) joint degree program in the summer of 2014. This new program enables students to earn MBA and MPH degrees simultaneously from 2 fully accredited schools in 22 months. Students will graduate with the knowledge and skills needed to become innovative leaders of health care organizations. We discuss the rationale for the program, the developmental process, the curriculum, benefits of the program, and potential challenges. PMID:25706023

Phonological mismatch makes aided speech recognition in noise cognitively taxing.

PubMed

Rudner, Mary; Foo, Catharina; Rönnberg, Jerker; Lunner, Thomas

2007-12-01

The working memory framework for Ease of Language Understanding predicts that speech processing becomes more effortful, thus requiring more explicit cognitive resources, when there is mismatch between speech input and phonological representations in long-term memory. To test this prediction, we changed the compression release settings in the hearing instruments of experienced users and allowed them to train for 9 weeks with the new settings. After training, aided speech recognition in noise was tested with both the trained settings and orthogonal settings. We postulated that training would lead to acclimatization to the trained setting, which in turn would involve establishment of new phonological representations in long-term memory. Further, we postulated that after training, testing with orthogonal settings would give rise to phonological mismatch, associated with more explicit cognitive processing. Thirty-two participants (mean=70.3 years, SD=7.7) with bilateral sensorineural hearing loss (pure-tone average=46.0 dB HL, SD=6.5), bilaterally fitted for more than 1 year with digital, two-channel, nonlinear signal processing hearing instruments and chosen from the patient population at the Linköping University Hospital were randomly assigned to 9 weeks training with new, fast (40 ms) or slow (640 ms), compression release settings in both channels. Aided speech recognition in noise performance was tested according to a design with three within-group factors: test occasion (T1, T2), test setting (fast, slow), and type of noise (unmodulated, modulated) and one between-group factor: experience setting (fast, slow) for two types of speech materials-the highly constrained Hagerman sentences and the less-predictable Hearing in Noise Test (HINT). Complex cognitive capacity was measured using the reading span and letter monitoring tests. PREDICTION: We predicted that speech recognition in noise at T2 with mismatched experience and test settings would be associated with more

Educational Mismatch and Retirement

ERIC Educational Resources Information Center

Bender, Keith A.; Heywood, John S.

2017-01-01

Using a panel data set of scientists in the US, we examine the hypothesis that workers in jobs poorly matched to their education are more likely to retire. In pooled estimates, we confirm that the mismatched are more likely to retire and that among retirees, the mismatched retire at younger ages. Hazard function estimates also support the…

[Impact of HLA mismatch on transplant outcomes].

PubMed

Kanda, Junya

Human leukocyte antigen (HLA) mismatch increases the risk of severe graft-versus-host disease (GVHD) and transplant-related mortality. However, the variety of stem cell sources such as cord blood units or the improvements in GVHD prophylaxis makes the interpretation of HLA mismatch more complex. In unrelated transplantation, the locus of HLA mismatch has a great impact on the donor candidate selection, whereas in related transplantation, it has an impact on the intensity of GVHD prophylaxis because donor availability is limited. Anti-thymocyte globulin and post-transplant cyclophosphamide are attractive GVHD prophylactic agents to reduce the risk of immune-associated complications in HLA-mismatched transplantations. HLA mismatch has a reduced impact in adult cord blood transplantation. In this review article, the impact of HLA mismatch based on graft sources is discussed.

Quantifying the causal effects of 20mph zones on road casualties in London via doubly robust estimation.

PubMed

Li, Haojie; Graham, Daniel J

2016-08-01

This paper estimates the causal effect of 20mph zones on road casualties in London. Potential confounders in the key relationship of interest are included within outcome regression and propensity score models, and the models are then combined to form a doubly robust estimator. A total of 234 treated zones and 2844 potential control zones are included in the data sample. The propensity score model is used to select a viable control group which has common support in the covariate distributions. We compare the doubly robust estimates with those obtained using three other methods: inverse probability weighting, regression adjustment, and propensity score matching. The results indicate that 20mph zones have had a significant causal impact on road casualty reduction in both absolute and proportional terms. Copyright © 2016 Elsevier Ltd. All rights reserved.

Novel disturbance-observer-based control for systems with high-order mismatched disturbances

NASA Astrophysics Data System (ADS)

Fang, Xing; Liu, Fei; Wang, Zhiguo; Dong, Na

2018-01-01

A novel disturbance-observer-based control method is investigated to attenuate the high-order mismatched disturbances. First, a finite-time disturbance observer (FTDO) is proposed to estimate the disturbances as well as the derivatives. By incorporating the outputs of FTDO, the original system is then reconstructed, where the mismatched disturbances are transformed to the matched ones that are compensated by feed-forward algorithm. Moreover, a feedback control law is developed to achieve the stability and tracking performance requirements for the systems. Finally, the proposed composite control method is applied to an unmanned helicopter system. The simulation results demonstrate that the proposed control method exhibits excellent control performance in the presence of high-order matched and mismatched disturbances.

Women's Contraceptive Preference-Use Mismatch

PubMed Central

He, Katherine; Dalton, Vanessa K.; Zochowski, Melissa K.

2017-01-01

Abstract Background: Family planning research has not adequately addressed women's preferences for different contraceptive methods and whether women's contraceptive experiences match their preferences. Methods: Data were drawn from the Women's Healthcare Experiences and Preferences Study, an Internet survey of 1,078 women aged 18–55 randomly sampled from a national probability panel. Survey items assessed women's preferences for contraceptive methods, match between methods preferred and used, and perceived reasons for mismatch. We estimated predictors of contraceptive preference with multinomial logistic regression models. Results: Among women at risk for pregnancy who responded with their preferred method (n = 363), hormonal methods (non-LARC [long-acting reversible contraception]) were the most preferred method (34%), followed by no method (23%) and LARC (18%). Sociodemographic differences in contraception method preferences were noted (p-values <0.05), generally with minority, married, and older women having higher rates of preferring less effective methods, compared to their counterparts. Thirty-six percent of women reported preference-use mismatch, with the majority preferring more effective methods than those they were using. Rates of match between preferred and usual methods were highest for LARC (76%), hormonal (non-LARC) (65%), and no method (65%). The most common reasons for mismatch were cost/insurance (41%), lack of perceived/actual need (34%), and method-specific preference concerns (19%). Conclusion: While preference for effective contraception was common among this sample of women, we found substantial mismatch between preferred and usual methods, notably among women of lower socioeconomic status and women using less effective methods. Findings may have implications for patient-centered contraceptive interventions. PMID:27710196

A practical assessment of magnetic resonance diffusion-perfusion mismatch in acute stroke: observer variation and outcome.

PubMed

Kane, I; Hand, P J; Rivers, C; Armitage, P; Bastin, M E; Lindley, R; Dennis, M; Wardlaw, J M

2009-11-01

MR diffusion/perfusion mismatch may help identify patients for acute stroke treatment, but mixed results from clinical trials suggest that further evaluation of the mismatch concept is required. To work effectively, mismatch should predict prognosis on arrival at hospital. We assessed mismatch duration and associations with functional outcome in acute stroke. We recruited consecutive patients with acute stroke, recorded baseline clinical variables, performed MR diffusion and perfusion imaging and assessed 3-month functional outcome. We assessed practicalities, agreement between mismatch on mean transit time (MTT) or cerebral blood flow (CBF) maps, visually and with lesion volume, and the relationship of each to functional outcome. Of 82 patients starting imaging, 14 (17%) failed perfusion imaging. Overall, 42% had mismatch (56% at <6 h; 41% at 12-24 h; 23% at 24-48 h). Agreement for mismatch by visual versus volume assessment was fair using MTT (kappa 0.59, 95% CI 0.34-0.84) but poor using CBF (kappa 0.24, 95% CI 0.01-0.48). Mismatch by either definition was not associated with functional outcome, even when the analysis was restricted to just those with mismatch. Visual estimation is a reasonable proxy for mismatch volume on MTT but not CBF. Perfusion is more difficult for acute stroke patients than diffusion imaging. Mismatch is present in many patients beyond 12 h after stroke. Mismatch alone does not distinguish patients with good and poor prognosis; both can do well or poorly. Other factors, e.g. reperfusion, may influence outcome more strongly, even in patients without mismatch.

A mutation in EXO1 defines separable roles in DNA mismatch repair and post-replication repair

PubMed Central

Tran, Phuoc T.; Fey, Julien P.; Erdeniz, Naz; Gellon, Lionel; Boiteux, Serge; Liskay, R. Michael

2007-01-01

Replication forks stall at DNA lesions or as a result of an unfavorable replicative environment. These fork stalling events have been associated with recombination and gross chromosomal rearrangements. Recombination and fork bypass pathways are the mechanisms accountable for restart of stalled forks. An important lesion bypass mechanism is the highly conserved post-replication repair (PRR) pathway that is composed of error-prone translesion and error-free bypass branches. EXO1 codes for a Rad2p family member nuclease that has been implicated in a multitude of eukaryotic DNA metabolic pathways that include DNA repair, recombination, replication, and telomere integrity. In this report, we show EXO1 functions in the MMS2 error-free branch of the PRR pathway independent of the role of EXO1 in DNA mismatch repair (MMR). Consistent with the idea that EXO1 functions independently in two separate pathways, we defined a domain of Exo1p required for PRR distinct from those required for interaction with MMR proteins. We then generated a point mutant exo1 allele that was defective for the function of Exo1p in MMR due to disrupted interaction with Mlh1p, but still functional for PRR. Lastly, by using a compound exo1 mutant that was defective for interaction with Mlh1p and deficient for nuclease activity, we provide further evidence that Exo1p plays both structural and catalytic roles during MMR. PMID:17602897

The Mismatch between Student Educational Expectations and Realities: Prevalence, Causes, and Consequences

ERIC Educational Resources Information Center

Maloshonok, Natalia; Terentev, Evgeniy

2017-01-01

This article aims to answer three questions concerning (1) the prevalence of the mismatch between student expectations and real university life, (2) factors influencing this mismatch, and (3) the effect of the expectation-reality mismatch on academic performance during the first year of study at university. The results of this study suggest that a…

The cost-effectiveness of mandatory 20 mph zones for the prevention of injuries.

PubMed

Peters, Jaime L; Anderson, Rob

2013-03-01

Traffic calming and speed limits are major public health strategies for further reducing road injuries, especially for vulnerable pedestrians such as children and the elderly. We conducted a cost-benefit analysis (CBA-favoured by transport economists) alongside a cost-utility analysis (CUA-favoured by health economists) of mandatory 20 mph zones, providing a unique opportunity to compare assumptions and results. A CUA from the public sector perspective and a CBA from a broader societal perspective. One-way, threshold and probabilistic sensitivity analyses were undertaken. In low casualty areas the intervention was not cost-effective regardless of approach (CUA: cost per QALY = £429 800; CBA: net present value = -£25 500). In high casualty areas, the intervention was cost-effective from the CBA (a saving of £90 600), but not from the CUA [cost per quality-adjusted life year (QALY) = £86 500; assuming National Institute for Health and Clinical Excellence's benchmark for approving health technologies]. Mandatory 20 mph zones may be cost-effective in high casualty areas when a CBA from a societal perspective is considered. Although CBA may appear, in principle, more appropriate, the quality, age or absence of reliable data for many parameters means that there is a great deal of uncertainty and the results should be interpreted with caution.

A teleofunctional account of evolutionary mismatch.

PubMed

Cofnas, Nathan

When the environment in which an organism lives deviates in some essential way from that to which it is adapted, this is described as "evolutionary mismatch," or "evolutionary novelty." The notion of mismatch plays an important role, explicitly or implicitly, in evolution-informed cognitive psychology, clinical psychology, and medicine. The evolutionary novelty of our contemporary environment is thought to have significant implications for our health and well-being. However, scientists have generally been working without a clear definition of mismatch. This paper defines mismatch as deviations in the environment that render biological traits unable, or impaired in their ability, to produce their selected effects (i.e., to perform their proper functions in Neander's sense). The machinery developed by Millikan in connection with her account of proper function, and with her related teleosemantic account of representation, is used to identify four major types, and several subtypes, of evolutionary mismatch. While the taxonomy offered here does not in itself resolve any scientific debates, the hope is that it can be used to better formulate empirical hypotheses concerning the effects of mismatch. To illustrate, it is used to show that the controversial hypothesis that general intelligence evolved as an adaptation to handle evolutionary novelty can, contra some critics, be formulated in a conceptually coherent way.

Educational mismatch and health status among foreign-born workers in Sweden.

PubMed

Dunlavy, A C; Garcy, A M; Rostila, M

2016-04-01

Foreign-born workers have been shown to experience poorer working conditions than native-born workers. Yet relationships between health and educational mismatch have been largely overlooked among foreign-born workers. This study uses objective and self-reported measures of educational mismatch to compare the prevalence of educational mismatch among native (n = 2359) and foreign-born (n = 1789) workers in Sweden and to examine associations between educational mismatch and poor self-rated health. Findings from weighted multivariate logistic regression which controlled for social position and individual-level demographic characteristics suggested that over-educated foreign-born workers had greater odds ratios for poor-self rated health compared to native-born matched workers. This association was particularly evident among men (OR = 2.14, 95% CI: 1.04-4.39) and women (OR = 2.13, 95% CI: 1.12-4.03) from countries outside of Western Europe, North America, and Australia/New Zealand. Associations between under-education and poor-self rated health were also found among women from countries outside of Western Europe, North America, and Australia/New Zealand (OR = 2.02, 95% CI: 1.27-3.18). These findings suggest that educational mismatch may be an important work-related social determinant of health among foreign-born workers. Future studies are needed to examine the effects of long-term versus short-term states of educational mismatch on health and to study relationships over time. Copyright © 2016 Elsevier Ltd. All rights reserved.

The unstructured linker arms of Mlh1-Pms1 are important for interactions with DNA during mismatch repair

PubMed Central

Plys, Aaron J.; Rogacheva, Maria V.; Greene, Eric C.; Alani, Eric

2012-01-01

DNA mismatch repair (MMR) models have proposed that MSH proteins identify DNA polymerase errors while interacting with the DNA replication fork. MLH proteins (primarily Mlh1-Pms1 in baker’s yeast) then survey the genome for lesion-bound MSH proteins. The resulting MSH-MLH complex formed at a DNA lesion initiates downstream steps in repair. MLH proteins act as dimers and contain long (20 – 30 nanometers) unstructured arms that connect two terminal globular domains. These arms can vary between 100 to 300 amino acids in length, are highly divergent between organisms, and are resistant to amino acid substitutions. To test the roles of the linker arms in MMR, we engineered a protease cleavage site into the Mlh1 linker arm domain of baker’s yeast Mlh1-Pms1. Cleavage of the Mlh1 linker arm in vitro resulted in a defect in Mlh1-Pms1 DNA binding activity, and in vivo proteolytic cleavage resulted in a complete defect in MMR. We then generated a series of truncation mutants bearing Mlh1 and Pms1 linker arms of varying lengths. This work revealed that MMR is greatly compromised when portions of the Mlh1 linker are removed, whereas repair is less sensitive to truncation of the Pms1 linker arm. Purified complexes containing truncations in Mlh1 and Pms1 linker arms were analyzed and found to have differential defects in DNA binding that also correlated with the ability to form a ternary complex with Msh2-Msh6 and mismatch DNA. These observations are consistent with the unstructured linker domains of MLH proteins providing distinct interactions with DNA during MMR. PMID:22659005

Educational Mismatches and Labor Market Outcomes: Evidence from Both Vertical and Horizontal Mismatches in Thailand

ERIC Educational Resources Information Center

Pholphirul, Piriya

2017-01-01

Purpose: Educational mismatches constitute negative impacts on labor markets in most countries, Thailand is no exception. The purpose of this paper is to quantify the degree of educational mismatch in Thailand and its impacts on labor market outcomes. Design/methodology/approach: This study analyzes data obtained from Thailand's Labor Force Survey…

Impact of MPH programs: contributing to health system strengthening in low- and middle-income countries?

PubMed

Zwanikken, Prisca A C; Alexander, Lucy; Scherpbier, Albert

2016-08-22

The "health workforce" crisis has led to an increased interest in health professional education, including MPH programs. Recently, it was questioned whether training of mid- to higher level cadres in public health prepared graduates with competencies to strengthen health systems in low- and middle-income countries. Measuring educational impact has been notoriously difficult; therefore, innovative methods for measuring the outcome and impact of MPH programs were sought. Impact was conceptualized as "impact on workplace" and "impact on society," which entailed studying how these competencies were enacted and to what effect within the context of the graduates' workplaces, as well as on societal health. This is part of a larger six-country mixed method study; in this paper, the focus is on the qualitative findings of two English language programs, one a distance MPH program offered from South Africa, the other a residential program in the Netherlands. Both offer MPH training to students from a diversity of countries. In-depth interviews were conducted with 10 graduates (per program), working in low- and middle-income health systems, their peers, and their supervisors. Impact on the workplace was reported as considerable by graduates and peers as well as supervisors and included changes in management and leadership: promotion to a leadership position as well as expanded or revitalized management roles were reported by many participants. The development of leadership capacity was highly valued amongst many graduates, and this capacity was cited by a number of supervisors and peers. Wider impact in the workplace took the form of introducing workplace innovations such as setting up an AIDS and addiction research center and research involvement; teaching and training, advocacy, and community engagement were other ways in which graduates' influence reached a wider target grouping. Beyond the workplace, an intersectoral approach, national reach through policy advisory roles

Effects of MPH-OROS on the Organizational, Time Management, and Planning Behaviors of Children with ADHD

ERIC Educational Resources Information Center

Abikoff, Howard; Nissley-Tsiopinis, Jenelle; Gallagher, Richard; Zambenedetti, Maurizio; Seyffert, Michael; Boorady, Roy; McCarthy, John

2009-01-01

A double-blind, placebo-controlled, crossover design study was done to evaluate the effects of methylphenidate-osmotic-release oral systems (MPH-OROS) on the organization, time management, and planning (OTMP) of children with attention deficit hyperactivity disorder (ADHD). Results show significant improvements on the OTMP of children with ADHD in…

Complete Remission Following Pembrolizumab in a Woman with Mismatch Repair-Deficient Endometrial Cancer and a Germline BRCA1 Mutation.

PubMed

Dizon, Don S; Dias-Santagata, Dora; Bregar, Amy; Sullivan, Laura; Filipi, Jennifer; DiTavi, Elizabeth; Miller, Lucy; Ellisen, Leif; Birrer, Michael; DelCarmen, Marcela

2018-02-22

Endometrial cancer is the most common gynecologic malignancy in the U.S. and, although the majority of cases present at an early stage and can be treated with curative intent, those who present with advanced disease, or develop metastatic or recurrent disease, have a poorer prognosis. A subset of endometrial cancers exhibit mismatch repair (MMR) deficiency. It is now recognized that MMR-deficient cancers are particularly susceptible to programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors, and in a landmark judgement in 2017, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab for these tumors, the first tumor-agnostic approval of a drug. However, less is known about the sensitivity to PD-1 blockade among patients with known mutations in double-strand break DNA repair pathways involving homologous recombination, such as those in BRCA1 or BRCA2 . Here we report a case of a patient with an aggressive somatic MMR-deficient endometrial cancer and a germline BRCA1 who experienced a rapid complete remission to pembrolizumab. Endometrial cancers, and in particular endometrioid carcinomas, should undergo immunohistochemical testing for mismatch repair proteins.Uterine cancers with documented mismatch repair deficiency are candidates for treatment with programmed cell death protein 1 inhibition.Genomic testing of recurrent, advanced, or metastatic tumors may be useful to determine whether patients are candidates for precision therapies. © AlphaMed Press 2018.

Mismatches in genetic markers in a large family study.

PubMed Central

Ashton, G C

1980-01-01

The Hawaii Family Study of Cognition provided an opportunity to investigate the frequency and implications of non-agreement, or mismatches, between observed and expected genetic marker phenotypes of husbands, wives, and children. Mismatch data from 68 families in which one or both spouses were known not to be a biological parent were used to determine the rate of undeclared nonparentage in 1,748 families in which conventional relationships were claimed. Two independent approaches gave consistent estimates, suggesting that approximately 2.3% of the 2,839 tested children from these families were probably the result of infidelity, concealed adoption, or another event. About two-thirds of the mismatches detected were probably due to properties of the techniques employed. PMID:6930820

The effectiveness of the 55 MPH national maximum speed limit as a life saving benefit : executive summary

DOT National Transportation Integrated Search

1981-01-01

The following report contains an analysis of the life saving benefits resulting from the 55 mph NMSL from 1974-1979. Monthly fatality data from 1970-1979 was used in a time series model to arrive at the estimated safety benefits (lives saved). The ti...

Rethinking the advantage of zero-HLA mismatches in unrelated living donor kidney transplantation: implications on kidney paired donation.

PubMed

Casey, Michael Jin; Wen, Xuerong; Rehman, Shehzad; Santos, Alfonso H; Andreoni, Kenneth A

2015-04-01

The OPTN/UNOS Kidney Paired Donation (KPD) Pilot Program allocates priority to zero-HLA mismatches. However, in unrelated living donor kidney transplants (LDKT)-the same donor source in KPD-no study has shown whether zero-HLA mismatches provide any advantage over >0 HLA mismatches. We hypothesize that zero-HLA mismatches among unrelated LDKT do not benefit graft survival. This retrospective SRTR database study analyzed LDKT recipients from 1987 to 2012. Among unrelated LDKT, subjects with zero-HLA mismatches were compared to a 1:1-5 matched (by donor age ±1 year and year of transplantation) control cohort with >0 HLA mismatches. The primary endpoint was death-censored graft survival. Among 32,654 unrelated LDKT recipients, 83 had zero-HLA mismatches and were matched to 407 controls with >0 HLA mismatches. Kaplan-Meier analyses for death-censored graft and patient survival showed no difference between study and control cohorts. In multivariate marginal Cox models, zero-HLA mismatches saw no benefit with death-censored graft survival (HR = 1.46, 95% CI 0.78-2.73) or patient survival (HR = 1.43, 95% CI 0.68-3.01). Our data suggest that in unrelated LDKT, zero-HLA mismatches may not offer any survival advantage. Therefore, particular study of zero-HLA mismatching is needed to validate its place in the OPTN/UNOS KPD Pilot Program allocation algorithm. © 2014 Steunstichting ESOT.

Visual-perceptual mismatch in robotic surgery.

PubMed

Abiri, Ahmad; Tao, Anna; LaRocca, Meg; Guan, Xingmin; Askari, Syed J; Bisley, James W; Dutson, Erik P; Grundfest, Warren S

2017-08-01

The principal objective of the experiment was to analyze the effects of the clutch operation of robotic surgical systems on the performance of the operator. The relative coordinate system introduced by the clutch operation can introduce a visual-perceptual mismatch which can potentially have negative impact on a surgeon's performance. We also assess the impact of the introduction of additional tactile sensory information on reducing the impact of visual-perceptual mismatch on the performance of the operator. We asked 45 novice subjects to complete peg transfers using the da Vinci IS 1200 system with grasper-mounted, normal force sensors. The task involves picking up a peg with one of the robotic arms, passing it to the other arm, and then placing it on the opposite side of the view. Subjects were divided into three groups: aligned group (no mismatch), the misaligned group (10 cm z axis mismatch), and the haptics-misaligned group (haptic feedback and z axis mismatch). Each subject performed the task five times, during which the grip force, time of completion, and number of faults were recorded. Compared to the subjects that performed the tasks using a properly aligned controller/arm configuration, subjects with a single-axis misalignment showed significantly more peg drops (p = 0.011) and longer time to completion (p < 0.001). Additionally, it was observed that addition of tactile feedback helps reduce the negative effects of visual-perceptual mismatch in some cases. Grip force data recorded from grasper-mounted sensors showed no difference between the different groups. The visual-perceptual mismatch created by the misalignment of the robotic controls relative to the robotic arms has a negative impact on the operator of a robotic surgical system. Introduction of other sensory information and haptic feedback systems can help in potentially reducing this effect.

Lattice QCD with mismatched fermi surfaces.

PubMed

Yamamoto, Arata

2014-04-25

We study two flavor fermions with mismatched chemical potentials in quenched lattice QCD. We first consider a large isospin chemical potential, where a charged pion is condensed, and then introduce a small mismatch between the chemical potentials of the up quark and the down antiquark. We find that the homogeneous pion condensate is destroyed by the mismatch of the chemical potentials. We also find that the two-point correlation function shows spatial oscillation, which indicates an inhomogeneous ground state, although it is not massless but massive in the present simulation setup.

Supply and Demand Mismatches in Training: Can Anything Be Done?

ERIC Educational Resources Information Center

Castro, Claudio de Moura; de Andrade, Antonio Cabral

1990-01-01

Vocational training often fails to provide what employers need and students want. To correct supply/demand mismatches requires improving feedback from employers, increasing the flow of information, bringing schools closer to businesses, rewarding institutions for successful employment of graduates, and providing incentives for entrepreneurs. (SK)

Measurement of mismatch loss in CPV modul

NASA Astrophysics Data System (ADS)

Liu, Mingguo; Kinsey, Geoffrey S.; Bagienski, Will; Nayak, Adi; Garboushian, Vahan

2012-10-01

A setup capable of simultaneously measuring I-V curves of a full string and its individual cells has been developed. This setup enables us to measure mismatch loss from individual cells in concert with various string combinations under varying field conditions. Mismatch loss from cells to plates at different off-track angles and mismatch from plates to strings in Amonix system during normal operation have been investigated.

Biallelic PMS2 Mutation and Heterozygous DICER1 Mutation Presenting as Constitutional Mismatch Repair Deficiency With Corpus Callosum Agenesis: Case Report and Review of Literature.

PubMed

Cheyuo, Cletus; Radwan, Walid; Ahn, Janice; Gyure, Kymberly; Qaiser, Rabia; Tomboc, Patrick

2017-10-01

Constitutional mismatch repair deficiency syndrome is a cancer predisposition syndrome caused by autosomal recessive biallelic (homozygous) germline mutations in the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). The clinical spectrum includes neoplastic and non-neoplastic manifestations. We present the case of a 7-year-old boy who presented with T-lymphoblastic lymphoma and glioblastoma, together with non-neoplastic manifestations including corpus callosum agenesis, arachnoid cyst, developmental venous anomaly, and hydrocephalus. Gene mutation analysis revealed pathogenic biallelic mutations of PMS2 and heterozygous DICER1 variant predicted to be pathogenic. This report is the first to allude to a possible interaction of the mismatch repair system with DICER1 to cause corpus callosum agenesis.

Is there a differential strength of specific HLA mismatches in kidney transplants?

PubMed

Sasaki, N; Idica, A; Terasaki, P

2008-05-01

In this article we attempted to identify whether there is a specific mismatched antigen that might be detrimental to kidney transplant outcome. The frequency of function versus failure of transplant cases was tallied within subpopulations among a subset of the 2006 United Network for Organ Sharing transplant dataset. We examined 7998 cadaveric and 11,420 living donor kidney transplants that were mismatched for a single class I antigen. When tested by five different criteria, the results were relatively similar for the HLA class I, A- and B-locus mismatches. HLA A1 was identified as the single most dominant immunogenic mismatch. However, when the P values were multiplied by 68, the number of comparisons, A1 was only marginally significant. We concluded that at least for class I specificities, the 68 specificities were about equal immunogenicity in kidney transplantation.

Structure of the EndoMS-DNA Complex as Mismatch Restriction Endonuclease.

PubMed

Nakae, Setsu; Hijikata, Atsushi; Tsuji, Toshiyuki; Yonezawa, Kouki; Kouyama, Ken-Ichi; Mayanagi, Kouta; Ishino, Sonoko; Ishino, Yoshizumi; Shirai, Tsuyoshi

2016-11-01

Archaeal NucS nuclease was thought to degrade the single-stranded region of branched DNA, which contains flapped and splayed DNA. However, recent findings indicated that EndoMS, the orthologous enzyme of NucS, specifically cleaves double-stranded DNA (dsDNA) containing mismatched bases. In this study, we determined the structure of the EndoMS-DNA complex. The complex structure of the EndoMS dimer with dsDNA unexpectedly revealed that the mismatched bases were flipped out into binding sites, and the overall architecture most resembled that of restriction enzymes. The structure of the apo form was similar to the reported structure of Pyrococcus abyssi NucS, indicating that movement of the C-terminal domain from the resting state was required for activity. In addition, a model of the EndoMS-PCNA-DNA complex was preliminarily verified with electron microscopy. The structures strongly support the idea that EndoMS acts in a mismatch repair pathway. Copyright © 2016 Elsevier Ltd. All rights reserved.

Spatial Mismatch: A Third Generation Survey.

ERIC Educational Resources Information Center

Eagan, J. Vincent

1999-01-01

The spatial mismatch argument hypothesizes that racial discrimination in the housing market, together with the suburbanization of low skilled jobs, contributes significantly to the high unemployment and/or low wages of inner city minority workers. Surveys recent spatial mismatch literature and discusses policy alternatives, focusing on areas…

Mismatch repair polymorphisms and the risk of colorectal cancer.

PubMed

Berndt, Sonja I; Platz, Elizabeth A; Fallin, M Daniele; Thuita, Lucy W; Hoffman, Sandra C; Helzlsouer, Kathy J

2007-04-01

Rare germline variants in mismatch repair genes have been linked to hereditary nonpolyposis colorectal cancer; however, it is unknown whether common polymorphisms in these genes alter the risk of colorectal cancer. To examine the association between common variants in mismatch repair genes and colorectal cancer, we conducted a case-cohort study within the CLUE II cohort. Four single nucleotide polymorphisms in 3 mismatch repair genes (MSH3 R940Q, MSH3 T1036A, MSH6 G39E and MLH1 I219V) were genotyped in 237 colorectal cancer cases and a subcohort of 2,189 participants. Incidence rate ratios (RRs) and 95% confidence intervals (95% CIs) for each polymorphism were estimated. The MSH3 1036A variant was found to be associated with an increased risk of colorectal cancer (RR=1.28, 95% CI: 0.94-1.74 and RR=1.65, 95% CI: 1.01-2.70 for the AT and TT genotypes, respectively, with p(trend)=0.02), particularly proximal colon cancer. Although the MSH3 940Q variant was only weakly associated with colorectal cancer overall (p(trend)=0.07), it was associated with a significant increased risk of proximal colon cancer (RR=1.69, 95% CI: 1.10-2.61 and RR=2.68, 95% CI: 0.96-7.47 for the RQ and QQ genotypes, respectively with p(trend)=0.005). Processed meat intake appeared to modify the association between the MSH3 polymorphisms and colorectal cancer (p(interaction) < 0.10 for both). No association was observed with the MSH6 and MLH1 polymorphisms overall. This study suggests that common polymorphisms in the mismatch repair gene, MSH3, may increase the risk of colorectal cancer, especially proximal colon cancer. (c) 2006 Wiley-Liss, Inc.

Infrequent identity mismatches are frequently undetected

PubMed Central

Goldinger, Stephen D.

2014-01-01

The ability to quickly and accurately match faces to photographs bears critically on many domains, from controlling purchase of age-restricted goods to law enforcement and airport security. Despite its pervasiveness and importance, research has shown that face matching is surprisingly error prone. The majority of face-matching research is conducted under idealized conditions (e.g., using photographs of individuals taken on the same day) and with equal proportions of match and mismatch trials, a rate that is likely not observed in everyday face matching. In four experiments, we presented observers with photographs of faces taken an average of 1.5 years apart and tested whether face-matching performance is affected by the prevalence of identity mismatches, comparing conditions of low (10 %) and high (50 %) mismatch prevalence. Like the low-prevalence effect in visual search, we observed inflated miss rates under low-prevalence conditions. This effect persisted when participants were allowed to correct their initial responses (Experiment 2), when they had to verify every decision with a certainty judgment (Experiment 3) and when they were permitted “second looks” at face pairs (Experiment 4). These results suggest that, under realistic viewing conditions, the low-prevalence effect in face matching is a large, persistent source of errors. PMID:24500751

Bacterial genes mutL, mutS, and dcm participate in repair of mismatches at 5-methylcytosine sites.

PubMed Central

Lieb, M

1987-01-01

Certain amber mutations in the cI gene of bacteriophage lambda appear to recombine very frequently with nearby mutations. The aberrant mutations included C-to-T transitions at the second cytosine in 5'CC(A/T)GG sequences (which are subject to methylation by bacterial cytosine methylase) and in 5'CCAG and 5'CAGG sequences. Excess cI+ recombinants arising in crosses that utilize these mutations are attributable to the correction of mismatches by a bacterial very-short-patch (VSP) mismatch repair system. In the present study I found that two genes required for methyladenine-directed (long-patch) mismatch repair, mutL and mutS, also functioned in VSP mismatch repair; mutH and mutU (uvrD) were dispensable. VSP mismatch repair was greatly reduced in a dcm Escherichia coli mutant, in which 5-methylcytosine was not methylated. However, mismatches in heteroduplexes prepared from lambda DNA lacking 5-methylcytosine were repaired in dcm+ bacteria. These results indicate that the product of gene dcm has a repair function in addition to its methylase activity. PMID:2959653

On Business-Driven IT Security Management and Mismatches between Security Requirements in Firms, Industry Standards and Research Work

NASA Astrophysics Data System (ADS)

Frühwirth, Christian

Industry managers have long recognized the vital importance of information security for their businesses, but at the same time they perceived security as a technology-driven rather then a business-driven field. Today, this notion is changing and security management is shifting from technology- to business-oriented approaches. Whereas there is evidence of this shift in the literature, this paper argues that security standards and academic work have not yet taken it fully into account. We examine whether this disconnect has lead to a misalignment of IT security requirements in businesses versus industry standards and academic research. We conducted 13 interviews with practitioners from 9 different firms to investigate this question. The results present evidence for a significant gap between security requirements in industry standards and actually reported security vulnerabilities. We further find mismatches between the prioritization of security factors in businesses, standards and real-world threats. We conclude that security in companies serves the business need of protecting information availability to keep the business running at all times.

49 CFR Appendix A to Part 236 - Civil Penalties 1

Code of Federal Regulations, 2010 CFR

2010-10-01

... protection; where required 1,000 2,000 236.13Spring switch; selection of signal control circuits through circuit controller 1,000 2,000 236.14Spring switch signal protection; requirements 1,000 2,000 236... speed through turnout greater than 45 m.p.h 2,500 5,000 (b) Track relay not in de-energized position or...

49 CFR Appendix A to Part 236 - Civil Penalties 1

Code of Federal Regulations, 2011 CFR

2011-10-01

... protection; where required 1,000 2,000 236.13Spring switch; selection of signal control circuits through circuit controller 1,000 2,000 236.14Spring switch signal protection; requirements 1,000 2,000 236... speed through turnout greater than 45 m.p.h 2,500 5,000 (b) Track relay not in de-energized position or...

Optic pathway glioma as part of a constitutional mismatch-repair deficiency syndrome in a patient meeting the criteria for neurofibromatosis type 1.

PubMed

Yeung, Jacky T; Pollack, Ian F; Shah, Sapana; Jaffe, Ronald; Nikiforova, Marina; Jakacki, Regina I

2013-01-01

Patients with constitutional mismatch repair-deficiency (CMMR-D) caused by the biallelic deletions of mismatch repair (MMR) genes have a high likelihood of developing malignancies of the bone marrow, bowel, and brain. Affected individuals often have phenotypic features of neurofibromatosis type 1 (NF-1), including café-au-lait spots. Optic pathway gliomas (OPGs), a common manifestation of NF-1, have not been reported. We report the case of a 3-year-old male with an extensive OPG who met the diagnostic criteria for NF-1. He was subsequently found to have multiple colonic polyps and bi-allelic loss of PMS2. Testing for NF-1 was negative. Copyright © 2012 Wiley Periodicals, Inc.

Molecular Recognition of 6′-N-5-Hexynoate Kanamyin A and RNA 1×1 Internal Loops Containing CA Mismatches

PubMed Central

Tran, Tuan; Disney, Matthew D.

2011-01-01

In our previous study to identify the RNA internal loops that bind an aminoglycoside derivative, we determined that 6′-N-5-hexynoate kanamycin A prefers to bind 1×1 nucleotide internal loops containing C•A mismatches. In this present study, the molecular recognition between a variety of RNAs that are mutated around the C•A loop and the ligand was investigated. Studies show that both loop nucleotides and loop closing pairs affect binding affinity. Most interestingly, it was shown that there is a correlation between the thermodynamic stability of the C•A internal loops and ligand affinity. Specifically, C•A loops that had relatively high or low stability bound the ligand most weakly whereas loops with intermediate stability bound the ligand most tightly. In contrast, there is no correlation between the likelihood that a loop forms a C-A+ pair at lower pH and ligand affinity. It was also found that a 1×1 nucleotide C•A loop that bound to the ligand with the highest affinity is identical to the consensus site in RNAs that are edited by adenosine deaminases acting on RNA type 2 (ADAR2). These studies provide a detailed investigation of factors affecting small molecule recognition of internal loops containing C•A mismatches, which are present in a variety of RNAs that cause disease. PMID:21207945

Distinct requirements within the Msh3 nucleotide binding pocket for mismatch and double-strand break repair.

PubMed

Kumar, Charanya; Williams, Gregory M; Havens, Brett; Dinicola, Michelle K; Surtees, Jennifer A

2013-06-12

In Saccharomyces cerevisiae, repair of insertion/deletion loops is carried out by Msh2-Msh3-mediated mismatch repair (MMR). Msh2-Msh3 is also required for 3' non-homologous tail removal (3' NHTR) in double-strand break repair. In both pathways, Msh2-Msh3 binds double-strand/single-strand junctions and initiates repair in an ATP-dependent manner. However, the kinetics of the two processes appear different; MMR is likely rapid in order to coordinate with the replication fork, whereas 3' NHTR has been shown to be a slower process. To understand the molecular requirements in both repair pathways, we performed an in vivo analysis of well-conserved residues in Msh3 that are hypothesized to be required for MMR and/or 3' NHTR. These residues are predicted to be involved in either communication between the DNA-binding and ATPase domains within the complex or nucleotide binding and/or exchange within Msh2-Msh3. We identified a set of aromatic residues within the FLY motif of the predicted Msh3 nucleotide binding pocket that are essential for Msh2-Msh3-mediated MMR but are largely dispensable for 3' NHTR. In contrast, mutations in other regions gave similar phenotypes in both assays. Based on these results, we suggest that the two pathways have distinct requirements with respect to the position of the bound ATP within Msh3. We propose that the differences are related, at least in part, to the kinetics of each pathway. Proper binding and positioning of ATP is required to induce rapid conformational changes at the replication fork, but is less important when more time is available for repair, as in 3' NHTR. Copyright © 2013 Elsevier Ltd. All rights reserved.

Distinct requirements within the Msh3 nucleotide binding pocket for mismatch and double-strand break repair

PubMed Central

Kumar, Charanya; Williams, Gregory M.; Havens, Brett; Dinicola, Michelle; Surtees, Jennifer A.

2013-01-01

In Saccharomyces cerevisiae, repair of insertion/deletion loops is carried out by Msh2-Msh3-mediated mismatch repair (MMR). Msh2-Msh3 is also required for 3’ non-homologous tail removal (3’NHTR) in double-strand break repair. In both pathways, Msh2-Msh3 binds double-strand/single-strand junctions and initiates repair in an ATP-dependent manner. However, the kinetics of the two processes appear different; MMR is likely rapid in order to coordinate with the replication fork, whereas 3’ NHTR has been shown to be a slower process. To understand the molecular requirements in both repair pathways, we performed an in vivo analysis of well conserved residues in Msh3 that are hypothesized to be required for MMR and/or 3’NHTR. These residues are predicted to be involved in either communication between the DNA-binding and ATPase domains within the complex or nucleotide binding and/or exchange within Msh2-Msh3. We identified a set of aromatic residues within the FLY motif of the predicted Msh3 nucleotide binding pocket that are essential for Msh2-Msh3-mediated MMR but are largely dispensable for 3’NHTR. In contrast, mutations in other regions gave similar phenotypes in both assays. Based on these results, we suggest the two pathways have distinct requirements with respect to the position of the bound ATP within Msh3. We propose that the differences are related, at least in part, to the kinetics of each pathway. Proper binding and positioning of ATP is required to induce rapid conformational changes at the replication fork, but is less important when more time is available for repair, as in 3’ NHTR. PMID:23458407

Technique to measure wavenumber mismatch between quadratically interacting modes

NASA Astrophysics Data System (ADS)

Hajj, M. R.; Davila, J. B.; Miksad, R. W.; Powers, E. J.

1995-02-01

Nonlinear energy cascade by means of three-wave resonant interactions is a characteristic feature of transitioning and turbulent flows. Resonant wavenumber mismatch between these interacting modes can arise from the dispersive characteristics of the interacting waves and from spectral broadening due to random effects. In this paper, a general technique is presented to estimate the average level of instantaneous wavenumber mismatch, (Delta k) = (k(sub m) - k(sub i) - k(sub j)), between components whose frequencies obey the resonant selection condition, f(sub m) - f(sub i) - f(sub j) = 0. Cross-correlation of the auto-bispectrum is used to quantify the level of mismatch. The concept of bispectrum coupling coherency is introduced to determine the confidence level in the wavenumber mismatch estimates. These techniques are then applied to measure wavenumber mismatch in the transitioning field of a plane wake. The results show that the average of the instantaneous mismatch between the actual interacting modes (k(sub m) - k(sub i) - k(sub j)) is in general not equal to the mismatch between the average wavenumbers of each interacting mode (k(sub m) - (k(sub i)) - (k(sub j)).

Influence of sequence mismatches on the specificity of recombinase polymerase amplification technology.

PubMed

Daher, Rana K; Stewart, Gale; Boissinot, Maurice; Boudreau, Dominique K; Bergeron, Michel G

2015-04-01

Recombinase polymerase amplification (RPA) technology relies on three major proteins, recombinase proteins, single-strand binding proteins, and polymerases, to specifically amplify nucleic acid sequences in an isothermal format. The performance of RPA with respect to sequence mismatches of closely-related non-target molecules is not well documented and the influence of the number and distribution of mismatches in DNA sequences on RPA amplification reaction is not well understood. We investigated the specificity of RPA by testing closely-related species bearing naturally occurring mismatches for the tuf gene sequence of Pseudomonas aeruginosa and/or Mycobacterium tuberculosis and for the cfb gene sequence of Streptococcus agalactiae. In addition, the impact of the number and distribution of mismatches on RPA efficiency was assessed by synthetically generating 14 types of mismatched forward primers for detecting five bacterial species of high diagnostic relevance such as Clostridium difficile, Staphylococcus aureus, S. agalactiae, P. aeruginosa, and M. tuberculosis as well as Bacillus atropheus subsp. globigii for which we use the spores as internal control in diagnostic assays. A total of 87 mismatched primers were tested in this study. We observed that target specific RPA primers with mismatches (n > 1) at their 3'extrimity hampered RPA reaction. In addition, 3 mismatches covering both extremities and the center of the primer sequence negatively affected RPA yield. We demonstrated that the specificity of RPA was multifactorial. Therefore its application in clinical settings must be selected and validated a priori. We recommend that the selection of a target gene must consider the presence of closely-related non-target genes. It is advisable to choose target regions with a high number of mismatches (≥36%, relative to the size of amplicon) with respect to closely-related species and the best case scenario would be by choosing a unique target gene. Copyright © 2014

Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in MSH2-dependent mismatch repair.

PubMed

Marsischky, G T; Filosi, N; Kane, M F; Kolodner, R

1996-02-15

Saccharomyces cerevisiae encodes six genes, MSH1-6, which encode proteins related to the bacterial MutS protein. In this study the role of MSH2, MSH3, and MSH6 in mismatch repair has been examined by measuring the rate of accumulating mutations and mutation spectrum in strains containing different combinations of msh2, msh3, and msh6 mutations and by studying the physical interaction between the MSH2 protein and the MSH3 and MSH6 proteins. The results indicate that S. cerevisiae has two pathways of MSH2-dependent mismatch repair: one that recognized single-base mispairs and requires MSH2 and MSH6, and a second that recognizes insertion/deletion mispairs and requires a combination of either MSH2 and MSH6 or MSH2 and MSH3. The redundancy of MSH3 and MSH6 explains the greater prevalence of hmsh2 mutations in HNPCC families and suggests how the role of hmsh3 and hmsh6 mutations in cancer susceptibility could be analyzed.

Interdependence of DNA mismatch repair proteins MLH1 and MSH2 in apoptosis in human colorectal carcinoma cell lines.

PubMed

Hassen, Samar; Ali, Akhtar A; Kilaparty, Surya P; Al-Anbaky, Qudes A; Majeed, Waqar; Boman, Bruce M; Fields, Jeremy Z; Ali, Nawab

2016-01-01

The mammalian DNA mismatch repair (MMR) system consists of a number of proteins that play important roles in repair of base pair mismatch mutations and in maintenance of genomic integrity. A defect in this system can cause genetic instability, which can lead to carcinogenesis. For instance, a germline mutation in one of the mismatch repair proteins, especially MLH1 or MSH2, is responsible for hereditary non-polyposis colorectal cancer. These MMR proteins also play an important role in the induction of apoptosis. Accordingly, altered expression of or a defect in MLH1 or MSH2 may confer resistance to anti-cancer drugs used in chemotherapy. We hypothesized that the ability of these two MMR proteins to regulate apoptosis are interdependent. Moreover, a defect in either one may confer resistance to chemotherapy by an inability to trigger apoptosis. To this end, we studied three cell lines-SW480, LoVo, and HTC116. These cell lines were selected based on their differential expression of MLH1 and MSH2 proteins. SW480 expresses both MLH1 and MSH2; LoVo expresses only MLH1 but not MSH2; HCT116 expresses only MSH2 but not MLH1 protein. MTT assays, a measure of cytotoxicity, showed that there were different cytotoxic effects of an anti-cancer drug, etoposide, on these cell lines, effects that were correlated with the MMR status of the cells. Cells that are deficient in MLH1 protein (HCT116 cells) were resistant to the drug. Cells that express both MLH1 and MSH2 proteins (SW480 cells) showed caspase-3 cleavage, an indicator of apoptosis. Cells that lack MLH1 (HCT116 cells) did not show any caspase-3 cleavage. Expression of full-length MLH1 protein was decreased in MMR proficient (SW480) cells during apoptosis; it remained unchanged in cells that lack MSH2 (LoVo cells). The expression of MSH2 protein remained unchanged during apoptosis both in MMR proficient (SW480) and deficient (HCT116) cells. Studies on translocation of MLH1 protein from nucleus to cytosolic fraction, an

Diff-seq: A high throughput sequencing-based mismatch detection assay for DNA variant enrichment and discovery

PubMed Central

Karas, Vlad O; Sinnott-Armstrong, Nicholas A; Varghese, Vici; Shafer, Robert W; Greenleaf, William J; Sherlock, Gavin

2018-01-01

Abstract Much of the within species genetic variation is in the form of single nucleotide polymorphisms (SNPs), typically detected by whole genome sequencing (WGS) or microarray-based technologies. However, WGS produces mostly uninformative reads that perfectly match the reference, while microarrays require genome-specific reagents. We have developed Diff-seq, a sequencing-based mismatch detection assay for SNP discovery without the requirement for specialized nucleic-acid reagents. Diff-seq leverages the Surveyor endonuclease to cleave mismatched DNA molecules that are generated after cross-annealing of a complex pool of DNA fragments. Sequencing libraries enriched for Surveyor-cleaved molecules result in increased coverage at the variant sites. Diff-seq detected all mismatches present in an initial test substrate, with specific enrichment dependent on the identity and context of the variation. Application to viral sequences resulted in increased observation of variant alleles in a biologically relevant context. Diff-Seq has the potential to increase the sensitivity and efficiency of high-throughput sequencing in the detection of variation. PMID:29361139

Constitutional mismatch repair deficiency syndrome: Do we know it?

PubMed

Ramachandra, C; Challa, Vasu Reddy; Shetty, Rachan

2014-04-01

Constitutional mismatch repair deficiency syndrome is a rare autosomal recessive syndrome caused by homozygous mutations in mismatch repair genes. This is characterized by the childhood onset of brain tumors, colorectal cancers, cutaneous manifestations of neurofibromatosis-1 like café au lait spots, hematological malignancies, and occasionally other rare malignancies. Here, we would like to present a family in which the sibling had glioblastoma, and the present case had acute lymphoblastic lymphoma and colorectal cancer. We would like to present this case because of its rarity and would add to literature.

Homozygous germ-line mutation of the PMS2 mismatch repair gene: a unique case report of constitutional mismatch repair deficiency (CMMRD).

PubMed

Ramchander, N C; Ryan, N A J; Crosbie, E J; Evans, D G

2017-04-05

Constitutional mismatch repair deficiency syndrome results from bi-allelic inheritance of mutations affecting the key DNA mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. Individuals with bi-allelic mutations have a dysfunctional mismatch repair system from birth; as a result, constitutional mismatch repair deficiency syndrome is characterised by early onset malignancies. Fewer than 150 cases have been reported in the literature over the past 20 years. This is the first report of the founder PMS2 mutation - NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11 and its associated cancers in this family. The proband is 30 years old and is alive today. She is of Pakistani ethnic origin and a product of consanguinity. She initially presented aged 24 with painless bleeding per-rectum from colorectal polyps and was referred to clinical genetics. Clinical examination revealed two café-au-lait lesions, lichen planus, and a dermoid cyst. Her sister had been diagnosed in childhood with an aggressive brain tumour followed by colorectal cancer. During follow up, the proband developed 37 colorectal adenomatous polyps, synchronous ovarian and endometrial adenocarcinomas, and ultimately a metachronous gastric adenocarcinoma. DNA sequencing of peripheral lymphocytes revealed a bi-allelic inheritance of the PMS2 mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11. Ovarian tumour tissue demonstrated low microsatellite instability. To date, she has had a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and a total gastrectomy. Aspirin and oestrogen-only hormone replacement therapy provide some chemoprophylaxis and manage postmenopausal symptoms, respectively. An 18-monthly colonoscopy surveillance programme has led to the excision of three high-grade dysplastic colorectal tubular adenomatous polyps. The proband's family pedigree displays multiple relatives with cancers including a likely case of 'true' Turcot syndrome. Constitutional mismatch repair

Measuring strand discontinuity-directed mismatch repair in yeast Saccharomyces cerevisiae by cell-free nuclear extracts.

PubMed

Yuan, Fenghua; Lai, Fangfang; Gu, Liya; Zhou, Wen; El Hokayem, Jimmy; Zhang, Yanbin

2009-05-01

Mismatch repair corrects biosynthetic errors generated during DNA replication, whose deficiency causes a mutator phenotype and directly underlies hereditary non-polyposis colorectal cancer and sporadic cancers. Because of remarkably high conservation of the mismatch repair machinery between the budding yeast (Saccharomyces cerevisiae) and humans, the study of mismatch repair in yeast has provided tremendous insights into the mechanisms of this repair pathway in humans. In addition, yeast cells possess an unbeatable advantage over human cells in terms of the easy genetic manipulation, the availability of whole genome deletion strains, and the relatively low cost for setting up the system. Although many components of eukaryotic mismatch repair have been identified, it remains unclear if additional factors, such as DNA helicase(s) and redundant nuclease(s) besides EXO1, participate in eukaryotic mismatch repair. To facilitate the discovery of novel mismatch repair factors, we developed a straightforward in vitro cell-free repair system. Here, we describe the practical protocols for preparation of yeast cell-free nuclear extracts and DNA mismatch substrates, and the in vitro mismatch repair assay. The validity of the cell-free system was confirmed by the mismatch repair deficient yeast strain (Deltamsh2) and the complementation assay with purified yeast MSH2-MSH6.

Mismatched HLA-DRB3 Can Induce a Potent Immune Response After HLA 10/10 Matched Stem Cell Transplantation.

PubMed

van Balen, Peter; van Luxemburg-Heijs, Simone A P; van de Meent, Marian; van Bergen, Cornelis A M; Halkes, Constantijn J M; Jedema, Inge; Falkenburg, J H Frederik

2017-12-01

Donors for allogeneic stem cell transplantation are preferentially matched with patients for HLA-A, -B, -C, and -DRB1. Mismatches between donor and patient in these alleles are associated with an increased risk of graft-versus-host disease (GVHD). In contrast, HLA-DRB3, 4 and 5, HLA-DQ and HLA-DP are usually assumed to be low expression loci with limited relevance, although mismatches in HLA-DQ and HLA-DP can result in alloimmune responses. Mismatches in HLA-DRB3, 4, and 5 are usually not taken into account in donor selection. Conversion of chimerism in the presence of GVHD after CD4 donor lymphocyte infusion was observed in a patient, HLA 10/10 matched, but mismatched for HLA-DRB3 and HLA-DPB1 compared with the donor. Alloreactive CD4 T cells were isolated from peripheral blood after CD4 donor lymphocyte infusion and recognition of donor-derived target cells transduced with the mismatched patient variant HLA-DRB3 and HLA-DPB1 molecule was tested. A dominant polyclonal CD4 T cell response against patient's mismatched HLA-DRB3 molecule was found in addition to an immune response against patient's mismatched HLA-DPB1 molecule. CD4 T cells specific for these HLA class II molecules recognized both hematopoietic target cells as well as GVHD target cells. In contrast to the assumption that mismatches in HLA-DRB3, 4, and 5 are not of immunogenic significance after HLA 10/10 matched allogeneic stem cell transplantation, we show that in this matched setting not only mismatches in HLA-DPB1, but also mismatches in HLA-DRB3 may induce a polyclonal allo-immune response associated with conversion of chimerism and severe GVHD.

Repeated human leukocyte antigen mismatches in lung re-transplantation.

PubMed

Sommer, Wiebke; Hallensleben, Michael; Ius, Fabio; Kühn, Christian; Tudorache, Igor; Avsar, Murat; Salman, Jawad; Siemeni, Thierry; Greer, Mark; Gottlieb, Jens; Boethig, Dietmar; Blasczyk, Rainer; Haverich, Axel; Warnecke, Gregor

2017-02-01

The role of HLA-sensitization in the absence of detectable DSA in lung re-transplantation is unclear. Antigens of the second donor matching the HLA typing of the first donor are considered 'unacceptable', by some tissue typing laboratories, especially in kidney re-transplantation. Thus, we performed a retrospective analysis of all lung re-transplantations focussing on the impact of HLA-homologies between the first and the second donor ('unacceptable' antigens; repeated HLA mismatch) on patient and graft survival. A total of 132 lung re-transplantations were performed at our centre between 1985 and 2014, of which 120 with complete HLA data were analysed. 55.8% of the recipients received re-transplants with repeated HLA mismatched antigens whereas 43.2% of the re-transplants were transplanted without repeated HLA mismatched antigens. Postoperative survival showed no difference between re-transplant procedures with or without repeated HLA mismatches (p=0.99). While neither homologies on the HLA-A, -B, -C, or -DR locus, nor the addition of several locus homologies (p=0.72) had an impact on survival, unexpectedly, repeated HLA mismatching on the HLA-DQ locus was correlated with better survival. Re-transplantations with repeated HLA mismatches did not result in more development of CLAD as compared to recipients without repeated HLA mismatches (p=0.99). Neither the number of repeated HLA mismatched antigens (p=0.52) nor the HLA locus (HLA-A(p=0.34), HLA-B(p=0.97), HLA-C (p=0.80), HLA-DR(p=0.49) and HLA-DQ(p=0.07)) had an impact on the development of CLAD after re-transplantation. Transplantation with repeated HLA mismatches due to sensitization by a previous transplantation in the absence of detectable HLA-antibodies does not have a negative impact on patient or graft survival. Copyright © 2016 Elsevier B.V. All rights reserved.

Immigrants' Educational Mismatch and the Penalty of Over-Education

ERIC Educational Resources Information Center

Kalfa, Eleni; Piracha, Matloob

2017-01-01

This paper analyses immigrants' educational mismatch and its impact on wages in Spain. The incidence of immigrants' education-occupation mismatch in the Spanish labour market can largely be explained by the mismatch in the last job held in the home country. The probability of having been over-educated in the home country has a higher effect on the…

Unnatural substrates reveal the importance of 8-oxoguanine for in vivo mismatch repair by MutY

PubMed Central

Livingston, Alison L.; O’Shea, Valerie L.; Kim, Taewoo; Kool, Eric T.; David, Sheila S.

2009-01-01

Escherchia coli MutY plays an important role in preventing mutations associated with the oxidative lesion 7,8-dihydro-8-oxo-2′-deoxyguanosine (OG) in DNA by excising adenines from OG:A mismatches as the first step of base excision repair. To determine the importance of specific steps in the base pair recognition and base removal process of MutY, we have evaluated the effects of modifications of the OG:A substrate on the kinetics of base removal, mismatch affinity and repair to G:C in an Escherchia coli-based assay. Surprisingly, adenine modification was tolerated in the cellular assay, while modification of OG results in minimal cellular repair. High affinity for the mismatch and efficient base removal require the presence of OG. Taken together, these results suggest that the presence of OG is a critical feature for MutY to locate OG:A mismatches and select the appropriate adenines for excision to initiate repair in vivo prior to replication. PMID:18026095

Upper tract urothelial carcinomas: frequency of association with mismatch repair protein loss and lynch syndrome.

PubMed

Harper, Holly L; McKenney, Jesse K; Heald, Brandie; Stephenson, Andrew; Campbell, Steven C; Plesec, Thomas; Magi-Galluzzi, Cristina

2017-01-01

Increased risk for upper tract urothelial carcinoma is described in patients with Lynch syndrome, caused by germline mutations in mismatch repair genes. We aimed to identify the frequency of mismatch repair protein loss in upper tract urothelial carcinoma and its potential for identifying an association with Lynch syndrome. We queried our database to identify upper tract urothelial carcinomas. Patients were cross-referenced for history of colorectal carcinoma or other common Lynch syndrome-associated neoplasms to enrich for potential Lynch syndrome cases. Tumor histopathologic characteristics were reviewed and each case was analyzed for loss of mismatch repair proteins, MLH1, MSH2, MSH6, and PMS2, by immunohistochemistry. Of 444 patients with upper tract urothelial carcinoma, a subset of 215 (encompassing 30 with upper tract urothelial carcinoma and another common Lynch syndrome-associated neoplasm) was analyzed for loss of mismatch repair protein expression. Of 30 patients with Lynch syndrome-associated neoplasms, six had documented Lynch syndrome, including two with Muir-Torre syndrome. Mismatch repair protein loss was identified in 7% of total upper tract urothelial carcinomas and 30% of patients with Lynch syndrome-associated neoplasms (including all patients with Lynch syndrome/Muir-Torre syndrome). Of patients without history of Lynch syndrome-associated neoplasms, 5 of 184 (2.7%) had loss of mismatch repair protein expression. Twelve cases with mismatch repair protein loss demonstrated loss of MSH2 and MSH6, and 2 had isolated loss of MSH6. MLH1 and PMS2 expression were consistently retained. Although increased intratumoral lymphocytes, inverted growth, pushing tumor-stromal interface, and lack of nuclear pleomorphism were more commonly seen in cases with mismatch repair protein loss, only intratumoral lymphocytes and presence of pushing borders were statistically significant. MLH1 and PMS2 testing appear to have little utility in upper tract urothelial

[Expression of DNA mismatch repair protein in endometrial carcinomas and its correlation with clinicopathologic features].

PubMed

Bi, R; Tu, X Y; Xiao, Y X; Shan, B E; Wang, H Y; Cai, X; Zhou, X Y; Yang, W T

2016-05-08

To study the expression of mismatch repair protein in a series of endometrial carcinomas and its correlation with clinicopathologic features. The clinical data of 150 consecutive cases of endometrial carcinoma were collected during the period from December, 2014 to August, 2015 in Fudan University Cancer Center. Morphologic features including tumor infiltrating lymphocytes (TIL), peritumoral lymphocytes and tumor heterogeneity were reviewed. Immunohistochemistry for expression of mismatch repair proteins was performed. The correlation with clinicopathologic features was analyzed. Loss of mismatch repair protein expression was observed in 43 cases (28.7%), including loss of MLH1/PMS2 in 27 cases (18%), loss of MSH2/MSH6 in 7 cases (4.7%), loss of MSH6 in 6 cases (4%) and loss of PMS2 in 3 cases (2%). There were 23.3% and 27.1% of mismatch repair protein-deficient endometrial carcinomas in women under and above 50 years of age, respectively, which was not statistically significant. Amongst the 12 cases with family history of tumors, 4 of the 6 mismatch repair protein-deficient cases were under 50 years of age, which was higher than that in the 6 cases with mismatch repair protein expression (P=0.014). The mismatch repair protein-deficient group showed significantly more prominent TIL and peritumoral lymphocytes than protein-expression group (P=0.033 and <0.001). Moreover, there were also significant differences in depth of myometrial invasion and occurrence of synchronous malignancy (2 cases of ovarian clear cell carcinoma and 1 case of colonic carcinoma) between the two groups (P=0.039 and 0.022). However, there were no significant differences in lymph node metastasis, tumor heterogeneity, lower uterine segment involvement and tumor stage between the two groups. Prominent TIL and peritumoral lymphocytes characteristically occur in mismatch repair protein-deficient endometrial carcinomas. Patient age does not significantly correlate with the loss of mismatch repair

The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts From Deceased Donors.

PubMed

Williams, Robert C; Opelz, Gerhard; McGarvey, Chelsea J; Weil, E Jennifer; Chakkera, Harini A

2016-05-01

Since the beginning of the technology, there has been active debate about the role of human leucocyte antigen (HLA) matching in kidney allograft survival. Recent studies have reported diminishing importance of HLA matching, which have, in turn, been challenged by reports that suggest the continuing importance of these loci. Given the controversies, we examined the effect of HLA compatibility on kidney allograft survival by studying all first adult kidney transplants in the United States from a deceased donor. Using the United Network for Organ Sharing data, we identified first deceased donor kidney transplants between October 1, 1987, and December 31, 2013. Recipients were classified by their number of HLA mismatches. Cox multivariate regression analyses adjusting for recipient and donor transplant characteristics were performed to determine the impact of HLA compatibility on kidney allograft survival. Study cohort included 189 141 first adult kidney alone transplants, with a total of 994 558 years of kidney allograft follow-up time. Analyses adjusted for recipient and donor characteristics demonstrated a 13% higher risk (hazard ratio, 1.13; 95% confidence interval, 1.06-1.21) with 1 mismatch and a 64% higher risk (hazard ratio, 1.64, 95% confidence interval, 1.56-1.73) with 6 mismatches. Dividing the mismatch categories into 27 ordered permutations, and testing their 57 within mismatch category differences, demonstrated that all but 1 were equal, independent of locus. A significant linear relationship of hazard ratios was associated with HLA mismatch and affects allograft survival even during the recent periods of increasing success in renal transplantation.

Convergent transmission of RNAi guide-target mismatch information across Argonaute internal allosteric network.

PubMed

Joseph, Thomas T; Osman, Roman

2012-01-01

In RNA interference, a guide strand derived from a short dsRNA such as a microRNA (miRNA) is loaded into Argonaute, the central protein in the RNA Induced Silencing Complex (RISC) that silences messenger RNAs on a sequence-specific basis. The positions of any mismatched base pairs in an miRNA determine which Argonaute subtype is used. Subsequently, the Argonaute-guide complex binds and silences complementary target mRNAs; certain Argonautes cleave the target. Mismatches between guide strand and the target mRNA decrease cleavage efficiency. Thus, loading and silencing both require that signals about the presence of a mismatched base pair are communicated from the mismatch site to effector sites. These effector sites include the active site, to prevent target cleavage; the binding groove, to modify nucleic acid binding affinity; and surface allosteric sites, to control recruitment of additional proteins to form the RISC. To examine how such signals may be propagated, we analyzed the network of internal allosteric pathways in Argonaute exhibited through correlations of residue-residue interactions. The emerging network can be described as a set of pathways emanating from the core of the protein near the active site, distributed into the bulk of the protein, and converging upon a distributed cluster of surface residues. Nucleotides in the guide strand "seed region" have a stronger relationship with the protein than other nucleotides, concordant with their importance in sequence selectivity. Finally, any of several seed region guide-target mismatches cause certain Argonaute residues to have modified correlations with the rest of the protein. This arises from the aggregation of relatively small interaction correlation changes distributed across a large subset of residues. These residues are in effector sites: the active site, binding groove, and surface, implying that direct functional consequences of guide-target mismatches are mediated through the cumulative effects of

Selective nanoscale growth of lattice mismatched materials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Seung-Chang; Brueck, Steven R. J.

Exemplary embodiments provide materials and methods of forming high-quality semiconductor devices using lattice-mismatched materials. In one embodiment, a composite film including one or more substantially-single-particle-thick nanoparticle layers can be deposited over a substrate as a nanoscale selective growth mask for epitaxially growing lattice-mismatched materials over the substrate.

A chloroplast thylakoid lumen protein is required for proper photosynthetic acclimation of plants under fluctuating light environments

PubMed Central

2017-01-01

Despite our increasingly sophisticated understanding of mechanisms ensuring efficient photosynthesis under laboratory-controlled light conditions, less is known about the regulation of photosynthesis under fluctuating light. This is important because—in nature—photosynthetic organisms experience rapid and extreme changes in sunlight, potentially causing deleterious effects on photosynthetic efficiency and productivity. Here we report that the chloroplast thylakoid lumenal protein MAINTENANCE OF PHOTOSYSTEM II UNDER HIGH LIGHT 2 (MPH2; encoded by At4g02530) is required for growth acclimation of Arabidopsis thaliana plants under controlled photoinhibitory light and fluctuating light environments. Evidence is presented that mph2 mutant light stress susceptibility results from a defect in photosystem II (PSII) repair, and our results are consistent with the hypothesis that MPH2 is involved in disassembling monomeric complexes during regeneration of dimeric functional PSII supercomplexes. Moreover, mph2—and previously characterized PSII repair-defective mutants—exhibited reduced growth under fluctuating light conditions, while PSII photoprotection-impaired mutants did not. These findings suggest that repair is not only required for PSII maintenance under static high-irradiance light conditions but is also a regulatory mechanism facilitating photosynthetic adaptation under fluctuating light environments. This work has implications for improvement of agricultural plant productivity through engineering PSII repair. PMID:28874535

A chloroplast thylakoid lumen protein is required for proper photosynthetic acclimation of plants under fluctuating light environments.

PubMed

Liu, Jun; Last, Robert L

2017-09-19

Despite our increasingly sophisticated understanding of mechanisms ensuring efficient photosynthesis under laboratory-controlled light conditions, less is known about the regulation of photosynthesis under fluctuating light. This is important because-in nature-photosynthetic organisms experience rapid and extreme changes in sunlight, potentially causing deleterious effects on photosynthetic efficiency and productivity. Here we report that the chloroplast thylakoid lumenal protein MAINTENANCE OF PHOTOSYSTEM II UNDER HIGH LIGHT 2 (MPH2; encoded by At4g02530 ) is required for growth acclimation of Arabidopsis thaliana plants under controlled photoinhibitory light and fluctuating light environments. Evidence is presented that mph2 mutant light stress susceptibility results from a defect in photosystem II (PSII) repair, and our results are consistent with the hypothesis that MPH2 is involved in disassembling monomeric complexes during regeneration of dimeric functional PSII supercomplexes. Moreover, mph2 -and previously characterized PSII repair-defective mutants-exhibited reduced growth under fluctuating light conditions, while PSII photoprotection-impaired mutants did not. These findings suggest that repair is not only required for PSII maintenance under static high-irradiance light conditions but is also a regulatory mechanism facilitating photosynthetic adaptation under fluctuating light environments. This work has implications for improvement of agricultural plant productivity through engineering PSII repair.

DNA Mismatch Repair Status Predicts Need for Future Colorectal Surgery for Metachronous Neoplasms in Young Individuals Undergoing Colorectal Cancer Resection.

PubMed

Aronson, Melyssa; Holter, Spring; Semotiuk, Kara; Winter, Laura; Pollett, Aaron; Gallinger, Steven; Cohen, Zane; Gryfe, Robert

2015-07-01

The treatment of colorectal cancer in young patients involves both management of the incident cancer and consideration of the possibility of Lynch syndrome and the development of metachronous colorectal cancers. This study aims to assess the prognostic role of DNA mismatch repair deficiency and extended colorectal resection for metachronous colorectal neoplasia risk in young patients with colorectal cancer. This is a retrospective review of 285 patients identified in our GI cancer registry with colorectal cancer diagnosed at 35 years or younger in the absence of polyposis. Using univariate and multivariate analysis, we assessed the prognostic role of mismatch repair deficiency and standard clinicopathologic characteristics, including the extent of resection, on the rate of developing metachronous colorectal neoplasia requiring resection. Mismatch repair deficiency was identified in biospecimens from 44% of patients and was significantly associated with an increased risk for metachronous colorectal neoplasia requiring resection (10-year cumulative risk, 13.5% ± 4.2%) compared with 56% of patients with mismatch repair-intact colorectal cancer (10-year cumulative risk, 5.8% ± 3.3%; p = 0.011). In multivariate analysis, mismatch repair deficiency was associated with a HR of 3.65 (95% CI, 1.44-9.21; p = 0.006) for metachronous colorectal neoplasia, whereas extended resection with ileorectal or ileosigmoid anastomosis significantly decreased the risk of metachronous colorectal neoplasia (HR, 0.21; 95% CI, 0.05-0.90; p = 0.036). This study had a retrospective design, and, therefore, recommendations for colorectal cancer surgery and screening were not fully standardized. Quality of life after colorectal cancer surgery was not assessed. Young patients with colorectal cancer with molecular hallmarks of Lynch syndrome were at significantly higher risk for the development of subsequent colorectal neoplasia. This risk was significantly reduced in those who underwent extended

78 FR 2797 - Federal Motor Vehicle Safety Standards; Minimum Sound Requirements for Hybrid and Electric Vehicles

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-14

... vehicles when 4.1% of the fleet is HV and EV would be 2790 fewer pedestrian and pedalcyclist injuries. We... Engine Vehicles to Hybrid and Electric Vehicles B. Need for Independent Mobility of People Who Are... requirements for hybrid and electric vehicles when operating under 30 kilometers per hour (km/h) (18 mph), when...

ABCB1 c.2677G>T variation is associated with adverse reactions of OROS-methylphenidate in children and adolescents with ADHD.

PubMed

Kim, So Won; Lee, Ji Hyun; Lee, Sung Hee; Hong, Hyun Ju; Lee, Min Goo; Yook, Ki-Hwan

2013-08-01

Osmotic-release oral system (OROS)-methylphenidate (MPH) is a safe and well-tolerated drug. Some patients cannot continue this regimen with adverse drug reactions (ADRs). As drug efflux transporters of the central nervous system, ABCB1 plays an important role in the clearance of psychotropic drugs and their metabolites from brain tissues. We hypothesized that genetic variations in the ABCB1 gene may affect ADRs to OROS-MPH. We analyzed ADRs of OROS-MPH in 134 children and adolescents with attention-deficit hyperactivity disorder who completed a 4-week trial of OROS-MPH. The ADRs of OROS-MPH were evaluated by administering the Barkley Stimulant Side Effects Rating Scale. Our study proved that MPH is a substrate for ABCB1 by using membrane vesicle assay. We analyzed the influence of ABCB1 polymorphisms on ADRs to OROS-MPH. From the association study between ABCB1 polymorphisms and ADRs of OROS-MPH, c.2677G>T (p.Ala893Ser, rs2032582) showed a strong association with OROS-MPH-related ADRs (P = 0.008; odds ratio, 5.72). Furthermore, logistic regression analysis indicated that the TT genotype at the ABCB1 2677 locus is an independent determinant of ADRs attributed to OROS-MPH. In a functional study, the 893Ser variant markedly reduced MPH transport across the cell membrane. This is the first study to demonstrate that the TT genotype at position 2677 in the ABCB1 gene is associated with ADRs to OROS-MPH.

Perceived match or mismatch on the Gottman conflict styles: associations with relationship outcome variables.

PubMed

Busby, Dean M; Holman, Thomas B

2009-12-01

Gottman has proposed that there are 3 functional styles of conflict management in couple relationships, labeled Avoidant, Validating, and Volatile, and 1 dysfunctional style, labeled Hostile. Using a sample of 1,983 couples in a committed relationship, we test the association of perceived matches or mismatches on these conflict styles with relationship outcome variables. The results indicate that 32% of the participants perceive there is a mismatch with their conflict style and that of their partner. The Volatile-Avoidant mismatch was particularly problematic and was associated with more stonewalling, relationship problems, and lower levels of relationship satisfaction and stability than the Validating matched style and than other mismatched styles. The most problematic style was the Hostile style. Contrary to existing assumptions by Gottman, the 3 matched functional styles were not equivalent, as the Validating Style was associated with substantially better results on relationship outcome measures than the Volatile and Avoidant styles.

Enhanced entrainability of genetic oscillators by period mismatch

PubMed Central

Hasegawa, Yoshihiko; Arita, Masanori

2013-01-01

Biological oscillators coordinate individual cellular components so that they function coherently and collectively. They are typically composed of multiple feedback loops, and period mismatch is unavoidable in biological implementations. We investigated the advantageous effect of this period mismatch in terms of a synchronization response to external stimuli. Specifically, we considered two fundamental models of genetic circuits: smooth and relaxation oscillators. Using phase reduction and Floquet multipliers, we numerically analysed their entrainability under different coupling strengths and period ratios. We found that a period mismatch induces better entrainment in both types of oscillator; the enhancement occurs in the vicinity of the bifurcation on their limit cycles. In the smooth oscillator, the optimal period ratio for the enhancement coincides with the experimentally observed ratio, which suggests biological exploitation of the period mismatch. Although the origin of multiple feedback loops is often explained as a passive mechanism to ensure robustness against perturbation, we study the active benefits of the period mismatch, which include increasing the efficiency of the genetic oscillators. Our findings show a qualitatively different perspective for both the inherent advantages of multiple loops and their essentiality. PMID:23389900

Marrow Ablative and Immunosuppressive Effects of I-131-anti-CD45 Antibody in Congenic and H2-Mismatched Murine Transplant Models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matthews, D. C.; Martin, P J.; Nourigat, C.

1998-12-01

Targeted hematopoietic irradiation delivered by I-131-anti-CD45 antibody has been combined with conventional marrow transplant preparative regimens in an effort to decrease relapse. Before increasing the proportion of therapy delivered by radiolabeled antibody, the myeloablative and immunosuppressive effects of such low dose rate irradiation must be quantitated. We have examined the ability of I-131-anti-CD45 antibody to facilitate engraftment in Ly5-congenic and H2-mismatched murine marrow transplant models. Recipient B6-Ly5-a mice were treated with 30F11 antibody labeled with 0.1 to 1.5 mCi I-131 and/or total body irradiation (TBI), followed by T-cell-depleted marrow from Ly5-b-congenic (C57BL/6) or H2-mismatched (BALB/c) donors. Engraftment was achieved readilymore » in the Ly5-congenic setting, with greater than 80% donor granulocytes and T cells after 0.5 mCi I-131 (estimated 17 Gy to marrow) or 8 Gy TBI. A higher TBI dose (14 Gy) was required to achieve engraftment of H2-mismatched mar row, and engraftment occurred in only 3 of 11 mice receiving 1.5 mCi I-131 delivered by anti-CD45 antibody. Engraftment of H2-mismatched marrow was achieved in 22 of 23 animals receiving 0.75 mCi I-131 delivered by anti-CD45 antibody combined with 8 Gy TBI. Thus, targeted radiation delivered via I-131-anti-CD45 antibody can enable engraftment of congenic marrow and can partially replace TBI when transplanting T-cell-depleted H2-mismatched marrow.« less

Connections between constitutional mismatch repair deficiency syndrome and neurofibromatosis type 1.

PubMed

Wimmer, K; Rosenbaum, T; Messiaen, L

2017-04-01

Constitutional mismatch repair (MMR) deficiency (CMMRD) is a rare childhood cancer susceptibility syndrome resulting from biallelic germline loss-of-function mutations in one of the MMR genes. Individuals with CMMRD have high risk to develop a broad spectrum of malignancies and frequently display features reminiscent of neurofibromatosis type 1 (NF1). Evaluation of the clinical findings of genetically proven CMMRD patients shows that not only multiple café-au-lait macules but also any of the diagnostic features of NF1 may be present in a CMMRD patient. This phenotypic overlap may lead to misdiagnosis of CMMRD patients as having NF1, which impedes adequate management of the patients and their families. The spectrum of CMMRD-associated childhood malignancies includes high-grade glioma, acute myeloid leukaemia or rhabdomyosarcoma, also reported as associated with NF1. Reported associations between NF1 and these malignancies are to a large extent based on studies that neither proved the presence of an NF1 germline mutation nor ruled-out CMMRD in the affected. Hence, these associations are challenged by our current knowledge of the phenotypic overlap between NF1 and CMMRD and should be re-evaluated in future studies. Recent advances in the diagnostics of CMMRD should render it possible to definitely state or refute this diagnosis in these individuals. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Population Pharmacokinetics of Methylphenidate in Healthy Adults Emphasizing Novel and Known Effects of Several Carboxylesterase 1 (CES1) Variants

PubMed Central

Stage, C; Bergmann, TK; Ferrero‐Milliani, L; Bjerre, D; Thomsen, R; Dalhoff, KP; Rasmussen, HB; Jürgens, G

2016-01-01

The aim of this study was to identify demographic and genetic factors that significantly affect methylphenidate (MPH) pharmacokinetics (PK), and may help explain interindividual variability and further increase the safety of MPH. d‐MPH plasma concentrations, demographic covariates, and carboxylesterase 1 (CES1) genotypes were gathered from 122 healthy adults and analyzed using nonlinear mixed effects modeling. The structural model that best described the data was a two‐compartment disposition model with absorption transit compartments. Novel effects of rs115629050 and CES1 diplotypes, as well as previously reported effects of rs71647871 and body weight, were included in the final model. Assessment of the independent and combined effect of CES1 covariates identified several specific risk factors that may result in severely increased d‐MPH plasma exposure. PMID:27754602

Insights into finding a mismatch through the structure of a mispaired DNA bound by a rhodium intercalator

PubMed Central

Pierre, Valérie C.; Kaiser, Jens T.; Barton, Jacqueline K.

2007-01-01

We report the 1.1-Å resolution crystal structure of a bulky rhodium complex bound to two different DNA sites, mismatched and matched in the oligonucleotide 5′-(dCGGAAATTCCCG)2-3′. At the AC mismatch site, the structure reveals ligand insertion from the minor groove with ejection of both mismatched bases and elucidates how destabilized mispairs in DNA may be recognized. This unique binding mode contrasts with major groove intercalation, observed at a matched site, where doubling of the base pair rise accommodates stacking of the intercalator. Mass spectral analysis reveals different photocleavage products associated with the two binding modes in the crystal, with only products characteristic of mismatch binding in solution. This structure, illustrating two clearly distinct binding modes for a molecule with DNA, provides a rationale for the interrogation and detection of mismatches. PMID:17194756

Single-base-pair discrimination of terminal mismatches by using oligonucleotide microarrays and neural network analyses

NASA Technical Reports Server (NTRS)

Urakawa, Hidetoshi; Noble, Peter A.; El Fantroussi, Said; Kelly, John J.; Stahl, David A.

2002-01-01

The effects of single-base-pair near-terminal and terminal mismatches on the dissociation temperature (T(d)) and signal intensity of short DNA duplexes were determined by using oligonucleotide microarrays and neural network (NN) analyses. Two perfect-match probes and 29 probes having a single-base-pair mismatch at positions 1 to 5 from the 5' terminus of the probe were designed to target one of two short sequences representing 16S rRNA. Nonequilibrium dissociation rates (i.e., melting profiles) of all probe-target duplexes were determined simultaneously. Analysis of variance revealed that position of the mismatch, type of mismatch, and formamide concentration significantly affected the T(d) and signal intensity. Increasing the concentration of formamide in the washing buffer decreased the T(d) and signal intensity, and it decreased the variability of the signal. Although T(d)s of probe-target duplexes with mismatches in the first or second position were not significantly different from one another, duplexes with mismatches in the third to fifth positions had significantly lower T(d)s than those with mismatches in the first or second position. The trained NNs predicted the T(d) with high accuracies (R(2) = 0.93). However, the NNs predicted the signal intensity only moderately accurately (R(2) = 0.67), presumably due to increased noise in the signal intensity at low formamide concentrations. Sensitivity analysis revealed that the concentration of formamide explained most (75%) of the variability in T(d)s, followed by position of the mismatch (19%) and type of mismatch (6%). The results suggest that position of the mismatch at or near the 5' terminus plays a greater role in determining the T(d) and signal intensity of duplexes than the type of mismatch.

Understanding the Transfer Deficit: Contextual Mismatch, Proactive Interference, and Working Memory Affect Toddlers' Video-Based Transfer.

PubMed

Choi, Koeun; Kirkorian, Heather L; Pempek, Tiffany A

2017-04-17

Researchers tested the impact of contextual mismatch, proactive interference, and working memory (WM) on toddlers' transfer across contexts. Forty-two toddlers (27-34 months) completed four object-retrieval trials, requiring memory updating on Trials 2-4. Participants watched hiding events on a tablet computer. Search performance was tested using another tablet (match) or a felt board (mismatch). WM was assessed. On earlier search trials, WM predicted transfer in both conditions, and toddlers in the match condition outperformed those in the mismatch condition; however, the benefit of contextual match and WM decreased over trials. Contextual match apparently increased proactive interference on later trials. Findings are interpreted within existing accounts of the transfer deficit, and a combined account is proposed. © 2017 The Authors. Child Development © 2017 Society for Research in Child Development, Inc.

Solution structure and stability of the DNA undecamer duplexes containing oxanine mismatch

PubMed Central

Pack, Seung Pil; Morimoto, Hirohisa; Makino, Keisuke; Tajima, Kunihiko; Kanaori, Kenji

2012-01-01

Solution structures of DNA duplexes containing oxanine (Oxa, O) opposite a cytosine (O:C duplex) and opposite a thymine (O:T duplex) have been solved by the combined use of 1H NMR and restrained molecular dynamics calculation. One mismatch pair was introduced into the center of the 11-mer duplex of [d(GTGACO6CACTG)/d(CAGTGX17GTCAC), X = C or T]. 1H NMR chemical shifts and nuclear Overhauser enhancement (NOE) intensities indicate that both the duplexes adopt an overall right-handed B-type conformation. Exchangeable resonances of C17 4-amino proton of the O:C duplex and of T17 imino proton of O:T duplex showed unusual chemical shifts, and disappeared with temperature increasing up to 30°C, although the melting temperatures were >50°C. The O:C mismatch takes a wobble geometry with positive shear parameter where the Oxa ring shifted toward the major groove and the paired C17 toward the minor groove, while, in the O:T mismatch pair with the negative shear, the Oxa ring slightly shifted toward the minor groove and the paired T17 toward the major groove. The Oxa mismatch pairs can be wobbled largely because of no hydrogen bond to the O1 position of the Oxa base, and may occupy positions in the strands that optimize the stacking with adjacent bases. PMID:22039100

Self-Selection of Frequency Tables with Bilateral Mismatches in an Acoustic Simulation of a Cochlear Implant

PubMed Central

Fitzgerald, Matthew B.; Prosolovich, Ksenia; Tan, Chin-Tuan; Glassman, E. Katelyn; Svirsky, Mario A.

2017-01-01

Background Many recipients of bilateral cochlear implants (CIs) may have differences in electrode insertion depth. Previous reports indicate that when a bilateral mismatch is imposed, performance on tests of speech understanding or sound localization becomes worse. If recipients of bilateral CIs cannot adjust to a difference in insertion depth, adjustments to the frequency table may be necessary to maximize bilateral performance. Purpose The purpose of this study was to examine the feasibility of using real-time manipulations of the frequency table to offset any decrements in performance resulting from a bilateral mismatch. Research Design A simulation of a CI was used because it allows for explicit control of the size of a bilateral mismatch. Such control is not available with users of CIs. Study Sample A total of 31 normal-hearing young adults participated in this study. Data Collection and Analysis Using a CI simulation, four bilateral mismatch conditions (0, 0.75, 1.5, and 3 mm) were created. In the left ear, the analysis filters and noise bands of the CI simulation were the same. In the right ear, the noise bands were shifted higher in frequency to simulate a bilateral mismatch. Then, listeners selected a frequency table in the right ear that was perceived as maximizing bilateral speech intelligibility. Word-recognition scores were then assessed for each bilateral mismatch condition. Listeners were tested with both a standard frequency table, which preserved a bilateral mismatch, or with their self-selected frequency table. Results Consistent with previous reports, bilateral mismatches of 1.5 and 3 mm yielded decrements in word recognition when the standard table was used in both ears. However, when listeners used the self-selected frequency table, performance was the same regardless of the size of the bilateral mismatch. Conclusions Self-selection of a frequency table appears to be a feasible method for ameliorating the negative effects of a bilateral

Single nucleotide polymorphisms of DNA mismatch repair genes MSH2 and MLH1 confer susceptibility to esophageal cancer.

PubMed

Sun, Ming-Zhong; Ju, Hui-Xiang; Zhou, Zhong-Wei; Jin, Hao; Zhu, Rong

2014-01-01

Defects in DNA mismatch repair genes like MSH2 and MLH1 confer increased risk of cancers. Here, single nucleotide polymorphisms (SNPs) in MSH2 and MLH1 were investigated for their potential contribution to the risk of esophageal cancer. This study recruited 614 participants from Affiliated Yancheng Hospital, School of Medicine, Southeast University, of which 289 were patients with esophageal cancer, and the remainder was healthy individuals who served as a control group. Two SNPs, MSH2 c.2063T>G and MLH1 IVS14-19A>G, were genotyped using PCR-RFLP. Statistical analysis was performed using chi-square test and logistic regression analysis. Carriers of the MSH2 c.2063G allele were at significantly higher risk for esophageal cancer compared to individuals with the TT genotype [OR = 3.36, 95% confidence interval (CI): 1.18-11.03]. The MLH1 IVS14-19A>G allele also conferred significantly increased (1.70-fold) for esophageal cancer compared to the AA genotype (OR = 1.70, 95% CI: 1.13-5.06). Further, the variant alleles interacted such that individuals with the susceptible genotypes at both MSH2 and MLH1 had a significantly exacerbated risk for esophageal cancer (OR = 12.38, 95% CI: 3.09-63.11). In brief, SNPs in the DNA mismatch repair genes MSH2 and MLH1 increase the risk of esophageal cancer. Molecular investigations are needed to uncover the mechanism behind their interaction effect.

Requirement for Msh6, but not for Swi4 (Msh3), in Msh2-dependent repair of base-base mismatches and mononucleotide loops in Schizosaccharomyces pombe.

PubMed

Tornier, C; Bessone, S; Varlet, I; Rudolph, C; Darmon, M; Fleck, O

2001-05-01

The msh6 mismatch repair gene of Schizosaccharomyces pombe was cloned, sequenced, and inactivated. Strains bearing all combinations of inactivated msh6, msh2, and swi4 (the S. pombe MSH3 ortholog) alleles were tested for their defects in mitotic and meiotic mismatch repair. Mitotic mutation rates were similarly increased in msh6 and msh2 mutants, both for reversion of a base-base substitution as well as of an insertion of one nucleotide in a mononucleotide run. Tetrad analysis and intragenic two-factor crosses revealed that meiotic mismatch repair was affected in msh6 to the same extent as in msh2 background. In contrast, loss of Swi4 likely did not cause a defect in mismatch repair, but rather resulted in reduced recombination frequency. Consistently, a mutated swi4 caused a two- to threefold reduction of recombinants in intergenic crosses, while msh2 and msh6 mutants were not significantly different from wild type. In summary, our study showed that Msh6 plays the same important role as Msh2 in the major mismatch repair pathway of S. pombe, while Swi4 rather functions in recombination.

The Effect of Basepair Mismatch on DNA Strand Displacement.

PubMed

Broadwater, D W Bo; Kim, Harold D

2016-04-12

DNA strand displacement is a key reaction in DNA homologous recombination and DNA mismatch repair and is also heavily utilized in DNA-based computation and locomotion. Despite its ubiquity in science and engineering, sequence-dependent effects of displacement kinetics have not been extensively characterized. Here, we measured toehold-mediated strand displacement kinetics using single-molecule fluorescence in the presence of a single basepair mismatch. The apparent displacement rate varied significantly when the mismatch was introduced in the invading DNA strand. The rate generally decreased as the mismatch in the invader was encountered earlier in displacement. Our data indicate that a single base pair mismatch in the invader stalls branch migration and displacement occurs via direct dissociation of the destabilized incumbent strand from the substrate strand. We combined both branch migration and direct dissociation into a model, which we term the concurrent displacement model, and used the first passage time approach to quantitatively explain the salient features of the observed relationship. We also introduce the concept of splitting probabilities to justify that the concurrent model can be simplified into a three-step sequential model in the presence of an invader mismatch. We expect our model to become a powerful tool to design DNA-based reaction schemes with broad functionality. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

The spatial mismatch effect is based on global configuration and not on perceptual records within the visual cache.

PubMed

Zimmer, Hubert D; Lehnert, Günther

2006-01-01

If configurations of objects are presented in a S1-S2 matching task for the identity of objects a spatial mismatch effect occurs. Changing the (irrelevant) spatial layout lengthens response times. We investigated what causes this effect. We observed a reliable mismatch effect that was not influenced by a secondary task during maintenance. Neither articulatory suppression (Experiment 1), nor unattended (Experiments 2 and 6) or attended visual material (Experiment 3) reduced the effect, and this was independent of the length of the retention interval (Experiment 6). The effect was also rather independent of the visual appearance of the local elements. It was of similar size with color patches (Experiment 4) and with completely different surface information when testing was cross modal (Experiment 5), and the name-ability of the global configuration was not relevant (Experiments 6 and 7). In contrast, the figurative similarity of the configurations of S1 and S2 systematically influenced the size of the spatial mismatch effect (Experiment 7). We conclude that the spatial mismatch effect is caused by a mismatch of the global shape of the configuration stored together with the objects of S1 and not by a mismatch of templates of perceptual records maintained in a visual cache.

Selective alkylation of T–T mismatched DNA using vinyldiaminotriazine–acridine conjugate

PubMed Central

Onizuka, Kazumitsu; Usami, Akira; Yamaoki, Yudai; Kobayashi, Tomohito; Hazemi, Madoka E; Chikuni, Tomoko; Sato, Norihiro; Sasaki, Kaname; Katahira, Masato

2018-01-01

Abstract The alkylation of the specific higher-order nucleic acid structures is of great significance in order to control its function and gene expression. In this report, we have described the T–T mismatch selective alkylation with a vinyldiaminotriazine (VDAT)–acridine conjugate. The alkylation selectively proceeded at the N3 position of thymidine on the T–T mismatch. Interestingly, the alkylated thymidine induced base flipping of the complementary base in the duplex. In a model experiment for the alkylation of the CTG repeats DNA which causes myotonic dystrophy type 1 (DM1), the observed reaction rate for one alkylation increased in proportion to the number of T–T mismatches. In addition, we showed that primer extension reactions with DNA polymerase and transcription with RNA polymerase were stopped by the alkylation. The alkylation of the repeat DNA will efficiently work for the inhibition of replication and transcription reactions. These functions of the VDAT–acridine conjugate would be useful as a new biochemical tool for the study of CTG repeats and may provide a new strategy for the molecular therapy of DM1. PMID:29309639

Foot-to-shoe mismatch and rates of referral in Special Olympics athletes.

PubMed

Jenkins, David W; Cooper, Kimbal; O'Connor, Rachel; Watanabe, Liane

2012-01-01

Improperly fitted shoes are frequently seen in athletes participating in Special Olympics competitions. This foot-to-shoe mismatch may result in deformities as well as discomfort and reduced performance or injuries in competitions. A primary purpose for providing medical screenings is to identify conditions unknown and to promptly refer to an appropriate provider for evaluation and care. This study attempts to determine the prevalence of improperly fitted shoes and the rate of referral for Special Olympics athletes screened at Fit Feet venues. To evaluate the foot-to-shoe mismatch and rate of referral, 4,094 Fit Feet screenings of Special Olympics athletes participating in US competitions in 2005 to 2009 were analyzed. The participants were 58.5% male and 41.5% female, with a median age of 25.6 years. A power analysis and the χ(2) test were used. The athletes voluntarily underwent a foot screening that followed the standardized Special Olympics Fit Feet protocol. The Brannock Device for measuring feet was used to assess proper fit. A proper fit was found in 58.56% of the athletes, with 28.60% wearing shoes too big and 12.84% wearing shoes too small. Unrelated to shoe fit, 20% of the athletes required referrals for professional follow-up based on abnormal clinical findings. There is a significant (41.44%) mismatch of foot to shoe in Special Olympics athletes. The most common mismatch is a shoe too big, with a much smaller number of athletes having shoes too small. Awareness of this foot-to-shoe incompatibility may be useful for the development of shoes better designed for athletes with a foot structure not consistent with conventional shoes. Because 20% of the athletes required a referral for professional follow-up, Fit Feet examinations are important for identifying athletes with conditions that can be more readily evaluated and treated, thus improving the athletes' comfort and performance. Beyond knowing the rate of referral, future studies can determine the

Convergent Transmission of RNAi Guide-Target Mismatch Information across Argonaute Internal Allosteric Network

PubMed Central

Joseph, Thomas T.; Osman, Roman

2012-01-01

In RNA interference, a guide strand derived from a short dsRNA such as a microRNA (miRNA) is loaded into Argonaute, the central protein in the RNA Induced Silencing Complex (RISC) that silences messenger RNAs on a sequence-specific basis. The positions of any mismatched base pairs in an miRNA determine which Argonaute subtype is used. Subsequently, the Argonaute-guide complex binds and silences complementary target mRNAs; certain Argonautes cleave the target. Mismatches between guide strand and the target mRNA decrease cleavage efficiency. Thus, loading and silencing both require that signals about the presence of a mismatched base pair are communicated from the mismatch site to effector sites. These effector sites include the active site, to prevent target cleavage; the binding groove, to modify nucleic acid binding affinity; and surface allosteric sites, to control recruitment of additional proteins to form the RISC. To examine how such signals may be propagated, we analyzed the network of internal allosteric pathways in Argonaute exhibited through correlations of residue-residue interactions. The emerging network can be described as a set of pathways emanating from the core of the protein near the active site, distributed into the bulk of the protein, and converging upon a distributed cluster of surface residues. Nucleotides in the guide strand “seed region” have a stronger relationship with the protein than other nucleotides, concordant with their importance in sequence selectivity. Finally, any of several seed region guide-target mismatches cause certain Argonaute residues to have modified correlations with the rest of the protein. This arises from the aggregation of relatively small interaction correlation changes distributed across a large subset of residues. These residues are in effector sites: the active site, binding groove, and surface, implying that direct functional consequences of guide-target mismatches are mediated through the cumulative

DNA mismatch repair gene MLH1 induces apoptosis in prostate cancer cells.

PubMed

Fukuhara, Shinichiro; Chang, Inik; Mitsui, Yozo; Chiyomaru, Takeshi; Yamamura, Soichiro; Majid, Shahana; Saini, Sharanjot; Hirata, Hiroshi; Deng, Guoren; Gill, Ankurpreet; Wong, Darryn K; Shiina, Hiroaki; Nonomura, Norio; Dahiya, Rajvir; Tanaka, Yuichiro

2014-11-30

Mismatch repair (MMR) enzymes have been shown to be deficient in prostate cancer (PCa). MMR can influence the regulation of tumor development in various cancers but their role on PCa has not been investigated. The aim of the present study was to determine the functional effects of the mutL-homolog 1 (MLH1) gene on growth of PCa cells. The DU145 cell line has been established as MLH1-deficient and thus, this cell line was utilized to determine effects of MLH1 by gene expression. Lack of MLH1 protein expression was confirmed by Western blotting in DU145 cells whereas levels were high in normal PWR-1E and RWPE-1 prostatic cells. MLH1-expressing stable transfectant DU145 cells were then created to characterize the effects this MMR gene has on various growth properties. Expression of MLH1 resulted in decreased cell proliferation, migration and invasion properties. Lack of cell growth in vivo also indicated a tumor suppressive effect by MLH1. Interestingly, MLH1 caused an increase in apoptosis along with phosphorylated c-Abl, and treatment with MLH1 siRNAs countered this effect. Furthermore, inhibition of c-Abl with STI571 also abrogated the effect on apoptosis caused by MLH1. These results demonstrate MLH1 protects against PCa development by inducing c-Abl-mediated apoptosis.

DNA mismatch repair gene MLH1 induces apoptosis in prostate cancer cells

PubMed Central

Mitsui, Yozo; Chiyomaru, Takeshi; Yamamura, Soichiro; Majid, Shahana; Saini, Sharanjot; Hirata, Hiroshi; Deng, Guoren; Gill, Ankurpreet; Wong, Darryn K.; Shiina, Hiroaki; Nonomura, Norio; Dahiya, Rajvir; Tanaka, Yuichiro

2014-01-01

Mismatch repair (MMR) enzymes have been shown to be deficient in prostate cancer (PCa). MMR can influence the regulation of tumor development in various cancers but their role on PCa has not been investigated. The aim of the present study was to determine the functional effects of the mutL-homolog 1 (MLH1) gene on growth of PCa cells. The DU145 cell line has been established as MLH1-deficient and thus, this cell line was utilized to determine effects of MLH1 by gene expression. Lack of MLH1 protein expression was confirmed by Western blotting in DU145 cells whereas levels were high in normal PWR-1E and RWPE-1 prostatic cells. MLH1-expressing stable transfectant DU145 cells were then created to characterize the effects this MMR gene has on various growth properties. Expression of MLH1 resulted in decreased cell proliferation, migration and invasion properties. Lack of cell growth in vivo also indicated a tumor suppressive effect by MLH1. Interestingly, MLH1 caused an increase in apoptosis along with phosphorylated c-Abl, and treatment with MLH1 siRNAs countered this effect. Furthermore, inhibition of c-Abl with STI571 also abrogated the effect on apoptosis caused by MLH1. These results demonstrate MLH1 protects against PCa development by inducing c-Abl-mediated apoptosis. PMID:25526032

Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair

PubMed Central

Kosinski, Jan; Hinrichsen, Inga; Bujnicki, Janusz M.; Friedhoff, Peter; Plotz, Guido

2010-01-01

Missense alterations of the mismatch repair gene MLH1 have been identified in a significant proportion of individuals suspected of having Lynch syndrome, a hereditary syndrome which predisposes for cancer of colon and endometrium. The pathogenicity of many of these alterations, however, is unclear. A number of MLH1 alterations are located in the C-terminal domain (CTD) of MLH1, which is responsible for constitutive dimerization with PMS2. We analyzed which alterations may result in pathogenic effects due to interference with dimerization. We used a structural model of CTD of MLH1-PMS2 heterodimer to select 19 MLH1 alterations located inside and outside two candidate dimerization interfaces in the MLH1-CTD. Three alterations (p.Gln542Leu, p.Leu749Pro, p.Tyr750X) caused decreased co-expression of PMS2, which is unstable in the absence of interaction with MLH1, suggesting that these alterations interfere with dimerization. All three alterations are located within the dimerization interface suggested by our model. They also compromised mismatch repair, suggesting that defects in dimerization abrogate repair and confirming that all three alterations are pathogenic. Additionally, we provided biochemical evidence that four alterations with uncertain pathogenicity (p.Ala586Pro, p.Leu636Pro, p.Thr662Pro, and p.Arg755Trp) are deleterious because of poor expression or poor repair efficiency, and confirm the deleterious effect of eight further alterations. PMID:20533529

Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair.

PubMed

Kosinski, Jan; Hinrichsen, Inga; Bujnicki, Janusz M; Friedhoff, Peter; Plotz, Guido

2010-08-01

Missense alterations of the mismatch repair gene MLH1 have been identified in a significant proportion of individuals suspected of having Lynch syndrome, a hereditary syndrome that predisposes for cancer of colon and endometrium. The pathogenicity of many of these alterations, however, is unclear. A number of MLH1 alterations are located in the C-terminal domain (CTD) of MLH1, which is responsible for constitutive dimerization with PMS2. We analyzed which alterations may result in pathogenic effects due to interference with dimerization. We used a structural model of CTD of MLH1-PMS2 heterodimer to select 19 MLH1 alterations located inside and outside two candidate dimerization interfaces in the MLH1-CTD. Three alterations (p.Gln542Leu, p.Leu749Pro, p.Tyr750X) caused decreased coexpression of PMS2, which is unstable in the absence of interaction with MLH1, suggesting that these alterations interfere with dimerization. All three alterations are located within the dimerization interface suggested by our model. They also compromised mismatch repair, suggesting that defects in dimerization abrogate repair and confirming that all three alterations are pathogenic. Additionally, we provided biochemical evidence that four alterations with uncertain pathogenicity (p.Ala586Pro, p.Leu636Pro, p.Thr662Pro, and p.Arg755Trp) are deleterious because of poor expression or poor repair efficiency, and confirm the deleterious effect of eight further alterations.

Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers

PubMed Central

Jansen, Anne ML; van Wezel, Tom; van den Akker, Brendy EWM; Ventayol Garcia, Marina; Ruano, Dina; Tops, Carli MJ; Wagner, Anja; Letteboer, Tom GW; Gómez-García, Encarna B; Devilee, Peter; Wijnen, Juul T; Hes, Frederik J; Morreau, Hans

2016-01-01

Many suspected Lynch Syndrome (sLS) patients who lack mismatch repair (MMR) germline gene variants and MLH1 or MSH2 hypermethylation are currently explained by somatic MMR gene variants or, occasionally, by germline POLE variants. To further investigate unexplained sLS patients, we analyzed leukocyte and tumor DNA of 62 sLS patients using gene panel sequencing including the POLE, POLD1 and MMR genes. Forty tumors showed either one, two or more somatic MMR variants predicted to affect function. Nine sLS tumors showed a likely ultramutated phenotype and were found to carry germline (n=2) or somatic variants (n=7) in the POLE/POLD1 exonuclease domain (EDM). Six of these POLE/POLD1-EDM mutated tumors also carried somatic MMR variants. Our findings suggest that faulty proofreading may result in loss of MMR and thereby in microsatellite instability. PMID:26648449

Selective Cytotoxicity of Rhodium Metalloinsertors in Mismatch Repair-Deficient Cells†

PubMed Central

Ernst, Russell J.; Komor, Alexis C.; Barton, Jacqueline K.

2011-01-01

Mismatches in DNA occur naturally during replication and as a result of endogenous DNA damaging agents, but the mismatch repair (MMR) pathway acts to correct mismatches before subsequent rounds of replication. Rhodium metalloinsertors bind to DNA mismatches with high affinity and specificity and represent a promising strategy to target mismatches in cells. Here we examine the biological fate of rhodium metalloinsertors bearing dipyridylamine ancillary ligands in cells deficient in MMR versus those that are MMR-proficient. These complexes are shown to exhibit accelerated cellular uptake which permits the observation of various cellular responses, including disruption of the cell cycle, monitored by flow cytometry assays, and induction of necrosis, monitored by dye exclusion and caspase inhibition assays, that occur preferentially in the MMR-deficient cell line. These cellular responses provide insight into the mechanisms underlying the selective activity of this novel class of targeted anti-cancer agents. PMID:22103240

Test report for twinax cable (Rockwell type MB0150-051). [effects of mismatched termination

NASA Technical Reports Server (NTRS)

Doland, G. D.

1978-01-01

A controlled impedance twisted pair shielded cable was tested to determine the frequency response and effects of mismatched termination. It was found that a long length of this cable, about 100 feet, exhibited a frequency sensitive attenuation roll-off greater than 1.5 db down at 5 MHz. It was also determined that improper termination resulted in losses of 1/2 to 1 db within the frequency range of 200 KHz to greater than 1-1/2 MHz. The test results indicate a possible problem where mismatched connectors are used in video signal cables.

Indoleamine 2,3-dioxygenase in endometrial cancer: a targetable mechanism of immune resistance in mismatch repair-deficient and intact endometrial carcinomas.

PubMed

Mills, Anne; Zadeh, Sara; Sloan, Emily; Chinn, Zachary; Modesitt, Susan C; Ring, Kari L

2018-03-20

Mismatch repair-deficient endometrial carcinomas are optimal candidates for immunotherapy given their high neoantigen loads, robust lymphoid infiltrates, and frequent PD-L1 expression. However, co-opting the PD-1/PD-L1 pathway is just one mechanism that tumors can utilize to evade host immunity. Another immune modulatory molecule that has been demonstrated in endometrial carcinoma is indoleamine 2,3-dioxygenase (IDO). We herein evaluate IDO expression in 60 endometrial carcinomas and assess results in relation to PD-L1 and mismatch repair status. IDO immunohistochemistry was performed on 60 endometrial carcinomas (20 Lynch syndrome (LS)-associated, 20 MLH1 promoter hypermethylated, and 20 mismatch repair-intact). Eight-five percent of endometrial carcinomas showed IDO tumor staining in >1% of cells. Twenty-five percent were positive in >25% of tumor cells and only 7% exceeded 50% staining. Mismatch repair-deficient cancers were more likely than mismatch repair-intact cancers to be >25% IDO-positive (35% vs. 5% p = 0.024). Differences were amplified when Lynch syndrome-associated cases were evaluated in isolation (50% Lynch syndrome-associated vs. 10% mismatch repair-intact and MLH1-hypermethylated, p = 0.001). Of the four cases showing >50% staining, three were Lynch syndrome-associated and one was MLH1-hypermethylated; no mismatch repair-intact cases had >50% staining. Forty-three percent of IDO-positive tumors were also positive for PD-L1, whereas only two cases showed tumoral PD-L1 in the absence of IDO. In summary, IDO expression is prevalent in endometrial carcinomas and diffuse staining is significantly more common in mismatch repair-deficient cancers, particularly Lynch syndrome-associated cases. Given that the majority of PD-L1 positive cancers also express IDO, synergistic combination therapy with anti-IDO and anti-PD1/PD-L1 may be relevant in this tumor type. Furthermore, anti-IDO therapy may be an option for a small subset of mismatch repair

Lattice mismatch modeling of aluminum alloys

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shin, Dongwon; Roy, Shibayan; Watkins, Thomas R.

We present a theoretical framework to accurately predict the lattice mismatch between the fcc matrix and precipitates in the multi-component aluminum alloys as a function of temperature and composition. We use a computational thermodynamic approach to model the lattice parameters of the multi-component fcc solid solution and θ'-Al2Cu precipitate phase. Better agreement between the predicted lattice parameters of fcc aluminum in five commercial alloys (206, 319, 356, A356, and A356 + 0.5Cu) and experimental data from the synchrotron X-ray diffraction (SXD) has been obtained when simulating supersaturated rather than equilibrium solid solutions. We use the thermal expansion coefficient of thermodynamicallymore » stable θ-Al2Cu to describe temperature-dependent lattice parameters of meta-stable θ' and to show good agreement with the SXD data. Both coherent and semi-coherent interface mismatches between the fcc aluminum matrix and θ' in Al-Cu alloys are presented as a function of temperature. Our calculation results show that the concentration of solute atoms, particularly Cu, in the matrix greatly affects the lattice mismatch« less

DNA Methylation-a Potential Source of Mitochondria DNA Base Mismatch in the Development of Diabetic Retinopathy.

PubMed

Mishra, Manish; Kowluru, Renu A

2018-04-21

In the development of diabetic retinopathy, retinal mitochondria are dysfunctional, and mitochondrial DNA (mtDNA) is damaged with increased base mismatches and hypermethylated cytosines. DNA methylation is also a potential source of mutation, and in diabetes, the noncoding region, the displacement loop (D-loop), experiences more methylation and base mismatches than other regions of the mtDNA. Our aim was to investigate a possible crosstalk between mtDNA methylation and base mismatches in the development of diabetic retinopathy. The effect of inhibition of Dnmts (by 5-aza-2'-deoxycytidine or Dnmt1-siRNA) on glucose-induced mtDNA base mismatches was investigated in human retinal endothelial cells by surveyor endonuclease digestion and validated by Sanger sequencing. The role of deamination factors on increased base mismatches was determined in the cells genetically modulated for mitochondrial superoxide dismutase (Sod2) or cytidine-deaminase (APOBEC3A). The results were confirmed in an in vivo model using retinal microvasculature from diabetic mice overexpressing Sod2. Inhibition of DNA methylation, or regulation of cytosine deamination, significantly inhibited an increase in base mismatches at the D-loop and prevented mitochondrial dysfunction. Overexpression of Sod2 in mice also prevented diabetes-induced D-loop hypermethylation and increase in base mismatches. The crosstalk between DNA methylation and base mismatches continued even after termination of hyperglycemia, suggesting its role in the metabolic memory phenomenon associated with the progression of diabetic retinopathy. Inhibition of DNA methylation limits the availability of methylated cytosine for deamination, suggesting a crosstalk between DNA methylation and base mismatches. Thus, regulation of DNA methylation, or its deamination, should impede the development of diabetic retinopathy by preventing formation of base mismatches and mitochondrial dysfunction.

Rhabdomyosarcoma in patients with constitutional mismatch-repair-deficiency syndrome.

PubMed

Kratz, C P; Holter, S; Etzler, J; Lauten, M; Pollett, A; Niemeyer, C M; Gallinger, S; Wimmer, K

2009-06-01

Biallelic germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 or PMS2 cause a recessive childhood cancer syndrome characterised by early-onset malignancies and signs reminiscent of neurofibromatosis type 1 (NF1). Alluding to the underlying genetic defect, we refer to this syndrome as constitutional mismatch repair-deficiency (CMMR-D) syndrome. The tumour spectrum of CMMR-D syndrome includes haematological neoplasias, brain tumours and Lynch syndrome-associated tumours. Other tumours, such as neuroblastoma, Wilm tumour, ovarian neuroectodermal tumour or infantile myofibromatosis, have so far been found only in individual cases. We analysed two consanguineous families that had members with suspected CMMR-D syndrome who developed rhabdomyosarcoma among other neoplasias. In the first family, we identified a pathogenic PMS2 mutation for which the affected patient was homozygous. In family 2, immunohistochemistry analysis showed isolated loss of PMS2 expression in all tumours in the affected patients, including rhabdomyosarcoma itself and the surrounding normal tissue. Together with the family history and microsatellite instability observed in one tumour this strongly suggests an underlying PMS2 alteration in family 2 also. Together, these two new cases show that rhabdomyosarcoma and possibly other embryonic tumours, such as neuroblastoma and Wilm tumour, belong to the tumour spectrum of CMMR-D syndrome. Given the clinical overlap of CMMR-D syndrome with NF1, we suggest careful examination of the family history in patients with embryonic tumours and signs of NF1 as well as analysis of the tumours for loss of one of the mismatch repair genes and microsatellite instability. Subsequent mutation analysis will lead to a definitive diagnosis of the underlying disorder.

Relative impact of human leukocyte antigen mismatching and graft ischemic time after lung transplantation.

PubMed

Brugière, Olivier; Thabut, Gabriel; Suberbielle, Caroline; Reynaud-Gaubert, Martine; Thomas, Pascal; Pison, Christophe; Saint Raymond, Christel; Mornex, Jean-François; Bertocchi, Michèle; Dromer, Claire; Velly, Jean-François; Stern, Marc; Philippe, Bruno; Dauriat, Gaëlle; Biondi, Giuseppina; Castier, Yves; Fournier, Michel

2008-06-01

Recent data strongly suggest that human leukocyte antigen (HLA) mismatching has a negative impact on development of bronchiolitis obliterans syndrome (BOS) and survival after lung transplantation (LTx). Because HLA matching is sometimes achieved by extending ischemic time in other solid-organ transplantation models and ischemic time is a risk factor per se for death after LTx, we sought to compare the theoretical benefit of HLA matching with the negative impact of lengthened ischemic time. In this collaborative study we compared the relative impact of HLA mismatching and ischemic time on BOS and survival in 182 LTx recipients. Using multivariate analyses, we observed a lower incidence of BOS (hazard ratio [HR] = 1.70, 95% confidence interval [CI]: 1.1 to 2.7, p = 0.03) and enhanced survival (HR = 1.91, 95% CI: 1.24 to 2.92, p = 0.01) in patients with zero or one HLA-A mismatch compared with those having two HLA-A mismatches. This beneficial effect on survival was equivalent to a reduction of ischemic time of 168 minutes. We observed a reduced incidence of BOS and a better survival rate in patients well-matched at the HLA-A locus, associated with an opposite effect of an enhanced ischemic time. This suggests that graft ischemic time should be taken into account in future studies of prospective HLA matching in LTx.

Open-label dose optimization of methylphenidate modified release long acting (MPH-LA): a post hoc analysis of real-life titration from a 40-week randomized trial.

PubMed

Huss, Michael; Ginsberg, Ylva; Arngrim, Torben; Philipsen, Alexandra; Carter, Katherine; Chen, Chien-Wei; Gandhi, Preetam; Kumar, Vinod

2014-09-01

In the management of attention-deficit hyperactivity disorder (ADHD) in adults it is important to recognize that individual patients respond to a wide range of methylphenidate doses. Studies with methylphenidate modified release long acting (MPH-LA) in children have reported the need for treatment optimization for improved outcomes. We report the results from a post hoc analysis of a 5-week dose optimization phase from a large randomized, placebo-controlled, multicenter 40-week study (9-week double-blind dose confirmation phase, 5-week open-label dose optimization phase, and 26-week double-blind maintenance of effect phase). Patients entering the open-label dose optimization phase initiated treatment with MPH-LA 20 mg/day; up/down titrated to their optimal dose (at which there was balance between control of symptoms and side effects) of 40, 60, or 80 mg/day in increments of 20 mg/week by week 12 or 13. Safety was assessed by monitoring the adverse events (AEs) and serious AEs. Efficacy was assessed by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, Attention-Deficit Hyperactivity Disorder Rating Scale (DSM-IV ADHD RS) and Sheehan Disability Scale (SDS) total scores. At the end of the dose confirmation phase, similar numbers of patients were treated optimally with each of the 40, 60, and 80 mg/day doses (152, 177, and 160, respectively) for MPH-LA. Mean improvement from baseline in the dose confirmation phase in total scores of DSM-IV ADHD RS and SDS were 23.5 ± 9.90 and 9.7 ± 7.36, respectively. Dose optimization with MPH-LA (40, 60, or 80 mg/day) improved treatment outcomes and was well-tolerated in adult ADHD patients.

Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington's disease mice: genome-wide and candidate approaches.

PubMed

Pinto, Ricardo Mouro; Dragileva, Ella; Kirby, Andrew; Lloret, Alejandro; Lopez, Edith; St Claire, Jason; Panigrahi, Gagan B; Hou, Caixia; Holloway, Kim; Gillis, Tammy; Guide, Jolene R; Cohen, Paula E; Li, Guo-Min; Pearson, Christopher E; Daly, Mark J; Wheeler, Vanessa C

2013-10-01

The Huntington's disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington's disease Hdh(Q111) mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.Hdh(Q111) ) than on a 129 background (129.Hdh(Q111) ). Linkage mapping in (B6x129).Hdh(Q111) F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR) gene Mlh1 as the most likely candidate modifier. Crossing B6.Hdh(Q111) mice onto an Mlh1 null background demonstrated that Mlh1 is essential for somatic CAG expansions and that it is an enhancer of nuclear huntingtin accumulation in striatal neurons. Hdh(Q111) somatic expansion was also abolished in mice deficient in the Mlh3 gene, implicating MutLγ (MLH1-MLH3) complex as a key driver of somatic expansion. Strikingly, Mlh1 and Mlh3 genes encoding MMR effector proteins were as critical to somatic expansion as Msh2 and Msh3 genes encoding DNA mismatch recognition complex MutSβ (MSH2-MSH3). The Mlh1 locus is highly polymorphic between B6 and 129 strains. While we were unable to detect any difference in base-base mismatch or short slipped-repeat repair activity between B6 and 129 MLH1 variants, repair efficiency was MLH1 dose-dependent. MLH1 mRNA and protein levels were significantly decreased in 129 mice compared to B6 mice, consistent with a dose-sensitive MLH1-dependent DNA repair mechanism underlying the somatic expansion difference between these strains. Together, these data identify Mlh1 and Mlh3 as novel critical genetic modifiers of HTT CAG instability, point to Mlh1 genetic variation as the likely source of the instability difference in B6 and 129 strains and suggest that MLH1

Mismatch Repair Genes Mlh1 and Mlh3 Modify CAG Instability in Huntington's Disease Mice: Genome-Wide and Candidate Approaches

PubMed Central

Pinto, Ricardo Mouro; Dragileva, Ella; Kirby, Andrew; Lloret, Alejandro; Lopez, Edith; St. Claire, Jason; Panigrahi, Gagan B.; Hou, Caixia; Holloway, Kim; Gillis, Tammy; Guide, Jolene R.; Cohen, Paula E.; Li, Guo-Min; Pearson, Christopher E.; Daly, Mark J.; Wheeler, Vanessa C.

2013-01-01

The Huntington's disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington's disease HdhQ111 mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.HdhQ111) than on a 129 background (129.HdhQ111). Linkage mapping in (B6x129).HdhQ111 F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR) gene Mlh1 as the most likely candidate modifier. Crossing B6.HdhQ111 mice onto an Mlh1 null background demonstrated that Mlh1 is essential for somatic CAG expansions and that it is an enhancer of nuclear huntingtin accumulation in striatal neurons. HdhQ111 somatic expansion was also abolished in mice deficient in the Mlh3 gene, implicating MutLγ (MLH1–MLH3) complex as a key driver of somatic expansion. Strikingly, Mlh1 and Mlh3 genes encoding MMR effector proteins were as critical to somatic expansion as Msh2 and Msh3 genes encoding DNA mismatch recognition complex MutSβ (MSH2–MSH3). The Mlh1 locus is highly polymorphic between B6 and 129 strains. While we were unable to detect any difference in base-base mismatch or short slipped-repeat repair activity between B6 and 129 MLH1 variants, repair efficiency was MLH1 dose-dependent. MLH1 mRNA and protein levels were significantly decreased in 129 mice compared to B6 mice, consistent with a dose-sensitive MLH1-dependent DNA repair mechanism underlying the somatic expansion difference between these strains. Together, these data identify Mlh1 and Mlh3 as novel critical genetic modifiers of HTT CAG instability, point to Mlh1 genetic variation as the likely source of the instability difference in B6 and 129 strains and suggest that MLH1 protein

Preoperative diagnosis of Lynch syndrome with DNA mismatch repair immunohistochemistry on a diagnostic biopsy.

PubMed

Warrier, S K; Trainer, A H; Lynch, A C; Mitchell, C; Hiscock, R; Sawyer, S; Boussioutas, A; Heriot, A G

2011-12-01

DNA mismatch repair immunohistochemistry on tumor tissue is a simple, readily available, and cost-effective method of identifying patients with Lynch syndrome in the postoperative setting. The aim of the study was to assess whether the mismatch repair status of a colorectal cancer can be confirmed by mismatch repair immunohistochemistry on preoperative biopsy. Germline positive patients with Lynch syndrome were identified from a prospectively collected Familial Cancer Clinic database. Preoperative colorectal cancer biopsy specimens were obtained from the source pathology provider to generate a cohort of matched preoperative and postoperative specimens. The specimens were sectioned and stained for 4 mismatch repair proteins (MLH1, MSH2, MSH6, PMS2). An age-matched cohort to compare specimens was selected from Bethesda positive but mismatch repair immunohistochemistry negative patients. All slides were reviewed by a single blinded pathologist. The Wilson method was used to calculate a true underlying proportion of patients for whom the preoperative result matched the postoperative test result with a 95% confidence interval. Of 128 germline positive mutation carriers, 40 patients (mean age 41, SD 11.3) had colorectal resections. Thirty-three preoperative specimens were retrievable and were matched with biopsies from 33 controls. The germline mutations included in the study were 8 MLH1, 19 MSH2, 3 MSH6, and 2 PMS2. In patients where germline positive status was known, sensitivity was 100% (95% CI 89.2-100) and specificity was 100% (95% CI 89.2-100). Identical sensitivity and specificity were observed in 33 age-matched patients. The sensitivity of the endoscopic biopsy in predicting germline status was 94.9% (95% CI 80.4-98.3). The mismatch repair disease status of a colorectal cancer can be reliably confirmed by mismatch repair immunohistochemistry on a diagnostic colorectal cancer biopsy sample before definitive surgery. Ascertaining a diagnosis of Lynch syndrome

Match and mismatch between opening area and resistance in mild and moderate rheumatic mitral stenosis.

PubMed

El-Dosouky, Ibtesam Ibrahim

2016-12-01

Mitral valve resistance (MVR) is a hemodynamic consequence of mitral stenosis (MS), but it has no clear threshold with a shortage of data to be reliable. We aimed to investigate match and mismatch between opening area and resistance especially in patients with moderate and mild MS. This study comprised 88 patients with moderate and mild rheumatic MS. Transthoracic echocardiographic study estimated the following: mitral valve area (MVA) by both planimetry (2D) and pressure half-time (PHT), mitral valve score (MVS), mean transmitral pressure gradient (MPG), diastolic filling time (DFT), left ventricular out flow tract diameter (LVOTd) and velocity-time integral (LVOTvti), and MVR = MPG/aortic flow ratio [(LVOTd) (LVOTvti)/DFT] in dynes·s/cm 5 . Patients were classified into two groups: group 1 (51 patients) with matched MVR and group 2 (37 patients) with mismatched higher MVR. In the matched group, moderate MS showed MVR <105 dynes·s/cm 5 and <76dynes·s/cm 5 with mild MS. Group 2 compared to group 1 had higher NYHA class (1.4±0.6 vs 1.2±0.4, P<.05) and higher MVS (8.1±1.8 vs 7±0.9, P<.05). MVR showed positive correlation with MVS (r=.5, P<.05), and logistic regression analysis showed that MVS is the only independent predictor of the MVR severity in the mismatched group (i.e., with higher MVR compared to the ROC analysis results) (B±SE=6.997±2.826, t=2.476, 95% CI 1.241±12.752 with an odds ratio=0.412, P<.05). On investigating match and mismatch between opening area and resistance, the only independent predictor of mismatch is the mitral valve score. © 2016, Wiley Periodicals, Inc.

[Constitutional mismatch repair deficiency syndrome].

PubMed

Jongmans, Marjolijn C; Gidding, Corrie E; Loeffen, Jan; Wesseling, Pieter; Mensenkamp, Arjen; Hoogerbrugge, Nicoline

2015-01-01

Constitutional mismatch repair deficiency (CMMR-D) syndrome is characterised by a significantly increased risk for developing cancer in childhood. It arises when both parents have a mutation in the same mismatch repair gene and pass it on to their child. An 8-year-old girl was diagnosed with CMMR-D syndrome after she developed a brain tumour at the age of 4 and a T-cell non-Hodgkin lymphoma at the age of 6. She had multiple hyperpigmented skin lesions and died of myelodysplastic syndrome at the age of 11. In children with cancer CMMR-D syndrome can be recognized particularly if there are multiple primary malignancies and skin hyperpigmentations and hypopigmentations. The parents of these children are at high risk for colorectal and endometrial cancer (Lynch syndrome), amongst others.

Femoral head retroposition as a potential compensatory mechanism in patients with a severe mismatch between pelvic incidence and lumbar lordosis.

PubMed

Cheng, Xiaofei; Zhang, Kai; Sun, Xiaojiang; Zhao, Changqing; Li, Hua; Zhao, Jie

2017-12-01

Severe mismatch between pelvic incidence (PI) and lumbar lordosis (LL) leads to extra anterior displacement of the gravity line. The objective of this study is to investigate whether femoral head retroposition is a separate compensatory mechanism responsible for the extra anterior displacement. Based on the values of PI and LL, 94 patients were divided into the PI-LL match group (PI-LL ≤ 0°), the mild PI-LL mismatch group (20°> PI-LL >0°), and the severe PI-LL mismatch group (PI-LL ≥ 20°). A series of parameters including PI, LL, PI-LL, thoracic kyphosis (TK), pelvic tilt (PT), sacral slope (SS), knee flexion angle (KFA), tibial obliquity angle (TOA), sagittal vertical axis (SVA), S1 overhang, femoral head shift (FHS), and pelvic shift (PS) were measured and compared among the three groups. The severe PI-LL mismatch group exhibited significantly greater PI, PI-LL, PT, KFA, SVA, PS, and FHS, and less LL and TK, compared with the control and mild PI-LL mismatch group. The mild PI-LL mismatch group had significantly greater PI-LL, PT, KFA, TOA, and S1 overhang, and less LL and SS than the control group. SS, TOA, and S1 overhang in the severe PI-LL mismatch group differed significantly from that in the control group, but did not differ significantly from that in the mild PI-LL mismatch group. Femoral head retroposition is an entirely separate compensatory mechanism and, in this study, participated in the compensation for the anterior displacement of the gravity line induced by extra-sagittal spinal malalignment in patients with severe PI-LL mismatch.

A Modified Protocol with Improved Detection Rate for Mis-Matched Donor HLA from Low Quantities of DNA in Urine Samples from Kidney Graft Recipients.

PubMed

Kwok, Janette; Choi, Leo C W; Ho, Jenny C Y; Chan, Gavin S W; Mok, Maggie M Y; Lam, Man-Fei; Chak, Wai-Leung; Cheuk, Au; Chau, Ka-Foon; Tong, Matthew; Chan, Kwok-Wah; Chan, Tak-Mao

2016-01-01

Urine from kidney transplant recipient has proven to be a viable source for donor DNA. However, an optimized protocol would be required to determine mis-matched donor HLA specificities in view of the scarcity of DNA obtained in some cases. In this study, fresh early morning urine specimens were obtained from 155 kidney transplant recipients with known donor HLA phenotype. DNA was extracted and typing of HLA-A, B and DRB1 loci by polymerase chain reaction-specific sequence primers was performed using tailor-made condition according to the concentration of extracted DNA. HLA typing of DNA extracted from urine revealed both recipient and donor HLA phenotypes, allowing the deduction of the unknown donor HLA and hence the degree of HLA mis-match. By adopting the modified procedures, mis-matched donor HLA phenotypes were successfully deduced in all of 35 tested urine samples at DNA quantities spanning the range of 620-24,000 ng. This urine-based method offers a promising and reliable non-invasive means for the identification of mis-matched donor HLA antigens in kidney transplant recipients with unknown donor HLA phenotype or otherwise inadequate donor information.

Job Supply and Demand for University Graduates in Spain: A (Relative) Mismatch Perspective

ERIC Educational Resources Information Center

Parellada, Marti; Duch, Nestor; Alvarez, Montserrat

2009-01-01

This article provides an analysis of job supply by Spanish firms and the demand for work, and the mismatch that occurs between these two variables. Data are taken for the year 2006, with particular attention to jobs offered by firms that require people with university degrees or other higher education qualifications. Demand and supply are broken…

Single-molecule multiparameter fluorescence spectroscopy reveals directional MutS binding to mismatched bases in DNA

PubMed Central

Cristóvão, Michele; Sisamakis, Evangelos; Hingorani, Manju M.; Marx, Andreas D.; Jung, Caroline P.; Rothwell, Paul J.; Seidel, Claus A. M.; Friedhoff, Peter

2012-01-01

Mismatch repair (MMR) corrects replication errors such as mismatched bases and loops in DNA. The evolutionarily conserved dimeric MMR protein MutS recognizes mismatches by stacking a phenylalanine of one subunit against one base of the mismatched pair. In all crystal structures of G:T mismatch-bound MutS, phenylalanine is stacked against thymine. To explore whether these structures reflect directional mismatch recognition by MutS, we monitored the orientation of Escherichia coli MutS binding to mismatches by FRET and anisotropy with steady state, pre-steady state and single-molecule multiparameter fluorescence measurements in a solution. The results confirm that specifically bound MutS bends DNA at the mismatch. We found additional MutS–mismatch complexes with distinct conformations that may have functional relevance in MMR. The analysis of individual binding events reveal significant bias in MutS orientation on asymmetric mismatches (G:T versus T:G, A:C versus C:A), but not on symmetric mismatches (G:G). When MutS is blocked from binding a mismatch in the preferred orientation by positioning asymmetric mismatches near the ends of linear DNA substrates, its ability to authorize subsequent steps of MMR, such as MutH endonuclease activation, is almost abolished. These findings shed light on prerequisites for MutS interactions with other MMR proteins for repairing the appropriate DNA strand. PMID:22367846

Educational Mismatch of Graduates: A Multidimensional and Fuzzy Indicator

ERIC Educational Resources Information Center

Betti, Gianni; D'Agostino, Antonella; Neri, Laura

2011-01-01

In this paper we attempt to measure the educational mismatch, seen as a problem of overeducation, using a multidimensional and fuzzy methodology. Educational mismatch can be difficult to measure because many factors can converge to its definition and the traditional unidimensional indicators presented in literature can offer a restricted view of…

Speaking Self-Assessment: Mismatches between Learners' and Teachers' Criteria

ERIC Educational Resources Information Center

Babaii, Esmat; Taghaddomi, Shahin; Pashmforoosh, Roya

2016-01-01

Perceptual (mis)matches between teachers and learners are said to affect learning success or failure. Self-assessment, as a formative assessment tool, may, inter alia, be considered a means to minimize such mismatches. Therefore, the present study investigated the extent to which learners' assessment of their own speaking performance, before and…

Biophysics of Artificially Expanded Genetic Information Systems. Thermodynamics of DNA Duplexes Containing Matches and Mismatches Involving 2-Amino-3-nitropyridin-6-one (Z) and Imidazo[1,2-a]-1,3,5-triazin-4(8H)one (P).

PubMed

Wang, Xiaoyu; Hoshika, Shuichi; Peterson, Raymond J; Kim, Myong-Jung; Benner, Steven A; Kahn, Jason D

2017-05-19

Synthetic nucleobases presenting non-Watson-Crick arrangements of hydrogen bond donor and acceptor groups can form additional nucleotide pairs that stabilize duplex DNA independent of the standard A:T and G:C pairs. The pair between 2-amino-3-nitropyridin-6-one 2'-deoxyriboside (presenting a {donor-donor-acceptor} hydrogen bonding pattern on the Watson-Crick face of the small component, trivially designated Z) and imidazo[1,2-a]-1,3,5-triazin-4(8H)one 2'-deoxyriboside (presenting an {acceptor-acceptor-donor} hydrogen bonding pattern on the large component, trivially designated P) is one of these extra pairs for which a substantial amount of molecular biology has been developed. Here, we report the results of UV absorbance melting measurements and determine the energetics of binding of DNA strands containing Z and P to give short duplexes containing Z:P pairs as well as various mismatches comprising Z and P. All measurements were done at 1 M NaCl in buffer (10 mM Na cacodylate, 0.5 mM EDTA, pH 7.0). Thermodynamic parameters (ΔH°, ΔS°, and ΔG° 37 ) for oligonucleotide hybridization were extracted. Consistent with the Watson-Crick model that considers both geometric and hydrogen bonding complementarity, the Z:P pair was found to contribute more to duplex stability than any mismatches involving either nonstandard nucleotide. Further, the Z:P pair is more stable than a C:G pair. The Z:G pair was found to be the most stable mismatch, forming either a deprotonated mismatched pair or a wobble base pair analogous to the stable T:G mismatch. The C:P pair is less stable, perhaps analogous to the wobble pair observed for C:O 6 -methyl-G, in which the pyrimidine is displaced into the minor groove. The Z:A and T:P mismatches are much less stable. Parameters for predicting the thermodynamics of oligonucleotides containing Z and P bases are provided. This represents the first case where this has been done for a synthetic genetic system.

A Jobs Mismatch. Commentary

ERIC Educational Resources Information Center

Marina, Brenda L. H.

2011-01-01

In the article "A Jobs Mismatch", Jaschik has compiled the findings of a new report that was released by the Georgetown University Center on Education and the Workforce. The Georgetown University report claims that there is a severe shortage of college graduates in America, and that this shortage has the United States on a…

Phase mismatched optical parametric generation in semiconductor magnetoplasma

NASA Astrophysics Data System (ADS)

Dubey, Swati; Ghosh, S.; Jain, Kamal

2017-05-01

Optical parametric generation involves the interaction of pump, signal, and idler waves satisfying law of conservation of energy. Phase mismatch parameter plays important role for the spatial distribution of the field along the medium. In this paper instead of exactly matching wave vector, a small mismatch is admitted with a degree of phase velocity mismatch between these waves. Hence the medium must possess certain finite coherence length. This wave mixing process is well explained by coupled mode theory and one dimensional hydrodynamic model. Based on this scheme, expressions for threshold pump field and transmitted intensity have been derived. It is observed that the threshold pump intensity and transmitted intensity can be manipulated by varying doping concentration and magnetic field under phase mismatched condition. A compound semiconductor crystal of n-InSb is assumed to be shined at 77 K by a 10.6μm CO2 laser with photon energy well below band gap energy of the crystal, so that only free charge carrier influence the optical properties of the medium for the I.R. parametric generation in a semiconductor plasma medium. Favorable parameters were explored to incite the said process keeping in mind the cost effectiveness and conversion efficiency of the process.

Discriminating DNA mismatches by electrochemical and gravimetric techniques.

PubMed

Mazouz, Zouhour; Fourati, Najla; Zerrouki, Chouki; Ommezine, Asma; Rebhi, Lamia; Yaakoubi, Nourdin; Kalfat, Rafik; Othmane, Ali

2013-10-15

A silicon nitride functionalized electrode and a 104 MHz lithium tantalate (LiTaO₃) surface acoustic wave (SAW) sensor have been used to investigate target-probe recognition processes. Electrochemical and gravimetric measurements have been considered to monitor hybridization of single base mismatch (SBM) in synthetic oligonucleotides and single-nucleotide polymorphisms ApoE in real clinical genotypes. Obvious discrimination of SBM in nucleotides has been shown by both gravimetric and electrochemical techniques, without labeling nor amplification. Investigations on mismatches nature and position have also been considered. For guanine-adenine (GA), guanine-thymine (GT) and guanine-guanine (GG) mismatches, the sensors responses present a dependence upon positions. Considering the capacitance variations and hybridization rates, results showed that gravimetric transduction is more sensitive than electrochemical one. Moreover, the highest value of GT hybridization rate (in the middle position) was found in accordance with the nearest-neighbor model, where the considered configuration appears as the most thermodynamically stable. For the real samples, where the electrochemical transduction, by combining capacitance and flat-band potential measurements, were found more sensitive, the results show that the realized sensor permits an unambiguous discrimination of recognition between fully complementary, non-complementary and single base mismatched targets, and even between the combination of differently matched strands. Copyright © 2013 Elsevier B.V. All rights reserved.

Effects of Mismatched Pictures on Retention of Illustrated Prose.

ERIC Educational Resources Information Center

Peeck, Joan

A study was conducted to test the findings of two earlier studies (Peeck l974 and Pressley l983) on the effects of occasional mismatches between verbal and pictorial content in children's retention of illustrated prose. While the Peeck study indicated a considerable impact of mismatched pictures, the Pressley study indicated that with some…

Implications of segment mismatch for influenza A virus evolution

PubMed Central

White, Maria C.; Lowen, Anice C.

2018-01-01

Influenza A virus (IAV) is an RNA virus with a segmented genome. These viral properties allow for the rapid evolution of IAV under selective pressure, due to mutation occurring from error-prone replication and the exchange of gene segments within a co-infected cell, termed reassortment. Both mutation and reassortment give rise to genetic diversity, but constraints shape their impact on viral evolution: just as most mutations are deleterious, most reassortment events result in genetic incompatibilities. The phenomenon of segment mismatch encompasses both RNA- and protein-based incompatibilities between co-infecting viruses and results in the production of progeny viruses with fitness defects. Segment mismatch is an important determining factor of the outcomes of mixed IAV infections and has been addressed in multiple risk assessment studies undertaken to date. However, due to the complexity of genetic interactions among the eight viral gene segments, our understanding of segment mismatch and its underlying mechanisms remain incomplete. Here, we summarize current knowledge regarding segment mismatch and discuss the implications of this phenomenon for IAV reassortment and diversity. PMID:29244017

UGT2B17 minor histocompatibility mismatch and clinical outcome after HLA-identical sibling donor stem cell transplantation.

PubMed

Santos, N; Rodríguez-Romanos, R; Nieto, J B; Buño, I; Vallejo, C; Jiménez-Velasco, A; Brunet, S; Buces, E; López-Jiménez, J; González, M; Ferrá, C; Sampol, A; de la Cámara, R; Martínez, C; Gallardo, D

2016-01-01

Minor histocompatibility Ags (mHags) have been implicated in the pathogenesis of GVHD after allogeneic hematopoietic stem cell transplantation (HSCT). Uridine diphospho-glucuronosyltransferase 2B17 (UGT2B17) gene deletion may act as a mHag and its association with acute GVHD (aGVHD) has been described. We retrospectively studied the clinical impact of a UGT2B17 mismatch in a cohort of 1127 patients receiving a HSCT from an HLA-identical sibling donor. UGT2B17 mismatch was present in 69 cases (6.1%). Incidence of severe aGVHD was higher in the UGT2B17 mismatched pairs (22.7% vs 14.6%), but this difference was not statistically significant (P: 0.098). We did not detect differences in chronic GVHD, overall survival, relapse-free survival, transplant-related mortality or relapse. Nevertheless, when we analyzed only those patients receiving grafts from a male donor (616 cases), aGVHD was significantly higher in the UGT2B17 mismatched group (25.1% vs 12.8%; P: 0.005) and this association was confirmed by the multivariate analysis (P: 0.043; hazard ratio: 2.16, 95% confidence interval: 1.03-4.57). Overall survival was worse for patients mismatched for UGT2B17 (P: 0.005). We conclude that UGT2B17 mismatch has a negative clinical impact in allogeneic HSCT from HLA-identical sibling donors only when a male donor is used. These results should be confirmed by other studies.

Comparative reactivity of mismatched and unpaired bases in relation to their type and surroundings. Chemical cleavage of DNA mismatches in mutation detection analysis.

PubMed

Yakubovskaya, Marianna G; Belyakova, Anna A; Gasanova, Viktoria K; Belitsky, Gennady A; Dolinnaya, Nina G

2010-07-01

Systematic study of chemical reactivity of non-Watson-Crick base pairs depending on their type and microenvironment was performed on a model system that represents two sets of synthetic DNA duplexes with all types of mismatched and unmatched bases flanked by T.A or G.C pairs. Using comparative cleavage pattern analysis, we identified the main and additional target bases and performed quantitative study of the time course and efficacy of DNA modification caused by potassium permanganate or hydroxylamine. Potassium permanganate in combination with tetraethylammonium chloride was shown to induce DNA cleavage at all mismatched or bulged T residues, as well as at thymines of neighboring canonical pairs. Other mispaired (bulged) bases and thymine residues located on the second position from the mismatch site were not the targets for KMnO(4) attack. In contrast, hydroxylamine cleaved only heteroduplexes containing mismatched or unmatched C residues, and did not modify adjacent cytosines. However when G.C pairs flank bulged C residue, neighboring cytosines are also attacked by hydroxylamine due to defect migration. Chemical reactivity of target bases was shown to correlate strongly with the local disturbance of DNA double helix at mismatch or bulge site. With our model system, we were able to prove the absence of false-negative and false-positive results. Portion of heteroduplex reliably revealed in a mixture with corresponding homoduplex consists of 5% for bulge bases and "open" non-canonical pairs, and 10% for wobble base pairs giving minimal violations in DNA structure. This study provides a complete understanding of the principles of mutation detection methodology based on chemical cleavage of mismatches and clarifies the advantages and limitations of this approach in various biological and conformational studies of DNA. Copyright 2010 Elsevier Masson SAS. All rights reserved.

A multicenter, open-label trial to evaluate the quality of life in adults with ADHD treated with long-acting methylphenidate (OROS MPH): Concerta Quality of Life (CONQoL) study.

PubMed

Mattos, Paulo; Louzã, Mário Rodrigues; Palmini, André Luís Fernandes; de Oliveira, Irismar Reis; Rocha, Fábio Lopes

2013-07-01

The available literature provides few studies on the effectiveness of methylphenidate in improving quality of life in individuals with ADHD. To assess the effectiveness of methylphenidate OROS formulation (OROS MPH) through QoL in adults with ADHD. A 12-week, multicenter, open-label trial involving 60 patients was used. The measures used were Adult Self-Rating Scale, Adult ADHD Quality of Life Scale (AAQoL), State and Trait Anxiety Inventory (STAI), Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression (CGI), and safety measures. A significance statistic level of 5% was adopted. Analyses included 60 patients (66.7% male; M age = 31.1 years) for safety and 58 patients for effectiveness. All AAQoL subscales improved from baseline to Week 12 (p < .0001), as well as the Total AAQoL (p < .0001). A significant reduction on Clinical Global Impression-Improvement (CGI-I), HAM-D, STAI, and ASRS scores was observed (p < .0001). No serious adverse event was reported. Treatment of adult ADHD patients with OROS MPH improves QoL.

Clinical Management and Tumor Surveillance Recommendations of Inherited Mismatch Repair Deficiency in Childhood.

PubMed

Tabori, Uri; Hansford, Jordan R; Achatz, Maria Isabel; Kratz, Christian P; Plon, Sharon E; Frebourg, Thierry; Brugières, Laurence

2017-06-01

Replication proofreading is crucial to avoid mutation accumulation in dividing cells. In humans, proofreading and replication repair is maintained by the exonuclease domains of DNA polymerases and the mismatch repair system. Individuals harboring germline mutations in genes involved in this process are at increased risk of early cancers from multiple organs. Biallelic mutations in any of the four mismatch repair genes MSH2, MSH6, MLH1 , and PMS2 result in one of the most aggressive childhood cancer predisposition syndromes, termed constitutional mismatch repair deficiency or constitutional mismatch repair deficiency syndrome (CMMRD). Data gathered in the last decade allow us to better define the clinical manifestations, tumor spectrum, and diagnostic algorithms for CMMRD. In this article, we summarize this information and present a comprehensive consensus surveillance protocol for these individuals. Ongoing research will allow for further definition of replication repair-deficient cancer syndromes, assessing the cost-effectiveness of such surveillance protocols and potential therapeutic interventions for these children and families. Clin Cancer Res; 23(11); e32-e37. ©2017 AACR See all articles in the online-only CCR Pediatric Oncology Series. ©2017 American Association for Cancer Research.

North American X-15 model tested in 300MPH Low Speed 7x10 Tunnel

NASA Image and Video Library

1958-09-07

A one-twentieth scale model of the X-15 originally suspended beneath the wing of a B-52 is observed by a scientist of the National Aeronautics and Space Administration (NASA) as it leaves the bomber model in tests to determine the release characteristics and drop motion of the research airplane. Caption: The aerodynamics of air launching the North American X-15 being investigated in the 300MPH Low Speed 7x10 Tunnel, about 1957. Photograph published in Engineer in Charge: A History of the Langley Aeronautical Laboratory, 1917-1958 by James R. Hansen. Page 366. Photograph also published in Sixty Years of Aeronautical Research 1917-1977 By David A. Anderton. A NASA publication. Page 49.

Frequency-response mismatch effects in Johnson noise thermometry

NASA Astrophysics Data System (ADS)

White, D. R.; Qu, J.-F.

2018-02-01

Johnson noise thermometry is of considerable interest at present due to the planned redefinition of the kelvin in 2019, and several determinations of the Boltzmann constant have recently been published in support of the redefinition. To determine the Boltzmann constant by noise thermometry, the thermal noise from a sensing resistor at the triple point of water is compared to a pseudo-random noise with a calculable power spectral density traceable to quantum electrical standards. In all the measurements to date, the two dominant sources of measurement uncertainty are strongly influenced by a single factor: the frequency-response mismatch between the sets of leads connecting the thermometer to the two noise sources. In the most recent determination at the National Institute of Metrology, China, substantial changes were made to the connecting leads to reduce the mismatch effects. The aims of this paper are, firstly, to describe and explain the rationale for the changes, and secondly, to better understand the effects of the least-squares fits and the bias-variance compromise in the analysis of measurements affected by the mismatch effects. While significant improvements can be made to the connecting leads to lessen the effects of the frequency-response mismatch, the efforts are unlikely to be rewarded by a significant increase in bandwidth or a significant reduction in uncertainty.

KENNEDY SPACE CENTER, FLA. - Like candles embedded in a sculptured “cake,” the Mobile Launcher Platform (MLP) number 3 with twin solid rocket boosters bolted to it inches along the crawlerway at various speeds up to 1 mph in an effort to achieve vibration data gathering goals. The boosters are braced at the top for stability. The primary purpose of these rollout tests is to gather data to develop future maintenance requirements on the transport equipment and the flight hardware. Various parts of the MLP and crawler transporter have been instrumented with vibration data collection equipment.

NASA Image and Video Library

2003-11-21

KENNEDY SPACE CENTER, FLA. - Like candles embedded in a sculptured “cake,” the Mobile Launcher Platform (MLP) number 3 with twin solid rocket boosters bolted to it inches along the crawlerway at various speeds up to 1 mph in an effort to achieve vibration data gathering goals. The boosters are braced at the top for stability. The primary purpose of these rollout tests is to gather data to develop future maintenance requirements on the transport equipment and the flight hardware. Various parts of the MLP and crawler transporter have been instrumented with vibration data collection equipment.

Warthin tumors do not have microsatellite instability and express normal DNA mismatch repair proteins.

PubMed

Hunt, Jennifer L

2006-01-01

Warthin tumors are controversial entities with a poorly understood etiology. Although some investigators have suggested a neoplastic origin, others have supported a developmental anomaly. A recent study described the absence of staining for hMLH1 and hMSH2 proteins in the epithelial component of Warthin tumors, suggesting that they arise secondary to defects in the DNA mismatch repair system. To determine if Warthin tumors exhibit evidence of DNA mismatch repair defects. Immunostains for hMLH1 and hMSH2 were performed using a standard approach. Microdissection of the epithelial component was followed by DNA extraction from the tissue fragments. Polymerase chain reaction and capillary electrophoresis analyses were performed for the following 5 National Cancer Institute-recommended microsatellites: D2s123, D5s346, D17s250, BAT25, and BAT26. Twelve patients with Warthin tumors were included. The immunostains for hMLH1 and hMSH2 showed preserved expression in the nuclei of the epithelial component of all Warthin tumors. No microsatellite instability was detected, and no loss of heterozygosity was seen. These results are not concordant with previously reported results showing loss of expression of the hMLH1 and hMSH2 DNA mismatch repair enzymes in the epithelial component of Warthin tumors. Furthermore, no microsatellite instability was detected in the 5 loci tested for each tumor in this series. These data demonstrate that Warthin tumors do not have evidence of DNA mismatch repair defects at the genomic or protein expression level.

The effect of 1/f fluctuation in inter-stimulus intervals on auditory evoked mismatch field.

PubMed

Harada, Nobuyoshi; Masuda, Tadashi; Endo, Hiroshi; Nakamura, Yukihiro; Takeda, Tsunehiro; Tonoike, Mitsuo

2005-05-13

This study focused on the effect of regularity of environmental stimuli on the informational order extracting function of human brain. The regularity of environmental stimuli can be described with the exponent n of the fluctuation 1/f(n). We studied the effect of the exponent of the fluctuation in the inter-stimulus interval (ISI) on the elicitation of auditory evoked mismatch fields (MMF) with two sounds with alternating frequency. ISI times were given by three types of fluctuation, 1/f(0), 1/f(1), 1/f(2), and with a fixed interval (1/f(infinity)). The root mean square (RMS) value of the MMF increased significantly (F(3/9)=4.95, p=0.027) with increases in the exponent of the fluctuation. Increments in the regularity of the fluctuation provoked enhancement of the MMF, which reflected the production of a memory trace, based on the anticipation of the stimulus timing. The gradient of the curve, indicating the ratio of increments between the MMF and the exponent of fluctuation, can express a subject's capability to extract regularity from fluctuating stimuli.

Donor/recipient sex mismatch and survival after heart transplantation: only an issue in male recipients? An analysis of the Spanish Heart Transplantation Registry.

PubMed

Martinez-Selles, Manuel; Almenar, Luis; Paniagua-Martin, Maria J; Segovia, Javier; Delgado, Juan F; Arizón, Jose M; Ayesta, Ana; Lage, Ernesto; Brossa, Vicens; Manito, Nicolás; Pérez-Villa, Félix; Diaz-Molina, Beatriz; Rábago, Gregorio; Blasco-Peiró, Teresa; De La Fuente Galán, Luis; Pascual-Figal, Domingo; Gonzalez-Vilchez, Francisco

2015-03-01

The results of studies on the association between sex mismatch and survival after heart transplantation are conflicting. Data from the Spanish Heart Transplantation Registry. From 4625 recipients, 3707 (80%) were men. The donor was female in 943 male recipients (25%) and male in 481 female recipients (52%). Recipients of male hearts had a higher body mass index (25.9 ± 4.1 vs. 24.3 ± 3.7; P < 0.01), and male donors were younger than female donors (33.4 ± 12.7 vs. 38.2 ± 12.3; P < 0.01). No further relevant differences related to donor sex were detected. In the univariate analysis, mismatch was associated with mortality in men (hazard ratio [HR], 1.18; 95% confidence interval [CI], 1.06-1.32; P = 0.003) but not in women (HR, 0.91; 95% CI 0.74-1.12; P = 0.4). A significant interaction was detected between sex mismatch and recipient gender (P = 0.02). In the multivariate analysis, sex mismatch was associated with long-term mortality (HR, 1.14; 95% CI 1.01-1.29; P = 0.04), and there was a tendency toward significance for the interaction between sex mismatch and recipient gender (P = 0.08). In male recipients, mismatch increased mortality mainly during the first month and in patients with pulmonary gradient >13 mmHg. Sex mismatch seems to be associated with mortality after heart transplantation in men but not in women. © 2014 Steunstichting ESOT.

An Inducible, Isogenic Cancer Cell Line System for Targeting the State of Mismatch Repair Deficiency

PubMed Central

Bailis, Julie M.; Gordon, Marcia L.; Gurgel, Jesse L.; Komor, Alexis C.; Barton, Jacqueline K.; Kirsch, Ilan R.

2013-01-01

The DNA mismatch repair system (MMR) maintains genome stability through recognition and repair of single-base mismatches and small insertion-deletion loops. Inactivation of the MMR pathway causes microsatellite instability and the accumulation of genomic mutations that can cause or contribute to cancer. In fact, 10-20% of certain solid and hematologic cancers are MMR-deficient. MMR-deficient cancers do not respond to some standard of care chemotherapeutics because of presumed increased tolerance of DNA damage, highlighting the need for novel therapeutic drugs. Toward this goal, we generated isogenic cancer cell lines for direct comparison of MMR-proficient and MMR-deficient cells. We engineered NCI-H23 lung adenocarcinoma cells to contain a doxycycline-inducible shRNA designed to suppress the expression of the mismatch repair gene MLH1, and compared single cell subclones that were uninduced (MLH1-proficient) versus induced for the MLH1 shRNA (MLH1-deficient). Here we present the characterization of these MMR-inducible cell lines and validate a novel class of rhodium metalloinsertor compounds that differentially inhibit the proliferation of MMR-deficient cancer cells. PMID:24205301

Characterization of Arabidopsis thaliana mismatch specific endonucleases: application to mutation discovery by TILLING in pea.

PubMed

Triques, Karine; Sturbois, Bénédicte; Gallais, Stéphane; Dalmais, Marion; Chauvin, Stéphanie; Clepet, Christian; Aubourg, Sébastien; Rameau, Catherine; Caboche, Michel; Bendahmane, Abdelhafid

2007-09-01

Scanning DNA sequences for mutations and polymorphisms has become one of the most challenging, often expensive and time-consuming obstacles in many molecular genetic applications, including reverse genetic and clinical diagnostic applications. Enzymatic mutation detection methods are based on the cleavage of heteroduplex DNA at the mismatch sites. These methods are often limited by the availability of a mismatch-specific endonuclease, their sensitivity in detecting one allele in a pool of DNA and their costs. Here, we present detailed biochemical analysis of five Arabidopsis putative mismatch-specific endonucleases. One of them, ENDO1, is presented as the first endonuclease that recognizes and cleaves all types of mismatches with high efficiency. We report on a very simple protocol for the expression and purification of ENDO1. The ENDO1 system could be exploited in a wide range of mutation diagnostic tools. In particular, we report the use of ENDO1 for discovery of point mutations in the gibberellin 3beta-hydrolase gene of Pisum sativum. Twenty-one independent mutants were isolated, five of these were characterized and two new mutations affecting internodes length were identified. To further evaluate the quality of the mutant population we screened for mutations in four other genes and identified 5-21 new alleles per target. Based on the frequency of the obtained alleles we concluded that the pea population described here would be suitable for use in a large reverse-genetics project.

The DNA mismatch repair genes Msh3 and Msh6 cooperate in intestinal tumor suppression.

PubMed

Edelmann, W; Umar, A; Yang, K; Heyer, J; Kucherlapati, M; Lia, M; Kneitz, B; Avdievich, E; Fan, K; Wong, E; Crouse, G; Kunkel, T; Lipkin, M; Kolodner, R D; Kucherlapati, R

2000-02-15

Repair of mismatches in DNA in mammalian cells is mediated by a complex of proteins that are members of two highly conserved families of genes referred to as MutS and MutL homologues. Germline mutations in several members of these families, MSH2, MSH6, MLH1, and PMS2, but not MSH3, are responsible for hereditary non-polyposis colorectal cancer. To examine the role of MSH3, we generated a mouse with a null mutation in this gene. Cells from Msh3-/- mice are defective in repair of insertion/ deletion mismatches but can repair base-base mismatches. Msh3-/- mice develop tumors at a late age. When the Msh3-/- and Msh6-/- mutations are combined, the tumor predisposition phenotype is indistinguishable from Msh2-/- or Mlh1-/- mice. These results suggest that MSH3 cooperates with MSH6 in tumor suppression.

Mismatch Repair Balances Leading and Lagging Strand DNA Replication Fidelity

DTIC Science & Technology

2012-10-11

mismatched base stacks with a conserved phenylalanine in Msh6, and/or (iii) DNA flexibility, since MutSa-bound mismatched DNA is kinked, and a...AB, Watt DL , Watts BE, et al. (2010) Genome instability due to ribonucleotide incorporation into DNA. Nat Chem Biol 6: 774–781. 24. Poloumienko A

Mismatch Responses to Lexical Tone, Initial Consonant, and Vowel in Mandarin-Speaking Preschoolers

ERIC Educational Resources Information Center

Lee, Chia-Ying; Yen, Huei-ling; Yeh, Pei-wen; Lin, Wan-Hsuan; Cheng, Ying-Ying; Tzeng, Yu-Lin; Wu, Hsin-Chi

2012-01-01

The present study investigates how age, phonological saliency, and deviance size affect the presence of mismatch negativity (MMN) and positive mismatch response (P-MMR). This work measured the auditory mismatch responses to Mandarin lexical tones, initial consonants, and vowels in 4- to 6-year-old preschoolers using the multiple-deviant oddball…

Higher Rate of Revision in PFC Sigma Primary Total Knee Arthroplasty With Mismatch of Femoro-Tibial Component Sizes.

PubMed

Young, Simon W; Clarke, Henry D; Graves, Stephen E; Liu, Yen-Liang; de Steiger, Richard N

2015-05-01

Total knee arthroplasty (TKA) systems permit a degree of femoro-tibial component size mismatch. The effect of mismatched components on revision rates has not been evaluated in a large study. We reviewed 21,906 fixed-bearing PFC Sigma primary TKAs using the Australian Orthopaedic Association National Joint Replacement Registry, dividing patients into three groups: no femoro-tibial size mismatch, tibial component size > femoral component size, and femoral component > tibial component. Revision rates were higher when the femoral size was greater than the tibia, compared to both equal size (HR = 1.20 (1.00, 1.45), P = 0.047) and to tibial size greater than femoral (HR = 1.60 (1.08, 2.37), P = 0.019). Potential mechanisms to explain these findings include edge loading of polyethylene and increased tibial component stresses. Copyright © 2014 Elsevier Inc. All rights reserved.

Using medication list--problem list mismatches as markers of potential error.

PubMed Central

Carpenter, James D.; Gorman, Paul N.

2002-01-01

The goal of this project was to specify and develop an algorithm that will check for drug and problem list mismatches in an electronic medical record (EMR). The algorithm is based on the premise that a patient's problem list and medication list should agree, and a mismatch may indicate medication error. Successful development of this algorithm could mean detection of some errors, such as medication orders entered into a wrong patient record, or drug therapy omissions, that are not otherwise detected via automated means. Additionally, mismatches may identify opportunities to improve problem list integrity. To assess the concept's feasibility, this study compared medications listed in a pharmacy information system with findings in an online nursing adult admission assessment, serving as a proxy for the problem list. Where drug and problem list mismatches were discovered, examination of the patient record confirmed the mismatch, and identified any potential causes. Evaluation of the algorithm in diabetes treatment indicates that it successfully detects both potential medication error and opportunities to improve problem list completeness. This algorithm, once fully developed and deployed, could prove a valuable way to improve the patient problem list, and could decrease the risk of medication error. PMID:12463796

Penalized or Protected? Gender and the Consequences of Nonstandard and Mismatched Employment Histories

PubMed Central

Pedulla, David S.

2016-01-01

Millions of workers are employed in positions that deviate from the full-time, standard employment relationship or work in jobs that are mismatched with their skills, education, or experience. Yet, little is known about how employers evaluate workers who have experienced these employment arrangements, limiting our knowledge about how part-time work, temporary agency employment, and skills underutilization affect workers’ labor market opportunities. Drawing on original field and survey experiment data, I examine three questions: (1) What are the consequences of having a nonstandard or mismatched employment history for workers’ labor market opportunities? (2) Are the effects of nonstandard or mismatched employment histories different for men and women? and (3) What are the mechanisms linking nonstandard or mismatched employment histories to labor market outcomes? The field experiment shows that skills underutilization is as scarring for workers as a year of unemployment, but that there are limited penalties for workers with histories of temporary agency employment. Additionally, although men are penalized for part-time employment histories, women face no penalty for part-time work. The survey experiment reveals that employers’ perceptions of workers’ competence and commitment mediate these effects. These findings shed light on the consequences of changing employment relations for the distribution of labor market opportunities in the “new economy.” PMID:27182069

A Direct Adaptive Control Approach in the Presence of Model Mismatch

NASA Technical Reports Server (NTRS)

Joshi, Suresh M.; Tao, Gang; Khong, Thuan

2009-01-01

This paper considers the problem of direct model reference adaptive control when the plant-model matching conditions are violated due to abnormal changes in the plant or incorrect knowledge of the plant's mathematical structure. The approach consists of direct adaptation of state feedback gains for state tracking, and simultaneous estimation of the plant-model mismatch. Because of the mismatch, the plant can no longer track the state of the original reference model, but may be able to track a new reference model that still provides satisfactory performance. The reference model is updated if the estimated plant-model mismatch exceeds a bound that is determined via robust stability and/or performance criteria. The resulting controller is a hybrid direct-indirect adaptive controller that offers asymptotic state tracking in the presence of plant-model mismatch as well as parameter deviations.

HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions.

PubMed

de Wind, N; Dekker, M; Claij, N; Jansen, L; van Klink, Y; Radman, M; Riggins, G; van der Valk, M; van't Wout, K; te Riele, H

1999-11-01

Cancer predisposition in hereditary non-polyposis colon cancer (HNPCC) is caused by defects in DNA mismatch repair (MMR). Mismatch recognition is attributed to two heterodimeric protein complexes: MutSalpha (refs 2, 3, 4, 5), a dimer of MutS homologues MSH2 and MSH6; and MutSbeta (refs 2,7), a dimer of MSH2 and MSH3. These complexes have specific and redundant mismatch recognition capacity. Whereas MSH2 deficiency ablates the activity of both dimers, causing strong cancer predisposition in mice and men, loss of MSH3 or MSH6 (also known as GTBP) function causes a partial MMR defect. This may explain the rarity of MSH6 and absence of MSH3 germline mutations in HNPCC families. To test this, we have inactivated the mouse genes Msh3 (formerly Rep3 ) and Msh6 (formerly Gtmbp). Msh6-deficient mice were prone to cancer; most animals developed lymphomas or epithelial tumours originating from the skin and uterus but only rarely from the intestine. Msh3 deficiency did not cause cancer predisposition, but in an Msh6 -deficient background, loss of Msh3 accelerated intestinal tumorigenesis. Lymphomagenesis was not affected. Furthermore, mismatch-directed anti-recombination and sensitivity to methylating agents required Msh2 and Msh6, but not Msh3. Thus, loss of MMR functions specific to Msh2/Msh6 is sufficient for lymphoma development in mice, whereas predisposition to intestinal cancer requires loss of function of both Msh2/Msh6 and Msh2/Msh3.

BRCA2, EGFR, and NTRK mutations in mismatch repair-deficient colorectal cancers with MSH2 or MLH1 mutations.

PubMed

Deihimi, Safoora; Lev, Avital; Slifker, Michael; Shagisultanova, Elena; Xu, Qifang; Jung, Kyungsuk; Vijayvergia, Namrata; Ross, Eric A; Xiu, Joanne; Swensen, Jeffrey; Gatalica, Zoran; Andrake, Mark; Dunbrack, Roland L; El-Deiry, Wafik S

2017-06-20

Deficient mismatch repair (MMR) and microsatellite instability (MSI) contribute to ~15% of colorectal cancer (CRCs). We hypothesized MSI leads to mutations in DNA repair proteins including BRCA2 and cancer drivers including EGFR. We analyzed mutations among a discovery cohort of 26 MSI-High (MSI-H) and 558 non-MSI-H CRCs profiled at Caris Life Sciences. Caris-profiled MSI-H CRCs had high mutation rates (50% vs 14% in non-MSI-H, P < 0.0001) in BRCA2. Of 1104 profiled CRCs from a second cohort (COSMIC), MSH2/MLH1-mutant CRCs showed higher mutation rates in BRCA2 compared to non-MSH2/MLH1-mutant tumors (38% vs 6%, P < 0.0000001). BRCA2 mutations in MSH2/MLH1-mutant CRCs included 75 unique mutations not known to occur in breast or pancreatic cancer per COSMIC v73. Only 5 deleterious BRCA2 mutations in CRC were previously reported in the BIC database as germ-line mutations in breast cancer. Some BRCA2 mutations were predicted to disrupt interactions with partner proteins DSS1 and RAD51. Some CRCs harbored multiple BRCA2 mutations. EGFR was mutated in 45.5% of MSH2/MLH1-mutant and 6.5% of non-MSH2/MLH1-mutant tumors (P < 0.0000001). Approximately 15% of EGFR mutations found may be actionable through TKI therapy, including N700D, G719D, T725M, T790M, and E884K. NTRK gene mutations were identified in MSH2/MLH1-mutant CRC including NTRK1 I699V, NTRK2 P716S, and NTRK3 R745L. Our findings have clinical relevance regarding therapeutic targeting of BRCA2 vulnerabilities, EGFR mutations or other identified oncogenic drivers such as NTRK in MSH2/MLH1-mutant CRCs or other tumors with mismatch repair deficiency.

78 FR 12063 - Announcement of Requirements and Registration for healthfinder.gov Mobile App Challenge; Correction

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-21

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Announcement of Requirements and Registration for..., Office of the Assistant Secretary for Health, Office of the Secretary, Department of Health and Human... subsection of the terms and conditions. FOR FURTHER INFORMATION CONTACT: Silje Lier, MPH, Communication...

Hydrophobic mismatch sorts SNARE proteins into distinct membrane domains

PubMed Central

Milovanovic, Dragomir; Honigmann, Alf; Koike, Seiichi; Göttfert, Fabian; Pähler, Gesa; Junius, Meike; Müllar, Stefan; Diederichsen, Ulf; Janshoff, Andreas; Grubmüller, Helmut; Risselada, Herre J.; Eggeling, Christian; Hell, Stefan W.; van den Bogaart, Geert; Jahn, Reinhard

2015-01-01

The clustering of proteins and lipids in distinct microdomains is emerging as an important principle for the spatial patterning of biological membranes. Such domain formation can be the result of hydrophobic and ionic interactions with membrane lipids as well as of specific protein–protein interactions. Here using plasma membrane-resident SNARE proteins as model, we show that hydrophobic mismatch between the length of transmembrane domains (TMDs) and the thickness of the lipid membrane suffices to induce clustering of proteins. Even when the TMDs differ in length by only a single residue, hydrophobic mismatch can segregate structurally closely homologous membrane proteins in distinct membrane domains. Domain formation is further fine-tuned by interactions with polyanionic phosphoinositides and homo and heterotypic protein interactions. Our findings demonstrate that hydrophobic mismatch contributes to the structural organization of membranes. PMID:25635869

49 CFR 581.5 - Requirements.

Code of Federal Regulations, 2014 CFR

2014-10-01

... the damage criteria of §§ 581.5(c)(1) through 581.5(c)(9) when impacted by a pendulum-type test device... of 1.5 m.p.h., and when impacted by a pendulum-type test device in accordance with the procedures of... original contours 30 minutes after completion of each pendulum and barrier impact, except where such damage...

49 CFR 581.5 - Requirements.

Code of Federal Regulations, 2011 CFR

2011-10-01

... the damage criteria of §§ 581.5(c)(1) through 581.5(c)(9) when impacted by a pendulum-type test device... of 1.5 m.p.h., and when impacted by a pendulum-type test device in accordance with the procedures of... original contours 30 minutes after completion of each pendulum and barrier impact, except where such damage...

49 CFR 581.5 - Requirements.

Code of Federal Regulations, 2012 CFR

2012-10-01

... the damage criteria of §§ 581.5(c)(1) through 581.5(c)(9) when impacted by a pendulum-type test device... of 1.5 m.p.h., and when impacted by a pendulum-type test device in accordance with the procedures of... original contours 30 minutes after completion of each pendulum and barrier impact, except where such damage...

49 CFR 581.5 - Requirements.

Code of Federal Regulations, 2010 CFR

2010-10-01

... the damage criteria of §§ 581.5(c)(1) through 581.5(c)(9) when impacted by a pendulum-type test device... of 1.5 m.p.h., and when impacted by a pendulum-type test device in accordance with the procedures of... original contours 30 minutes after completion of each pendulum and barrier impact, except where such damage...

49 CFR 581.5 - Requirements.

Code of Federal Regulations, 2013 CFR

2013-10-01

... the damage criteria of §§ 581.5(c)(1) through 581.5(c)(9) when impacted by a pendulum-type test device... of 1.5 m.p.h., and when impacted by a pendulum-type test device in accordance with the procedures of... original contours 30 minutes after completion of each pendulum and barrier impact, except where such damage...

Robust image matching via ORB feature and VFC for mismatch removal

NASA Astrophysics Data System (ADS)

Ma, Tao; Fu, Wenxing; Fang, Bin; Hu, Fangyu; Quan, Siwen; Ma, Jie

2018-03-01

Image matching is at the base of many image processing and computer vision problems, such as object recognition or structure from motion. Current methods rely on good feature descriptors and mismatch removal strategies for detection and matching. In this paper, we proposed a robust image match approach based on ORB feature and VFC for mismatch removal. ORB (Oriented FAST and Rotated BRIEF) is an outstanding feature, it has the same performance as SIFT with lower cost. VFC (Vector Field Consensus) is a state-of-the-art mismatch removing method. The experiment results demonstrate that our method is efficient and robust.

Who Is Ahead in the Labor Queue? Institutions' and Employers' Perspective on Overeducation, Undereducation, and Horizontal Mismatches

ERIC Educational Resources Information Center

Di Stasio, Valentina

2017-01-01

Using vignettes, this study compares employers' assessments of matched and mismatched job applicants in England and the Netherlands. It contributes to the overeducation literature in several ways. First, matching is measured from the perspective of employers, who are better informed about job requirements than employees. Second, overeducated…

Pms2 and uracil-DNA glycosylases act jointly in the mismatch repair pathway to generate Ig gene mutations at A-T base pairs.

PubMed

Girelli Zubani, Giulia; Zivojnovic, Marija; De Smet, Annie; Albagli-Curiel, Olivier; Huetz, François; Weill, Jean-Claude; Reynaud, Claude-Agnès; Storck, Sébastien

2017-04-03

During somatic hypermutation (SHM) of immunoglobulin genes, uracils introduced by activation-induced cytidine deaminase are processed by uracil-DNA glycosylase (UNG) and mismatch repair (MMR) pathways to generate mutations at G-C and A-T base pairs, respectively. Paradoxically, the MMR-nicking complex Pms2/Mlh1 is apparently dispensable for A-T mutagenesis. Thus, how detection of U:G mismatches is translated into the single-strand nick required for error-prone synthesis is an open question. One model proposed that UNG could cooperate with MMR by excising a second uracil in the vicinity of the U:G mismatch, but it failed to explain the low impact of UNG inactivation on A-T mutagenesis. In this study, we show that uracils generated in the G1 phase in B cells can generate equal proportions of A-T and G-C mutations, which suggests that UNG and MMR can operate within the same time frame during SHM. Furthermore, we show that Ung -/- Pms2 -/- mice display a 50% reduction in mutations at A-T base pairs and that most remaining mutations at A-T bases depend on two additional uracil glycosylases, thymine-DNA glycosylase and SMUG1. These results demonstrate that Pms2/Mlh1 and multiple uracil glycosylases act jointly, each one with a distinct strand bias, to enlarge the immunoglobulin gene mutation spectrum from G-C to A-T bases. © 2017 Girelli Zubani et al.

Pms2 and uracil-DNA glycosylases act jointly in the mismatch repair pathway to generate Ig gene mutations at A-T base pairs

PubMed Central

De Smet, Annie; Albagli-Curiel, Olivier; Huetz, François; Weill, Jean-Claude

2017-01-01

During somatic hypermutation (SHM) of immunoglobulin genes, uracils introduced by activation-induced cytidine deaminase are processed by uracil-DNA glycosylase (UNG) and mismatch repair (MMR) pathways to generate mutations at G-C and A-T base pairs, respectively. Paradoxically, the MMR-nicking complex Pms2/Mlh1 is apparently dispensable for A-T mutagenesis. Thus, how detection of U:G mismatches is translated into the single-strand nick required for error-prone synthesis is an open question. One model proposed that UNG could cooperate with MMR by excising a second uracil in the vicinity of the U:G mismatch, but it failed to explain the low impact of UNG inactivation on A-T mutagenesis. In this study, we show that uracils generated in the G1 phase in B cells can generate equal proportions of A-T and G-C mutations, which suggests that UNG and MMR can operate within the same time frame during SHM. Furthermore, we show that Ung−/−Pms2−/− mice display a 50% reduction in mutations at A-T base pairs and that most remaining mutations at A-T bases depend on two additional uracil glycosylases, thymine-DNA glycosylase and SMUG1. These results demonstrate that Pms2/Mlh1 and multiple uracil glycosylases act jointly, each one with a distinct strand bias, to enlarge the immunoglobulin gene mutation spectrum from G-C to A-T bases. PMID:28283534

Large lattice mismatch effects on the epitaxial growth and magnetic properties of FePt films

NASA Astrophysics Data System (ADS)

Deng, Jinyu; Dong, Kaifeng; Yang, Ping; Peng, Yingguo; Ju, Ganping; Hu, Jiangfeng; Chow, Gan Moog; Chen, Jingsheng

2018-01-01

Heteroepitaxial film growth is crucial for magnetic and electronic devices. In this work, we reported the effects of the large lattice mismatch and film thickness on the epitaxial growth and magnetic properties of FePt films on ZrxTi1-xN (0 0 1) intermediate layer. FePt films with different thickness were deposited on ZrTiN intermediate layers with various doping concentration of TiN in ZrN. The increase in doping concentration of TiN caused a decrease in the lattice parameters of ZrTiN intermediate layer. It was found that (0 0 1) epitaxy of FePt 10 nm films was only achieved on ZrTiN intermediate layer when the TiN composition was ≥25 vol%, while (0 0 1) texture of 5 nm films was achieved on ZrTiN intermediate layer with a minimum of 50 vol% TiN composition. The in-plane lattice constants of FePt and Zr0.70Ti0.30N (25 vol% TiN) were 3.870 Å and 4.476 Å, respectively, which resulted in a lattice mismatch as large as 15.7%. These large lattice mismatch heterostructures adopted 7/6 domain matching epitaxy. The magneto-crystalline anisotropy of FePt films was improved with the increase in lattice mismatch. Intrinsic magnetic properties were extrapolated for FePt (30 nm)/Zr0.70Ti0.30N (30 nm)/TaN (30 nm)/MgO, and the Ms(0 K) and K1(0 K) were 1042 emu/cc and 5.10 × 107 erg/cc, respectively, which is comparable to that of bulk L10 FePt.

Are Educational Mismatches Responsible for the "Inequality Increasing Effect" of Education?

ERIC Educational Resources Information Center

Budria, Santiago

2011-01-01

This paper asks whether educational mismatches can account for the positive association between education and wage inequality found in the data. We use two different data sources, the European Community Household Panel and the Portuguese Labour Force Survey, and consider several types of mismatch, including overqualification, underqualification…

The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts 2: Living Donors, Summary, Guide

PubMed Central

Williams, Robert C.; Opelz, Gerhard; Weil, E. Jennifer; McGarvey, Chelsea J.; Chakkera, Harini A.

2017-01-01

Background Allografts from living donors survive longer than those from deceased donors but the role of HLA mismatching in living kidney donation is still in question. We examined the effect of HLA compatibility on kidney allograft survival from living donors by studying all first adult kidney transplants performed in the United States over 25 years. Methods Using the United Network for Organ Sharing data, we identified first kidney transplants between October 1, 1987, and December 31, 2013. Recipients were classified by their number of HLA mismatches and stratified by donor origin. Cox multivariate regression analyses adjusting for recipient and donor transplant characteristics were performed to determine impact of HLA compatibility on kidney allograft survival for all living donors and for living related and living unrelated subsets. Results There were 66 596 first adult transplants from living donors with 348 960 years of follow-up. We found a linear relationship between HLA mismatch and allograft survival. In adjusted analyses, among all living donors, 1 mismatch conferred a 44% higher risk, whereas 6 mismatches conferred a twofold higher risk of allograft failure. When using 0-mismatched full siblings as a reference, living-donor kidneys reduce the hazard of failure by approximately 34% when compared with deceased donors. Twenty-five years of transplant experience, stratified by donor source, was summarized and presented as a guide for allocation. Conclusions These data reinforce the importance of optimizing HLA matching to further improve survival in first adult kidney allografts in the future, especially in living unrelated donations, when possible. PMID:28573187

The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts 2: Living Donors, Summary, Guide.

PubMed

Williams, Robert C; Opelz, Gerhard; Weil, E Jennifer; McGarvey, Chelsea J; Chakkera, Harini A

2017-05-01

Allografts from living donors survive longer than those from deceased donors but the role of HLA mismatching in living kidney donation is still in question. We examined the effect of HLA compatibility on kidney allograft survival from living donors by studying all first adult kidney transplants performed in the United States over 25 years. Using the United Network for Organ Sharing data, we identified first kidney transplants between October 1, 1987, and December 31, 2013. Recipients were classified by their number of HLA mismatches and stratified by donor origin. Cox multivariate regression analyses adjusting for recipient and donor transplant characteristics were performed to determine impact of HLA compatibility on kidney allograft survival for all living donors and for living related and living unrelated subsets. There were 66 596 first adult transplants from living donors with 348 960 years of follow-up. We found a linear relationship between HLA mismatch and allograft survival. In adjusted analyses, among all living donors, 1 mismatch conferred a 44% higher risk, whereas 6 mismatches conferred a twofold higher risk of allograft failure. When using 0-mismatched full siblings as a reference, living-donor kidneys reduce the hazard of failure by approximately 34% when compared with deceased donors. Twenty-five years of transplant experience, stratified by donor source, was summarized and presented as a guide for allocation. These data reinforce the importance of optimizing HLA matching to further improve survival in first adult kidney allografts in the future, especially in living unrelated donations, when possible.

Sex differences, learning flexibility, and striatal dopamine D1 and D2 following adolescent drug exposure in rats

PubMed Central

Izquierdo, Alicia; Pozos, Hilda; De La Torre, Adrianna; DeShields, Simone; Cevallos, James; Rodriguez, Jonathan; Stolyarova, Alexandra

2016-01-01

Corticostriatal circuitry supports flexible reward learning and emotional behavior from the critical neurodevelopmental stage of adolescence through adulthood. It is still poorly understood how prescription drug exposure in adolescence may impact these outcomes in the long-term. We studied adolescent methylphenidate (MPH) and fluoxetine (FLX) exposure in rats and their impact on learning and emotion in adulthood. In Experiment 1, male and female rats were administered MPH, FLX, or saline (SAL), and compared with methamphetamine (mAMPH) treatment beginning in postnatal day (PND) 37. The rats were then tested on discrimination and reversal learning in adulthood. In Experiment 2, animals were administered MPH or SAL also beginning in PND 37 and later tested in adulthood for anxiety levels. In Experiment 3, we analyzed striatal dopamine D1 and D2 receptor expression in adulthood following either extensive learning (after Experiment 1) or more brief emotional measures (after Experiment 2). We found sex differences in discrimination learning and attenuated reversal learning after MPH and only sex differences in adulthood anxiety. In learners, there was enhanced striatal D1, but not D2, after either adolescent MPH or mAMPH. Lastly, also in learners, there was a sex x treatment group interaction for D2, but not D1, driven by the MPH-pretreated females, who expressed significantly higher D2 levels compared to SAL. These results show enduring effects of adolescent MPH on reversal learning in rats. Developmental psychostimulant exposure may interact with learning to enhance D1 expression in adulthood, and affect D2 expression in a sex-dependent manner. PMID:27091300

Twin-mediated epitaxial growth of highly lattice-mismatched Cu/Ag core-shell nanowires.

PubMed

Weng, Wei-Lun; Hsu, Chin-Yu; Lee, Jheng-Syun; Fan, Hsin-Hsin; Liao, Chien-Neng

2018-05-31

Lattice-mismatch is an important factor for the heteroepitaxial growth of core-shell nanostructures. A large lattice-mismatch usually leads to a non-coherent interface or a polycrystalline shell layer. In this study, a conformal Ag layer is coated on Cu nanowires with dense nanoscale twin boundaries through a galvanic replacement reaction. Despite a large lattice mismatch between Ag and Cu (∼12.6%), the Ag shell replicates the twinning structure in Cu nanowires and grows epitaxially on the nanotwinned Cu nanowire. A twin-mediated growth mechanism is proposed to explain the epitaxy of high lattice-mismatch bimetallic systems in which the misfit dislocations are accommodated by coherent twin boundaries.

Phenotypic Mismatches Reveal Escape from Arms-Race Coevolution

PubMed Central

Hanifin, Charles T; Brodie, Edmund D; Brodie, Edmund D

2008-01-01

Because coevolution takes place across a broad scale of time and space, it is virtually impossible to understand its dynamics and trajectories by studying a single pair of interacting populations at one time. Comparing populations across a range of an interaction, especially for long-lived species, can provide insight into these features of coevolution by sampling across a diverse set of conditions and histories. We used measures of prey traits (tetrodotoxin toxicity in newts) and predator traits (tetrodotoxin resistance of snakes) to assess the degree of phenotypic mismatch across the range of their coevolutionary interaction. Geographic patterns of phenotypic exaggeration were similar in prey and predators, with most phenotypically elevated localities occurring along the central Oregon coast and central California. Contrary to expectations, however, these areas of elevated traits did not coincide with the most intense coevolutionary selection. Measures of functional trait mismatch revealed that over one-third of sampled localities were so mismatched that reciprocal selection could not occur given current trait distributions. Estimates of current locality-specific interaction selection gradients confirmed this interpretation. In every case of mismatch, predators were “ahead” of prey in the arms race; the converse escape of prey was never observed. The emergent pattern suggests a dynamic in which interacting species experience reciprocal selection that drives arms-race escalation of both prey and predator phenotypes at a subset of localities across the interaction. This coadaptation proceeds until the evolution of extreme phenotypes by predators, through genes of large effect, allows snakes to, at least temporarily, escape the arms race. PMID:18336073

Relationship among mismatch repair deficiency, CDX2 loss, p53 and E-cadherin in colon carcinoma and suitability of using a double panel of mismatch repair proteins by immunohistochemistry.

PubMed

Sayar, Ilyas; Akbas, Emin Murat; Isik, Arda; Gokce, Aysun; Peker, Kemal; Demirtas, Levent; Gürbüzel, Mehmet

2015-09-01

Biomarkers such as mismatch repair proteins, CDX2, p53, and E-cadherin are blamed for colon cancers, but the relationships of these biomarkers with each other and with pathological risk factors in colon carcinoma are still not clear. The aim of this study was to evaluate the association of these biomarkers with each other by using immunohistochemical staining and to compare their expression with pathological risk factors for colonic adenocarcinoma. We also aimed to study the usability of a double panel of mismatch repair proteins. One hundred and eleven cases with colonic adenocarcinoma were examined. There was a statistically significant relationship between tumor histological differentiation and perineural invasion, vascular invasion, mismatch repair deficiency, p53, CDX2, and E-cadherin (p < 0.05). PMS2 and MSH6 loss covered 100% of cases with mismatch repair deficiency. Mismatch repair deficiency was correlated with CDX2 loss and E-cadherin expression (p < 0.05). It was also observed that cases with PMS2 loss covered all the cases with CDX2 loss. In conclusion, this double panel may be used instead of a quadruple panel for detecting mismatch repair deficiency. Association of CDX2 and PMS2 in the present study is necessary to conduct further genetic and pathological studies focusing on these two markers together.

Major Histocompatibility Mismatch and Donor Choice for Second Allogeneic Bone Marrow Transplantation.

PubMed

Imus, Philip H; Blackford, Amanda L; Bettinotti, Maria; Iglehart, Brian; Dietrich, August; Tucker, Noah; Symons, Heather; Cooke, Kenneth R; Luznik, Leo; Fuchs, Ephraim J; Brodsky, Robert A; Matsui, William H; Huff, Carol Ann; Gladstone, Douglas; Ambinder, Richard F; Borrello, Ivan M; Swinnen, Lode J; Jones, Richard J; Bolaños-Meade, Javier

2017-11-01

Large alternative donor pools provide the potential for selecting a different donor for a second allogeneic (allo) bone or marrow transplant (BMT). As HLA disparity may contribute to the graft-versus-tumor effect, utilizing new mismatched haplotype donors may potentially improve the antitumor activity for relapsed hematologic malignancies despite a previous alloBMT. Data from patients who received a second alloBMT for relapsed hematologic malignancies at Johns Hopkins were analyzed. Outcomes were compared between patients who received a second allograft with the same MHC composition and those who received an allograft with a new mismatched haplotype. Loss of heterozygosity analysis was performed for patients with acute myeloid leukemia (AML) whose first allograft was haploidentical. Between 2005 and 2015, 40 patients received a second BMT for a relapsed hematologic malignancy. The median follow-up is 750 (range, 26 to 2950) days. The median overall survival (OS) in the cohort is 928 days (95% confidence interval [CI], 602 to not reached [NR]); median event-free survival (EFS) for the cohort is 500 days (95% CI, 355 to NR). The 4-year OS is 40% (95% CI, 25% to 64%), and the 4-year EFS is 36% (95% CI, 24% to 55%). The cumulative incidence of nonrelapsed mortality by 2 years was 27% (95% CI, 13% to 42%). The cumulative incidence of grade 3 to 4 acute graft-versus-host disease (GVHD) at 100 days was 15% (95% CI, 4% to 26%); the cumulative incidence of extensive chronic GVHD at 2 years was 22% (95% CI, 9% to 36%). The median survival was 552 days (95% CI, 376 to 2950+) in the group who underwent transplantation with a second allograft that did not harbor a new mismatched haplotype, while it was not reached in the group whose allograft contained a new mismatched haplotype (hazard ratio [HR], .36; 95% CI, .14 to .9; P = .02). EFS was also longer in the group who received an allograft containing a new mismatched haplotype, (NR versus 401 days; HR, .50; 95% CI, .22 to 1

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

PubMed Central

Noordam, Lisanne; Sprengers, Dave; Boor, Patrick P. C.; Mancham, Shanta; Menon, Anand G.; Lange, Johan F.; Burger, Pim J. W. A.; Brandt, Alexandra; Galjart, Boris; Kwekkeboom, Jaap; Bruno, Marco J.

2018-01-01

ABSTRACT Purpose: Liver metastasis develops in >50% of patients with colorectal cancer (CRC), and is a leading cause of CRC-related mortality. We aimed to identify which inhibitory immune checkpoint pathways can be targeted to enhance functionality of intra-tumoral T-cells in mismatch repair-proficient liver metastases of colorectal cancer (LM-CRC). Methodology: Intra-tumoral expression of multiple inhibitory molecules was compared among mismatch repair-proficient LM-CRC, peritoneal metastases of colorectal cancer (PM-CRC) and primary CRC. Expression of inhibitory molecules was also analyzed on leukocytes isolated from paired resected metastatic liver tumors, tumor-free liver tissues, and blood of patients with mismatch repair-proficient LM-CRC. The effects of blocking inhibitory pathways on tumor-infiltrating T-cell responses were studied in ex vivo functional assays. Results: Mismatch repair-proficient LM-CRC showed higher expression of inhibitory receptors on intra-tumoral T-cells and contained higher proportions of CD8+ T-cells, dendritic cells and monocytes than mismatch repair-proficient primary CRC and/or PM-CRC. Inhibitory receptors LAG3, PD-1, TIM3 and CTLA4 were higher expressed on CD8+ T-cells, CD4+ T-helper and/or regulatory T-cells in LM-CRC tumors compared with tumor-free liver and blood. Antibody blockade of LAG3 or PD-L1 increased proliferation and effector cytokine production of intra-tumoral T-cells isolated from LM-CRC in response to both polyclonal and autologous tumor-specific stimulations. Higher LAG3 expression on intra-tumoral CD8+ T-cells associated with longer progression-free survival of LM-CRC patients. Conclusion: Mismatch repair-proficient LM-CRC may be more sensitive to immune checkpoint inhibitors than mismatch repair-proficient primary CRC. Blocking LAG3 enhances tumor-infiltrating T-cell responses of mismatch repair-proficient LM-CRC, and therefore may be a new promising immunotherapeutic target for LM-CRC.

SHIP1 intrinsically regulates NK cell signaling and education, resulting in tolerance of an MHC class I-mismatched bone marrow graft in mice.

PubMed

Gumbleton, Matthew; Vivier, Eric; Kerr, William G

2015-03-15

NK cells are an important component of host immune defense against malignancy and infection. NK cells are educated by MHC class I ligands to ensure self-tolerance while also promoting lytic competency against altered self and damaged self targets. However, the intracellular molecular events that culminate in tolerance and functional competency of educated NK cells remain undefined. Mice with germline deficiency in SHIP1 were shown to have a defective NK cell compartment. However, SHIP1 is expressed in all hematopoietic lineages, and consequently several hematolymphoid phenotypes have already been identified in certain cell types that are the result of SHIP1 deficiency in cells in separate and distinct lineages, that is, cell-extrinsic phenotypes. Thus, it was previously impossible to determine the NK cell-intrinsic role of SHIP1. In the present study, through the creation of an NK cell-specific deletion mouse model of SHIP1, we show that SHIP1 plays a profound NK lineage-intrinsic role in NK cell homeostasis, development, education, and cytokine production. Moreover, we show SHIP1 expression by NK cells is required for in vivo-mismatched bone marrow allograft rejection as well as for NK memory responses to hapten. Copyright © 2015 by The American Association of Immunologists, Inc.

Bandpass mismatch error for satellite CMB experiments I: estimating the spurious signal

NASA Astrophysics Data System (ADS)

Thuong Hoang, Duc; Patanchon, Guillaume; Bucher, Martin; Matsumura, Tomotake; Banerji, Ranajoy; Ishino, Hirokazu; Hazumi, Masashi; Delabrouille, Jacques

2017-12-01

Future Cosmic Microwave Background (CMB) satellite missions aim to use the B mode polarization to measure the tensor-to-scalar ratio r with a sensitivity σr lesssim 10-3. Achieving this goal will not only require sufficient detector array sensitivity but also unprecedented control of all systematic errors inherent in CMB polarization measurements. Since polarization measurements derive from differences between observations at different times and from different sensors, detector response mismatches introduce leakages from intensity to polarization and thus lead to a spurious B mode signal. Because the expected primordial B mode polarization signal is dwarfed by the known unpolarized intensity signal, such leakages could contribute substantially to the final error budget for measuring r. Using simulations we estimate the magnitude and angular spectrum of the spurious B mode signal resulting from bandpass mismatch between different detectors. It is assumed here that the detectors are calibrated, for example using the CMB dipole, so that their sensitivity to the primordial CMB signal has been perfectly matched. Consequently the mismatch in the frequency bandpass shape between detectors introduces differences in the relative calibration of galactic emission components. We simulate this effect using a range of scanning patterns being considered for future satellite missions. We find that the spurious contribution to r from the reionization bump on large angular scales (l < 10) is ≈ 10-3 assuming large detector arrays and 20 percent of the sky masked. We show how the amplitude of the leakage depends on the nonuniformity of the angular coverage in each pixel that results from the scan pattern.

Relationship between PTEN, DNA mismatch repair, and tumor histotype in endometrial carcinoma: retained positive expression of PTEN preferentially identifies sporadic non-endometrioid carcinomas.

PubMed

Djordjevic, Bojana; Barkoh, Bedia A; Luthra, Rajyalakshmi; Broaddus, Russell R

2013-10-01

Loss of PTEN (phosphatase and tensin homolog) expression and microsatellite instability are two of the more common molecular alterations in endometrial carcinoma. From the published literature, it is controversial as to whether there is a relationship between these different molecular mechanisms. Therefore, a cohort of 187 pure endometrioid and non-endometrioid endometrial carcinomas, carefully characterized as to clinical and pathological features, was examined for PTEN sequence abnormalities and the immunohistochemical expression of PTEN and the DNA mismatch repair proteins MLH1, MSH2, MSH6, and PMS2. MLH1 methylation analysis was performed when tumors had loss of MLH1 protein. Mismatch repair protein loss was more frequent in endometrioid carcinomas compared with non-endometrioid carcinomas, a difference primarily attributable to the presence of MLH1 methylation in a greater proportion of endometrioid tumors. Among the non-endometrioid group, mixed endometrioid/non-endometrioid carcinomas were the histotype that most commonly had loss of a mismatch repair protein. In endometrioid tumors, the frequency of PTEN loss measured by immunohistochemistry and mutation did not differ significantly between the mismatch repair protein intact or mismatch repair protein loss groups, suggesting that PTEN loss is independent of mismatch protein repair status in this group. However, in non-endometrioid carcinomas, both intact positive PTEN immunohistochemical expression and PTEN wild type were highly associated with retained positive expression of mismatch repair proteins in the tumor. Relevant to screening endometrial cancers for Lynch Syndrome, an initial PTEN immunohistochemistry determination may be able to replace the use of four mismatch repair immunohistochemical markers in 63% of patients with non-endometrioid endometrial carcinoma. Therefore, PTEN immunohistochemistry, in combination with tumor histotype, is a useful adjunct in the clinical evaluation of endometrial

Relationship between PTEN, DNA Mismatch Repair, and Tumor Histotype in Endometrial Carcinoma: Retained Positive Expression of PTEN Preferentially Identifies Sporadic Non-Endometrioid Carcinomas

PubMed Central

Djordjevic, Bojana; Barkoh, Bedia A.; Luthra, Rajyalakshmi; Broaddus, Russell R.

2013-01-01

Loss of PTEN (phosphatase and tensin homolog) expression and microsatellite instability are two of the more common molecular alterations in endometrial carcinoma. From the published literature, it is controversial as to whether there is a relationship between these different molecular mechanisms. Therefore, a cohort of 187 pure endometrioid and non-endometrioid endometrial carcinomas, carefully characterized as to clinical and pathological features, was examined for PTEN sequence abnormalities and the immunohistochemical expression of PTEN and the DNA mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. MLH1 methylation analysis was performed when tumors had loss of MLH1 protein. Mismatch repair protein loss was more frequent in endometrioid carcinomas compared to non-endometrioid carcinomas, a difference primarily attributable to the presence of MLH1 methylation in a greater proportion of endometrioid tumors. Among the non-endometrioid group, mixed endometrioid/non-endometrioid carcinomas were the histotype that most commonly had loss of a mismatch repair protein. In endometrioid tumors, the frequency of PTEN loss measured by immunohistochemistry and mutation did not differ significantly between the mismatch repair protein intact or mismatch repair protein loss groups, suggesting that PTEN loss is independent of mismatch protein repair status in this group. However, in non-endometrioid carcinomas, both intact positive PTEN immunohistochemical expression and PTEN wild type were highly associated with retained positive expression of mismatch repair proteins in the tumor. Relevant to screening endometrial cancers for Lynch Syndrome, an initial PTEN immunohistochemistry determination may be able to replace the use of four mismatch repair immunohistochemical markers in 63% of patients with non-endometrioid endometrial carcinoma. Therefore, PTEN immunohistochemistry, in combination with tumor histotype, is a useful adjunct in the clinical evaluation of endometrial

Effects of impedance mismatch and coaxial cable length on absolute gravimeters

NASA Astrophysics Data System (ADS)

Křen, Petr; Pálinkáš, Vojtech; Mašika, Pavel; Vaľko, Miloš

2017-04-01

The systematic effects of absolute gravimeters have to be investigated to fully utilize their capabilities in metrology and geosciences. In Křen et al (2016 Metrologia 53 27-40) we found that for an FG5 gravimeter, even a few meter long coaxial cable used for transmission of fringe signal causes systematic features in residuals and errors at the level of 1-2 µGal. In this paper, we present experimental results and appropriate models to explain the effects that were found to be caused by impedance mismatches of electronic components and dispersion effects in coaxial cables of gravimeters. The experimental results have been obtained for analogue and transistor-transistor logic (TTL) compatible signals in the FG5-215 gravimeter and for a TTL signal in the FG5X-251 gravimeter. We found that dispersion and impedance mismatch effects are similar for both gravimeters. Furthermore, we describe a model of the dispersion that allows an evaluation of the effect/correction for a given range of the free-fall and thus it is also applicable to other gravimeters. The effect of impedance mismatch for the analogue fringe signal is modelled as an effect of the reflected electronic signal on the evaluation of zero-crossings. The applicability of this model for TTL signal is also discussed.

Neighboring extremal optimal control design including model mismatch errors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, T.J.; Hull, D.G.

1994-11-01

The mismatch control technique that is used to simplify model equations of motion in order to determine analytic optimal control laws is extended using neighboring extremal theory. The first variation optimal control equations are linearized about the extremal path to account for perturbations in the initial state and the final constraint manifold. A numerical example demonstrates that the tuning procedure inherent in the mismatch control method increases the performance of the controls to the level of a numerically-determined piecewise-linear controller.

Indirectly Recognized HLA-C Mismatches and Their Potential Role in Transplant Outcome

PubMed Central

Thus, Kirsten A.; Te Boome, Liane; Kuball, Jürgen; Spierings, Eric

2014-01-01

HLA-C mismatches are clearly associated to alloreactivity after hematopoietic stem-cell transplantation; in a number of large cohorts, HLA-C mismatches are correlated to an increased risk of acute graft-versus-host disease (GVHD) or even impaired survival. While for HLA-A and -B, both antigenic as well as allelic mismatches are associated with an increased risk of acute GVHD, such an increased risk is only observed for antigenic HLA-C mismatches and not for allelic mismatches. These observations raise the question what sets HLA-C apart from HLA-A and -B. The difference may well be related to the reduced levels of cell-surface expression of HLA-C as compared to HLA-A and -B, possibly due to, among other factors, a limited peptide-binding capacity. This limited peptide-binding capacity may retain HLA-C in the ER and enhance degradation of the HLA-C protein. Once degraded, HLA-C-derived peptides can be presented to the immune system via other HLA alleles and are thus available for indirect recognition. Indeed, such HLA-C-derived peptides have previously been eluted from other HLA alleles. We have recently developed an approach to predict indirect recognition of HLA molecules, by establishing the numbers of predicted indirectly recognizable HLA epitopes (PIRCHES). The number of PIRCHES presented on HLA class I and II (PIRCHE-I and -II, respectively), are highly correlated to clinical measures of alloreactivity, such as acute GVHD. In the present “Hypothesis & Theory,” we reviewed the current knowledge on HLA-C mismatches and alloreactivity. Moreover, we speculate about the role of direct and indirect recognition of HLA-C and the consequences for donor selection in HLA-C mismatched stem-cell transplantation. PMID:24860572

High fitness costs of climate change-induced camouflage mismatch.

PubMed

Zimova, Marketa; Mills, L Scott; Nowak, J Joshua

2016-03-01

Anthropogenic climate change has created myriad stressors that threaten to cause local extinctions if wild populations fail to adapt to novel conditions. We studied individual and population-level fitness costs of a climate change-induced stressor: camouflage mismatch in seasonally colour molting species confronting decreasing snow cover duration. Based on field measurements of radiocollared snowshoe hares, we found strong selection on coat colour molt phenology, such that animals mismatched with the colour of their background experienced weekly survival decreases up to 7%. In the absence of adaptive response, we show that these mortality costs would result in strong population-level declines by the end of the century. However, natural selection acting on wide individual variation in molt phenology might enable evolutionary adaptation to camouflage mismatch. We conclude that evolutionary rescue will be critical for hares and other colour molting species to keep up with climate change. © 2016 The Authors. Ecology Letters published by CNRS and John Wiley & Sons Ltd.

Removal of N-6-methyladenine by the nucleotide excision repair pathway triggers the repair of mismatches in yeast gap-repair intermediates.

PubMed

Guo, Xiaoge; Jinks-Robertson, Sue

2013-12-01

Gap-repair assays have been an important tool for studying the genetic control of homologous recombination in yeast. Sequence analysis of recombination products derived when a gapped plasmid is diverged relative to the chromosomal repair template additionally has been used to infer structures of strand-exchange intermediates. In the absence of the canonical mismatch repair pathway, mismatches present in these intermediates are expected to persist and segregate at the next round of DNA replication. In a mismatch repair defective (mlh1Δ) background, however, we have observed that recombination-generated mismatches are often corrected to generate gene conversion or restoration events. In the analyses reported here, the source of the aberrant mismatch removal during gap repair was examined. We find that most mismatch removal is linked to the methylation status of the plasmid used in the gap-repair assay. Whereas more than half of Dam-methylated plasmids had patches of gene conversion and/or restoration interspersed with unrepaired mismatches, mismatch removal was observed in less than 10% of products obtained when un-methylated plasmids were used in transformation experiments. The methylation-linked removal of mismatches in recombination intermediates was due specifically to the nucleotide excision repair pathway, with such mismatch removal being partially counteracted by glycosylases of the base excision repair pathway. These data demonstrate that nucleotide excision repair activity is not limited to bulky, helix-distorting DNA lesions, but also targets removal of very modest perturbations in DNA structure. In addition to its effects on mismatch removal, methylation reduced the overall gap-repair efficiency, but this reduction was not affected by the status of excision repair pathways. Finally, gel purification of DNA prior to transformation reduced gap-repair efficiency four-fold in a nucleotide excision repair-defective background, indicating that the collateral

Removal of N-6-methyladenine by the nucleotide excision repair pathway triggers the repair of mismatches in yeast gap-repair intermediates

PubMed Central

Guo, Xiaoge; Jinks-Robertson, Sue

2013-01-01

Gap-repair assays have been an important tool for studying the genetic control of homologous recombination in yeast. Sequence analysis of recombination products derived when a gapped plasmid is diverged relative to the chromosomal repair template additionally has been used to infer structures of strand-exchange intermediates. In the absence of the canonical mismatch repair pathway, mismatches present in these intermediates are expected to persist and segregate at the next round of DNA replication. In a mismatch repair defective (mlh1Δ) background, however, we have observed that recombination-generated mismatches are often corrected to generate gene conversion or restoration events. In the analyses reported here, the source of the aberrant mismatch removal during gap repair was examined. We find that most mismatch removal is linked to the methylation status of the plasmid used in the gap-repair assay. Whereas more than half of Dam-methylated plasmids had patches of gene conversion and/or restoration interspersed with unrepaired mismatches, mismatch removal was observed in less than 10% of products obtained when un-methylated plasmids were used in transformation experiments. The methylation-linked removal of mismatches in recombination intermediates was due specifically to the nucleotide excision repair pathway, with such mismatch removal being partially counteracted by glycosylases of the base excision repair pathway. These data demonstrate that nucleotide excision repair activity is not limited to bulky, helix-distorting DNA lesions, but also targets removal of very modest perturbations in DNA structure. In addition to its effects on mismatch removal, methylation reduced the overall gap-repair efficiency, but this reduction was not affected by the status of excision repair pathways. Finally, gel purification of DNA prior to transformation reduced gap-repair efficiency four-fold in a nucleotide excision repair-defective background, indicating that the cillateral

Cytosine-based nucleoside analogs are selectively lethal to DNA mismatch repair-deficient tumour cells by enhancing levels of intracellular oxidative stress

PubMed Central

Hewish, M; Martin, S A; Elliott, R; Cunningham, D; Lord, C J; Ashworth, A

2013-01-01

Background: DNA mismatch repair deficiency is present in a significant proportion of a number of solid tumours and is associated with distinct clinical behaviour. Methods: To identify the therapeutic agents that might show selectivity for mismatch repair-deficient tumour cells, we screened a pair of isogenic MLH1-deficient and MLH1-proficient tumour cell lines with a library of clinically used drugs. To test the generality of hits in the screen, selective agents were retested in cells deficient in the MSH2 mismatch repair gene. Results: We identified cytarabine and other related cytosine-based nucleoside analogues as being selectively toxic to MLH1 and MSH2-deficient tumour cells. The selective cytotoxicity we observed was likely caused by increased levels of cellular oxidative stress, as it could be abrogated by antioxidants. Conclusion: We propose that cytarabine-based chemotherapy regimens may represent a tumour-selective treatment strategy for mismatch repair-deficient cancers. PMID:23361057

PCNA function in the activation and strand direction of MutLα endonuclease in mismatch repair

PubMed Central

Pluciennik, Anna; Dzantiev, Leonid; Iyer, Ravi R.; Constantin, Nicoleta; Kadyrov, Farid A.; Modrich, Paul

2010-01-01

MutLα (MLH1–PMS2) is a latent endonuclease that is activated in a mismatch-, MutSα-, proliferating cell nuclear antigen (PCNA)-, replication factor C (RFC)-, and ATP-dependent manner, with nuclease action directed to the heteroduplex strand that contains a preexisting break. RFC depletion experiments and use of linear DNAs indicate that RFC function in endonuclease activation is limited to PCNA loading. Whereas nicked circular heteroduplex DNA is a good substrate for PCNA loading and for endonuclease activation on the incised strand, covalently closed, relaxed circular DNA is a poor substrate for both reactions. However, covalently closed supercoiled or bubble-containing relaxed heteroduplexes, which do support PCNA loading, also support MutLα activation, but in this case cleavage strand bias is largely abolished. Based on these findings we suggest that PCNA has two roles in MutLα function: The clamp is required for endonuclease activation, an effect that apparently involves interaction of the two proteins, and by virtue of its loading orientation, PCNA determines the strand direction of MutLα incision. These results also provide a potential mechanism for activation of mismatch repair on nonreplicating DNA, an effect that may have implications for the somatic phase of triplet repeat expansion. PMID:20713735

Fabrication and characterization of multiband solar cells based on highly mismatched alloys

NASA Astrophysics Data System (ADS)

López, N.; Braña, A. F.; García Núñez, C.; Hernández, M. J.; Cervera, M.; Martínez, M.; Yu, K. M.; Walukiewicz, W.; García, B. J.

2015-10-01

Multiband solar cells are one type of third generation photovoltaic devices in which an increase of the power conversion efficiency is achieved through the absorption of low energy photons while preserving a large band gap that determines the open circuit voltage. The ability to absorb photons from different parts of the solar spectrum originates from the presence of an intermediate energy band located within the band gap of the material. This intermediate band, acting as a stepping stone allows the absorption of low energy photons to transfer electrons from the valence band to the conduction band by a sequential two photons absorption process. It has been demonstrated that highly mismatched alloys offer a potential to be used as a model material system for practical realization of multiband solar cells. Dilute nitride GaAs1-xNx highly mismatched alloy with low mole fraction of N is a prototypical multiband semiconductor with a well-defined intermediate band. Currently, we are using chemical beam epitaxy to synthesize dilute nitride highly mismatched alloys. The materials are characterized by a variety of structural and optical methods to optimize their properties for multiband photovoltaic devices.

Constitutional mismatch repair deficiency in a healthy child: On the spot diagnosis?

PubMed

Suerink, M; Potjer, T P; Versluijs, A B; Ten Broeke, S W; Tops, C M; Wimmer, K; Nielsen, M

2018-01-01

Constitutional mismatch repair deficiency (CMMRD) is a rare, recessively inherited childhood cancer predisposition syndrome caused by biallelic germline mutations in one of the mismatch repair genes. The CMMRD phenotype overlaps with that of neurofibromatosis type 1 (NF1), since many patients have multiple café-au-lait macules (CALM) and other NF1 signs, but no germline NF1 mutations. We report of a case of a healthy 6-year-old girl who fulfilled the diagnostic criteria of NF1 with >6 CALM and freckling. Since molecular genetic testing was unable to confirm the diagnosis of NF1 or Legius syndrome and the patient was a child of consanguineous parents, we suspected CMMRD and found a homozygous PMS2 mutation that impairs MMR function. Current guidelines advise testing for CMMRD only in cancer patients. However, this case illustrates that including CMMRD in the differential diagnosis in suspected sporadic NF1 without causative NF1 or SPRED1 mutations may facilitate identification of CMMRD prior to cancer development. We discuss the advantages and potential risks of this CMMRD testing scenario. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Advancing the match-mismatch framework for large herbivores in the Arctic: Evaluating the evidence for a trophic mismatch in caribou

PubMed Central

Barboza, Perry; Adams, Layne; Griffith, Brad; Whitten, Kenneth

2017-01-01

Climate-induced shifts in plant phenology may adversely affect animals that cannot or do not shift the timing of their reproductive cycle. The realized effect of potential trophic “mismatches” between a consumer and its food varies with the degree to which species rely on dietary income and stored capital. Large Arctic herbivores rely heavily on maternal capital to reproduce and give birth near the onset of the growing season but are they vulnerable to trophic mismatch? We evaluated the long-term changes in the temperatures and characteristics of the growing seasons (1970–2013), and compared growing conditions and dynamics of forage quality for caribou at peak parturition, peak lactation, and peak forage biomass, and plant senescence between two distinct time periods over 36 years (1977 and 2011–13). Despite advanced thaw dates (7−12 days earlier), increased growing season lengths (15−21 days longer), and consistent parturition dates, we found no decline in forage quality and therefore no evidence within this dataset for a trophic mismatch at peak parturition or peak lactation from 1977 to 2011–13. In Arctic ungulates that use stored capital for reproduction, reproductive demands are largely met by body stores deposited in the previous summer and autumn, which reduces potential adverse effects of any mismatch between food availability and timing of parturition. Climate-induced effects on forages growing in the summer and autumn ranges, however, do correspond with the demands of female caribou and their offspring to gain mass for the next reproductive cycle and winter. Therefore, we suggest the window of time to examine the match-mismatch framework in Arctic ungulates is not at parturition but in late summer-autumn, where the multiplier effects of small changes in forage quality are amplified by forage abundance, peak forage intake, and resultant mass gains in mother-offspring pairs. PMID:28231256

Advancing the match-mismatch framework for large herbivores in the Arctic: Evaluating the evidence for a trophic mismatch in caribou

USGS Publications Warehouse

Gustine, David D.; Barboza, Perry; Adams, Layne G.; Griffith, Brad; Cameron, Raymond D.; Whitten, Kenneth R.

2017-01-01

Climate-induced shifts in plant phenology may adversely affect animals that cannot or do not shift the timing of their reproductive cycle. The realized effect of potential trophic “mismatches” between a consumer and its food varies with the degree to which species rely on dietary income and stored capital. Large Arctic herbivores rely heavily on maternal capital to reproduce and give birth near the onset of the growing season but are they vulnerable to trophic mismatch? We evaluated the long-term changes in the temperatures and characteristics of the growing seasons (1970–2013), and compared growing conditions and dynamics of forage quality for caribou at peak parturition, peak lactation, and peak forage biomass, and plant senescence between two distinct time periods over 36 years (1977 and 2011–13). Despite advanced thaw dates (7−12 days earlier), increased growing season lengths (15−21 days longer), and consistent parturition dates, we found no decline in forage quality and therefore no evidence within this dataset for a trophic mismatch at peak parturition or peak lactation from 1977 to 2011–13. In Arctic ungulates that use stored capital for reproduction, reproductive demands are largely met by body stores deposited in the previous summer and autumn, which reduces potential adverse effects of any mismatch between food availability and timing of parturition. Climate-induced effects on forages growing in the summer and autumn ranges, however, do correspond with the demands of female caribou and their offspring to gain mass for the next reproductive cycle and winter. Therefore, we suggest the window of time to examine the match-mismatch framework in Arctic ungulates is not at parturition but in late summer-autumn, where the multiplier effects of small changes in forage quality are amplified by forage abundance, peak forage intake, and resultant mass gains in mother-offspring pairs.

Sex differences, learning flexibility, and striatal dopamine D1 and D2 following adolescent drug exposure in rats.

PubMed

Izquierdo, Alicia; Pozos, Hilda; Torre, Adrianna De La; DeShields, Simone; Cevallos, James; Rodriguez, Jonathan; Stolyarova, Alexandra

2016-07-15

Corticostriatal circuitry supports flexible reward learning and emotional behavior from the critical neurodevelopmental stage of adolescence through adulthood. It is still poorly understood how prescription drug exposure in adolescence may impact these outcomes in the long-term. We studied adolescent methylphenidate (MPH) and fluoxetine (FLX) exposure in rats and their impact on learning and emotion in adulthood. In Experiment 1, male and female rats were administered MPH, FLX, or saline (SAL), and compared with methamphetamine (mAMPH) treatment beginning in postnatal day (PND) 37. The rats were then tested on discrimination and reversal learning in adulthood. In Experiment 2, animals were administered MPH or SAL also beginning in PND 37 and later tested in adulthood for anxiety levels. In Experiment 3, we analyzed striatal dopamine D1 and D2 receptor expression in adulthood following either extensive learning (after Experiment 1) or more brief emotional measures (after Experiment 2). We found sex differences in discrimination learning and attenuated reversal learning after MPH and only sex differences in adulthood anxiety. In learners, there was enhanced striatal D1, but not D2, after either adolescent MPH or mAMPH. Lastly, also in learners, there was a sex x treatment group interaction for D2, but not D1, driven by the MPH-pretreated females, who expressed significantly higher D2 levels compared to SAL. These results show enduring effects of adolescent MPH on reversal learning in rats. Developmental psychostimulant exposure may interact with learning to enhance D1 expression in adulthood, and affect D2 expression in a sex-dependent manner. Copyright © 2016 Elsevier B.V. All rights reserved.

Repair of naturally occurring mismatches can induce mutations in flanking DNA

PubMed Central

Chen, Jia; Miller, Brendan F; Furano, Anthony V

2014-01-01

‘Normal’ genomic DNA contains hundreds of mismatches that are generated daily by the spontaneous deamination of C (U/G) and methyl-C (T/G). Thus, a mutagenic effect of their repair could constitute a serious genetic burden. We show here that while mismatches introduced into human cells on an SV40-based episome were invariably repaired, this process induced mutations in flanking DNA at a significantly higher rate than no mismatch controls. Most mutations involved the C of TpC, the substrate of some single strand-specific APOBEC cytidine deaminases, similar to the mutations that can typify the ‘mutator phenotype’ of numerous tumors. siRNA knockdowns and chromatin immunoprecipitation showed that TpC preferring APOBECs mediate the mutagenesis, and siRNA knockdowns showed that both the base excision and mismatch repair pathways are involved. That naturally occurring mispairs can be converted to mutators, represents an heretofore unsuspected source of genetic changes that could underlie disease, aging, and evolutionary change. DOI: http://dx.doi.org/10.7554/eLife.02001.001 PMID:24843013

Investigating methods for determining mismatch in near side vehicle impacts - biomed 2009.

PubMed

Loftis, Kathryn; Martin, R Shayn; Meredith, J Wayne; Stitzel, Joel

2009-01-01

This study investigates vehicle mismatch in severe side-impact motor vehicle collisions. Research conducted by the Insurance Institute for Highway Safety has determined that vehicle mismatch often leads to very severe injuries for occupants in the struck vehicle, because the larger striking vehicle does not engage the lower sill upon impact, resulting in severe intrusions into the occupant compartment. Previous studies have analyzed mismatched collisions according to vehicle type, not by the difference in vehicle height and weight. It is hypothesized that the combination of a heavier striking vehicle at a taller height results in more intrusion for the struck vehicle and severe injury for the near side occupant. By analyzing Crash Injury Research and Engineering Network (CIREN) data and occupant injury severity, it is possible to study intrusion and injuries that occur due to vehicle mismatch. CIREN enrolls seriously injured occupants involved in motor vehicle crashes (MVC) across the United States. From the Toyota-Wake Forest University CIREN center, 23 near side impact cases involving two vehicles were recorded. Only 3 of these seriously injured occupant cases were not considered mismatched according to vehicle curb weight, and only 2 were not considered vehicle mismatched according to height differences. The mismatched CIREN cases had an average difference in vehicle curb weight of 737.0 kg (standard deviation of 646.8) and an average difference in vehicle height of 16.38 cm (standard deviation of 7.186). There were 13 occupants with rib fractures, 12 occupants with pelvic fractures, 9 occupants with pulmonary contusion, and 5 occupants with head injuries, among other multiple injuries. The average Injury Severity Score (ISS) for these occupants was 27, with a standard deviation of 16. The most serious injuries resulted in an Abbreviated Injury Scale (AIS) of 5, which included 3 occupants. Each of these AIS 5 injuries were to different body regions on different

Genetic imaging study with [Tc-99m] TRODAT-1 SPECT in adolescents with ADHD using OROS-methylphenidate.

PubMed

Akay, Aynur Pekcanlar; Kaya, Gamze Çapa; Kose, Samet; Yazıcıoğlu, Çiğdem Eresen; Erkuran, Handan Özek; Güney, Sevay Alşen; Oğuz, Kaya; Keskin, Duygu; Baykara, Burak; Emiroğlu, Neslihan İnal; Eren, Mine Şencan; Kızıldağ, Sefa; Ertay, Türkan; Özsoylu, Dua; Miral, Süha; Durak, Hatice; Gönül, Ali Saffet; Rohde, Luis Augusto

2018-04-20

To examine theeffects on the brain of 2-month treatment withamethylphenidate extended-release formulation (OROS-MPH) using [Tc- 99m ] TRODAT-1SPECT in a sample of treatment-naïve adolescents with Attention Deficit/Hyperactivity Disorder (ADHD). In addition, to assess whether risk alleles (homozygosity for 10-repeat allele at the DAT1 gene were associated with alterations in striatal DAT availability. Twenty adolescents with ADHD underwent brain single-photon emission computed tomography (SPECT) scans with [Tc- 99m ] TRODAT-1 at baseline and two months after starting OROS-MPH treatment with dosages up to 1 mg/kg/day. Severity of illness was estimated using the Clinical Global Impression Scale (CGI-S) and DuPaul ADHD Rating Scale-Clinician version (ARS) before treatment,1 month and 2 months after initiating OROS-MPH treatment. Decreased DAT availability was found in both the right caudate (pretreatment DAT binding: 224.76 ± 33.77, post-treatment DAT binding: 208.86 ± 28.75, p = 0.02) and right putamen (pre-treatment DAT binding: 314.41 ± 55.24, post-treatment DAT binding: 285.66 ± 39.20, p = 0.05) in adolescents with ADHD receiving OROS-MPH treatment. Adolescents with ADHD who showed a robust response to OROS-MPH (n = 7) had significantly greater reduction of DAT density in the right putamen than adolescents who showed less robust response to OROS-MPH (n = 13) (p = 0.02). However, between-group differences by treatment responses were not related with DAT density in the right caudate. Risk alleles (homozygosity for the 10-repeat allele of DAT1 gene) in the DAT1 gene were not associated with alterations in striatal DAT availability. Two months of OROS-MPH treatment decreased DAT availability in both the right caudate and putamen. Adolescents with ADHD who showed a robust response to OROS-MPH had greater reduction of DAT density in the right putamen. However,our findings did not support an association between homozygosity

Decentralized Adaptive Control of Systems with Uncertain Interconnections, Plant-Model Mismatch and Actuator Failures

NASA Technical Reports Server (NTRS)

Patre, Parag; Joshi, Suresh M.

2011-01-01

Decentralized adaptive control is considered for systems consisting of multiple interconnected subsystems. It is assumed that each subsystem s parameters are uncertain and the interconnection parameters are not known. In addition, mismatch can exist between each subsystem and its reference model. A strictly decentralized adaptive control scheme is developed, wherein each subsystem has access only to its own state but has the knowledge of all reference model states. The mismatch is estimated online for each subsystem and the mismatch estimates are used to adaptively modify the corresponding reference models. The adaptive control scheme is extended to the case with actuator failures in addition to mismatch.

Correlation and agreement between eplet mismatches calculated using serological, low-intermediate and high resolution molecular human leukocyte antigen typing methods.

PubMed

Fidler, Samantha; D'Orsogna, Lloyd; Irish, Ashley B; Lewis, Joshua R; Wong, Germaine; Lim, Wai H

2018-03-02

Structural human leukocyte antigen (HLA) matching at the eplet level can be identified by HLAMatchmaker, which requires the entry of four-digit alleles. The aim of this study was to evaluate the agreement between eplet mismatches calculated by serological and two-digit typing methods compared to high-resolution four-digit typing. In a cohort of 264 donor/recipient pairs, the evaluation of measurement error was assessed using intra-class correlation to confirm the absolute agreement between the number of eplet mismatches at class I (HLA-A, -B, C) and II loci (HLA-DQ and -DR) calculated using serological or two-digit molecular typing compared to four-digit molecular typing methods. The proportion of donor/recipient pairs with a difference of >5 eplet mismatches between the HLA typing methods was also determined. Intra-class correlation coefficients between serological and four-digit molecular typing methods were 0.969 (95% confidence intervals [95% CI] 0.960-0.975) and 0.926 (95% CI 0.899-0.944), respectively; and 0.995 (95% CI 0.994-0.996) and 0.993 (95% CI 0.991-0.995), respectively between two-digit and four-digit molecular typing methods. The proportion of donor/recipient pairs with a difference of >5 eplet mismatches at class I and II loci was 4% and 16% for serological versus four-digit molecular typing methods, and 0% and 2% for two-digit versus four-digit molecular typing methods, respectively. In this small predominantly Caucasian population, compared with serology, there is a high level of agreement in the number of eplet mismatches calculated using two-compared to four-digit molecular HLA-typing methods, suggesting that two-digit typing may be sufficient in determining eplet mismatch load in kidney transplantation.

Correlation and agreement between eplet mismatches calculated using serological, low-intermediate and high resolution molecular human leukocyte antigen typing methods

PubMed Central

Fidler, Samantha; D’Orsogna, Lloyd; Irish, Ashley B.; Lewis, Joshua R.; Wong, Germaine; Lim, Wai H.

2018-01-01

Structural human leukocyte antigen (HLA) matching at the eplet level can be identified by HLAMatchmaker, which requires the entry of four-digit alleles. The aim of this study was to evaluate the agreement between eplet mismatches calculated by serological and two-digit typing methods compared to high-resolution four-digit typing. In a cohort of 264 donor/recipient pairs, the evaluation of measurement error was assessed using intra-class correlation to confirm the absolute agreement between the number of eplet mismatches at class I (HLA-A, -B, C) and II loci (HLA-DQ and -DR) calculated using serological or two-digit molecular typing compared to four-digit molecular typing methods. The proportion of donor/recipient pairs with a difference of >5 eplet mismatches between the HLA typing methods was also determined. Intra-class correlation coefficients between serological and four-digit molecular typing methods were 0.969 (95% confidence intervals [95% CI] 0.960–0.975) and 0.926 (95% CI 0.899–0.944), respectively; and 0.995 (95% CI 0.994–0.996) and 0.993 (95% CI 0.991–0.995), respectively between two-digit and four-digit molecular typing methods. The proportion of donor/recipient pairs with a difference of >5 eplet mismatches at class I and II loci was 4% and 16% for serological versus four-digit molecular typing methods, and 0% and 2% for two-digit versus four-digit molecular typing methods, respectively. In this small predominantly Caucasian population, compared with serology, there is a high level of agreement in the number of eplet mismatches calculated using two-compared to four-digit molecular HLA-typing methods, suggesting that two-digit typing may be sufficient in determining eplet mismatch load in kidney transplantation. PMID:29568344

Mismatch and G-Stack Modulated Probe Signals on SNP Microarrays

PubMed Central

Binder, Hans; Fasold, Mario; Glomb, Torsten

2009-01-01

Background Single nucleotide polymorphism (SNP) arrays are important tools widely used for genotyping and copy number estimation. This technology utilizes the specific affinity of fragmented DNA for binding to surface-attached oligonucleotide DNA probes. We analyze the variability of the probe signals of Affymetrix GeneChip SNP arrays as a function of the probe sequence to identify relevant sequence motifs which potentially cause systematic biases of genotyping and copy number estimates. Methodology/Principal Findings The probe design of GeneChip SNP arrays enables us to disentangle different sources of intensity modulations such as the number of mismatches per duplex, matched and mismatched base pairings including nearest and next-nearest neighbors and their position along the probe sequence. The effect of probe sequence was estimated in terms of triple-motifs with central matches and mismatches which include all 256 combinations of possible base pairings. The probe/target interactions on the chip can be decomposed into nearest neighbor contributions which correlate well with free energy terms of DNA/DNA-interactions in solution. The effect of mismatches is about twice as large as that of canonical pairings. Runs of guanines (G) and the particular type of mismatched pairings formed in cross-allelic probe/target duplexes constitute sources of systematic biases of the probe signals with consequences for genotyping and copy number estimates. The poly-G effect seems to be related to the crowded arrangement of probes which facilitates complex formation of neighboring probes with at minimum three adjacent G's in their sequence. Conclusions The applied method of “triple-averaging” represents a model-free approach to estimate the mean intensity contributions of different sequence motifs which can be applied in calibration algorithms to correct signal values for sequence effects. Rules for appropriate sequence corrections are suggested. PMID:19924253

The role of Homer 1a in increasing locomotor activity and non-selective attention, and impairing learning and memory abilities.

PubMed

Yang, Lei; Hong, Qin; Zhang, Min; Liu, Xiao; Pan, Xiao-Qin; Guo, Mei; Fei, Li; Guo, Xi-Rong; Tong, Mei-Ling; Chi, Xia

2013-06-17

The current study aimed to investigate the possible role of Homer 1a in the etiology and pathogenesis of attention deficit hyperactivity disorder (ADHD). We divided 32 rats into four groups. The rats in the RNAi-MPH group were given the lentiviral vector containing Homer 1a-specific miRNA (Homer 1a-RNAi-LV) by intracerebroventricular injection, and 7 days later they were given three daily doses of methylphenidate (MPH) by intragastric gavage. The RNAi-SAL group was given Homer 1a-RNAi-LV and saline later. The NC-MPH group was given the negative control lentiviral vector (NC-LV) and MPH later. The NC-SAL group was given NC-LV and saline later. Rats that were given Homer 1a RNAi exhibited increased locomotor activity and non-selective attention, and impaired learning and memory abilities, which is in line with the behavioral findings of animal models of ADHD. However, MPH ameliorated these abnormal behaviors. All findings indicated that Homer 1a may play an important role in the etiology and pathogenesis of ADHD. Copyright © 2013 Elsevier B.V. All rights reserved.

On the Mismatch between Multicultural Education and Its Subjects in the Field

ERIC Educational Resources Information Center

Mizrachi, Nissim

2012-01-01

This article draws attention to the growing evidence of a mismatch between sociological categorization and actors' worlds of meaning as expressed in the classroom. The mismatch is especially blatant in cases where students from disadvantaged groups are introduced to what educators and theorists presume to be the liberating discourse of…

Processes influencing model-data mismatch in drought-stressed, fire-disturbed eddy flux sites

NASA Astrophysics Data System (ADS)

Mitchell, Stephen; Beven, Keith; Freer, Jim; Law, Beverly

2011-06-01

Semiarid forests are very sensitive to climatic change and among the most difficult ecosystems to accurately model. We tested the performance of the Biome-BGC model against eddy flux data taken from young (years 2004-2008), mature (years 2002-2008), and old-growth (year 2000) ponderosa pine stands at Metolius, Oregon, and subsequently examined several potential causes for model-data mismatch. We used the Generalized Likelihood Uncertainty Estimation methodology, which involved 500,000 model runs for each stand (1,500,000 total). Each simulation was run with randomly generated parameter values from a uniform distribution based on published parameter ranges, resulting in modeled estimates of net ecosystem CO2 exchange (NEE) that were compared to measured eddy flux data. Simulations for the young stand exhibited the highest level of performance, though they overestimated ecosystem C accumulation (-NEE) 99% of the time. Among the simulations for the mature and old-growth stands, 100% and 99% of the simulations underestimated ecosystem C accumulation. One obvious area of model-data mismatch is soil moisture, which was overestimated by the model in the young and old-growth stands yet underestimated in the mature stand. However, modeled estimates of soil water content and associated water deficits did not appear to be the primary cause of model-data mismatch; our analysis indicated that gross primary production can be accurately modeled even if soil moisture content is not. Instead, difficulties in adequately modeling ecosystem respiration, mainly autotrophic respiration, appeared to be the fundamental cause of model-data mismatch.

Processes influencing model-data mismatch in drought-stressed, fire-disturbed eddy flux sites

NASA Astrophysics Data System (ADS)

Mitchell, S. R.; Beven, K.; Freer, J. E.; Law, B. E.

2010-12-01

Semi-arid forests are very sensitive to climatic change and among the most difficult ecosystems to accurately model. We tested the performance of the Biome-BGC model against eddy flux data taken from young (years 2004-2008), mature (years 2002-2008), and old-growth (year 2000) Ponderosa pine stands at Metolius, Oregon, and subsequently examined several potential causes for model-data mismatch. We used the generalized likelihood uncertainty estimation (GLUE) methodology, which involved 500,000 model runs for each stand (1,500,000 total). Each simulation was run with randomly generated parameter values from a uniform distribution based on published parameter ranges, resulting in modeled estimates of net ecosystem CO2 exchange (NEE) that were compared to measured eddy flux data. Simulations for the young stand exhibited the highest level of performance, though they over-estimated ecosystem C accumulation (-NEE) 99% of the time. Among the simulations for the mature and old-growth stands, 100% and 99% of the simulations under-estimated ecosystem C accumulation. One obvious area of model-data mismatch is soil moisture, which was overestimated by the model in the young and old-growth stands yet underestimated in the mature stand. However, modeled estimates of soil water content and associated water deficits did not appear to be the primary cause of model-data mismatch; our analysis indicated that gross primary production can be accurately modeled even if soil moisture content is not. Instead, difficulties in adequately modeling ecosystem respiration, both autotrophic and heterotrophic, appeared to be fundamental causes of model-data mismatch.

Scandiatransplant acceptable mismatch program (STAMP) a bridge to transplanting highly immunized patients.

PubMed

Koefoed-Nielsen, P; Weinreich, I; Bengtsson, M; Lauronen, J; Naper, C; Gäbel, M; Sørensen, S S; Wennberg, L; Reisaeter, A V; Møller, B K

2017-07-01

Highly immunized patients are a challenge for organ transplantation programs. One way of increasing the likelihood of transplantation in this group of patients is to expand the possible donations by defining acceptable HLA mismatches. In the Scandiatransplant Acceptable Mismatch Program (STAMP), a de-centralized approach has been implemented in 2009. The program has been improved during the years from utilizing HLA-A, -B, -DR matching only to include typing of all deceased donors for HLA-A, -B, -C, -DRB1 and -DQB1. The calculation of a transplantability score (TS) has been introduced in order to take both HLA and AB0 into consideration resulting in a more realistic picture of the transplantability chance. Patients were selected for eligibility and results of immunisation status were prepared in each of the 9 tissue typing laboratories, while access to the program is finally governed by a common steering group of immunologists and clinicians. In the period from March 2009 until February 2015, 96 patients were transplanted within this program. The mean recipient age was 49 years and 57% were females, 30% of the patients were first transplants and of these 93% were females. The majority of the patients had 2-5 HLA-A, -B. -DR mismatches. The allograft survival at 60 months was 79.1%. Applying the TS to the cohort confirmed that patients with a low TS score had longer waiting times. The program has matured during the years and now proves to be a valid approach for transplanting highly immunized patients. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Spontaneous Improvement of Compensatory Knee Flexion After Surgical Correction of Mismatch Between Pelvic Incidence and Lumbar Lordosis.

PubMed

Cheng, Xiaofei; Zhang, Feng; Wu, Jigong; Zhu, Zhenan; Dai, Kerong; Zhao, Jie

2016-08-15

A retrospective study. The aim of this study was to investigate the correlation between pelvic incidence (PI) and lumbar lordosis (LL) mismatch and knee flexion during standing in patients with lumbar degenerative diseases and to examine the effects of surgical correction of the PI-LL mismatch on knee flexion. Only several studies focused on knee flexion as a compensatory mechanism of the PI-LL mismatch. Little information is currently available on the effects of lumbar correction on knee flexion in patients with the PI-LL mismatch. A group of patients with lumbar degenerative diseases were divided into PI-LL match group (PI-LL ≤ 10°) and PI-LL mismatch group (PI-LL > 10°). A series of radiographic parameters and knee flexion angle (KFA) were compared between the two groups. The PI-LL mismatch group was further subdivided into operative and nonoperative group. The changes in KFA with PI-LL were examined. The PI-LL mismatch group exhibited significantly greater sagittal vertical axis (SVA), pelvic tilt (PT) and KFA, and smaller LL, thoracic kyphosis (TK), and sacral slope than the PI-LL match group. PI-LL, LL, PI, SVA, and PT were significantly correlated with KFA in the PI-LL mismatch group. From baseline to 6-month follow-up, all variables were significantly different in the operative group with the exception of PI, although there was no significant difference in any variable in the nonoperative group. The magnitude of surgical correction in the PI-LL mismatch was significantly correlated with the degree of spontaneous changes in KFA, PT, and TK. The PI-LL mismatch would contribute to compensatory knee flexion during standing in patients with lumbar degenerative disease. Surgical correction of the PI-LL mismatch could lead to a spontaneous improvement of compensatory knee flexion. The degree of improvement in knee flexion depends in part on the amount of correction in the PI-LL mismatch. 3.

Optimization of single-base-pair mismatch discrimination in oligonucleotide microarrays

NASA Technical Reports Server (NTRS)

Urakawa, Hidetoshi; El Fantroussi, Said; Smidt, Hauke; Smoot, James C.; Tribou, Erik H.; Kelly, John J.; Noble, Peter A.; Stahl, David A.

2003-01-01

The discrimination between perfect-match and single-base-pair-mismatched nucleic acid duplexes was investigated by using oligonucleotide DNA microarrays and nonequilibrium dissociation rates (melting profiles). DNA and RNA versions of two synthetic targets corresponding to the 16S rRNA sequences of Staphylococcus epidermidis (38 nucleotides) and Nitrosomonas eutropha (39 nucleotides) were hybridized to perfect-match probes (18-mer and 19-mer) and to a set of probes having all possible single-base-pair mismatches. The melting profiles of all probe-target duplexes were determined in parallel by using an imposed temperature step gradient. We derived an optimum wash temperature for each probe and target by using a simple formula to calculate a discrimination index for each temperature of the step gradient. This optimum corresponded to the output of an independent analysis using a customized neural network program. These results together provide an experimental and analytical framework for optimizing mismatch discrimination among all probes on a DNA microarray.

Ductile Crack Initiation Criterion with Mismatched Weld Joints Under Dynamic Loading Conditions.

PubMed

An, Gyubaek; Jeong, Se-Min; Park, Jeongung

2018-03-01

Brittle failure of high toughness steel structures tends to occur after ductile crack initiation/propagation. Damages to steel structures were reported in the Hanshin Great Earthquake. Several brittle failures were observed in beam-to-column connection zones with geometrical discontinuity. It is widely known that triaxial stresses accelerate the ductile fracture of steels. The study examined the effects of geometrical heterogeneity and strength mismatches (both of which elevate plastic constraints due to heterogeneous plastic straining) and loading rate on critical conditions initiating ductile fracture. This involved applying the two-parameter criterion (involving equivalent plastic strain and stress triaxiality) to estimate ductile cracking for strength mismatched specimens under static and dynamic tensile loading conditions. Ductile crack initiation testing was conducted under static and dynamic loading conditions using circumferentially notched specimens (Charpy type) with/without strength mismatches. The results indicated that the condition for ductile crack initiation using the two parameter criterion was a transferable criterion to evaluate ductile crack initiation independent of the existence of strength mismatches and loading rates.

A review of climate-driven mismatches between interdependent phenophases in terrestrial and aquatic ecosystems.

PubMed

Donnelly, Alison; Caffarra, Amelia; O'Neill, Bridget F

2011-11-01

Mismatches in phenology between mutually dependent species, resulting from climate change, can have far-reaching consequences throughout an ecosystem at both higher and lower trophic levels. Rising temperatures, due to climate warming, have resulted in advances in development and changes in behaviour of many organisms around the world. However, not all species or phenophases are responding to this increase in temperature at the same rate, thus creating a disruption to previously synchronised interdependent key life-cycle stages. Mismatches have been reported between plants and pollinators, predators and prey, and pests and hosts. Here, we review mismatches between interdependent phenophases at different trophic levels resulting from climate change. We categorized the studies into (1) terrestrial (natural and agricultural) ecosystems, and (2) aquatic (freshwater and marine) ecosystems. As expected, we found reports of 'winners' and 'losers' in each system, such as earlier emergence of prey enabling partial avoidance of predators, potential reductions in crop yield if herbivore pests emerge before their predators and possible declines in marine biodiversity due to disruption in plankton-fish phenologies. Furthermore, in the marine environment rising temperatures have resulted in synchrony in a previously mismatched prey and predator system, resulting in an abrupt population decline in the prey species. The examples reviewed suggest that more research into the complex interactions between species in terrestrial and aquatic ecosystems is necessary to make conclusive predictions of how climate warming may impact the fragile balances within ecosystems in future.

Indium arsenide-on-SOI MOSFETs with extreme lattice mismatch

NASA Astrophysics Data System (ADS)

Wu, Bin

Both molecular beam epitaxy (MBE) and metal organic chemical vapor deposition (MOCVD) have been used to explore the growth of InAs on Si. Despite 11.6% lattice mismatch, planar InAs structures have been observed by scanning electron microscopy (SEM) when nucleating using MBE on patterned submicron Si-on-insulator (SOI) islands. Planar structures of size as large as 500 x 500 nm 2 and lines of width 200 nm and length a few microns have been observed. MOCVD growth of InAs also generates single grain structures on Si islands when the size is reduced to 100 x 100 nm2. By choosing SOI as the growth template, selective growth is enabled by MOCVD. Post-growth pattern-then-anneal process, in which MOCVD InAs is deposited onto unpatterned SOI followed with patterning and annealing of InAs-on-Si structure, is found to change the relative lattice parameters of encapsulated 17/5 nm InAs/Si island. Observed from transmission electron diffraction (TED) patterns, the lattice mismatch of 17/5 nm InAs/Si island reduces from 11.2 to 4.2% after being annealed at 800°C for 30 minutes. High-k Al2O3 dielectrics have been deposited by both electron-beam-enabled physical vapor deposition (PVD) and atomic layer deposition (ALD). Films from both techniques show leakage currents on the order of 10-9A/cm2, at ˜1 MV/cm electric field, breakdown field > ˜6 MV/cm, and dielectric constant > 6, comparable to those of reported ALD prior arts by Groner. The first MOSFETs with extreme lattice mismatch InAs-on-SOI channels using PVD Al2O3 as the gate dielectric are characterized. Channel recess was used to improve the gate control of the drain current.

Decadal declines in avian herbivore reproduction: density-dependent nutrition and phenological mismatch in the Arctic

USGS Publications Warehouse

Ross, Megan V.; Alisaukas, Ray T.; Douglas, David C.; Kellett, Dana K.

2017-01-01

A full understanding of population dynamics depends not only on estimation of mechanistic contributions of recruitment and survival, but also knowledge about the ecological processes that drive each of these vital rates. The process of recruitment in particular may be protracted over several years, and can depend on numerous ecological complexities until sexually mature adulthood is attained. We addressed long-term declines (23 breeding seasons, 1992–2014) in the per capita production of young by both Ross's Geese (Chen rossii) and Lesser Snow Geese (Chen caerulescens caerulescens) nesting at Karrak Lake in Canada's central Arctic. During this period, there was a contemporaneous increase from 0.4 to 1.1 million adults nesting at this colony. We evaluated whether (1) density-dependent nutritional deficiencies of pre-breeding females or (2) phenological mismatch between peak gosling hatch and peak forage quality, inferred from NDVI on the brood-rearing areas, may have been behind decadal declines in the per capita production of goslings. We found that, in years when pre-breeding females arrived to the nesting grounds with diminished nutrient reserves, the proportional composition of young during brood-rearing was reduced for both species. Furthermore, increased mismatch between peak gosling hatch and peak forage quality contributed additively to further declines in gosling production, in addition to declines caused by delayed nesting with associated subsequent negative effects on clutch size and nest success. The degree of mismatch increased over the course of our study because of advanced vegetation phenology without a corresponding advance in Goose nesting phenology. Vegetation phenology was significantly earlier in years with warm surface air temperatures measured in spring (i.e., 25 May–30 June). We suggest that both increased phenological mismatch and reduced nutritional condition of arriving females were behind declines in population-level recruitment

Social, Spatial, and Skill Mismatch among Immigrants and Native-Born Workers in Los Angeles. Working Paper.

ERIC Educational Resources Information Center

Pastor, Manuel, Jr.; Marcelli, Enrico A.

Racially different economic outcomes stem from multiple causes, including various "mismatches" between minority employees and available jobs. A skill mismatch occurs when individuals' education and job skills do not qualify them for existing jobs. A spatial mismatch means that people live far from the work for which they qualify. A…

Behavioral and physiological responses to prey match-mismatch in larval herring

NASA Astrophysics Data System (ADS)

Illing, Björn; Moyano, Marta; Berg, Julia; Hufnagl, Marc; Peck, Myron A.

2018-02-01

The year-class success of Atlantic herring (Clupea harengus) spawning in the autumn/winter in the North Sea (NSAS stock) and in the spring in the western Baltic Sea (WBSS) appears driven by prey match-mismatch dynamics affecting the survival of larvae during the first weeks of life. To better understand and model the consequences of prey match-mismatch from an individual-based perspective, we measured aspects of the physiology and behavior of NSAS and WBSS herring larvae foraging in markedly different prey concentrations. When matched with prey (ad libitum concentrations of the copepod Acartia tonsa) larval growth, swimming activity, nutritional condition and metabolic rates were relatively high. When prey was absent (mismatch), swimming and feeding behavior rapidly declined within 2 and 4 days, for WBSS and NSAS larvae, respectively, concomitant with reductions in nutritional (RNA-DNA ratio) and somatic (weight-at-length) condition. After several days without prey, respiration measurements made on WBSS larvae suggested metabolic down-regulation (8-34%). An individual-based model depicting the time course of these Behavioral and physiological responses suggested that 25-mm larvae experiencing a mismatch would survive 25-33% (10, 7 °C) longer than 12-mm larvae. Warmer temperatures exacerbate starvation-induced decrements in performance. Without Behavioral and metabolic adjustments, survival of 25-mm larvae would be reduced from 8 to 6 days at 7 °C. Our findings highlight how adaptive Behavioral and physiological responses are tightly linked to prey match-mismatch dynamics in larval herring and how these responses can be included in models to better explore how bottom-up processes regulate larval fish growth and survival.

Constitutional mismatch repair deficiency and Lynch syndrome among consecutive Arab Bedouins with colorectal cancer in Israel.

PubMed

Abu Freha, Naim; Leibovici Weissman, Yaara; Fich, Alexander; Barnes Kedar, Inbal; Halpern, Marisa; Sztarkier, Ignacio; Behar, Doron M; Arbib Sneh, Orly; Vilkin, Alex; Baris, Hagit N; Gingold, Rachel; Lejbkowicz, Flavio; Niv, Yaron; Goldberg, Yael; Levi, Zohar

2018-01-01

We assessed the molecular characteristics and the frequency of mutations in mismatch-repair genes among Bedouin patients with colorectal cancer (CRC) in Israel. Bedouin patients with a diagnosis of CRC at a major hospital in the southern part of Israel were deemed eligible for this study. The primary screening method was immunohistochemical staining for mismatch-repair proteins (MLH1, MSH2, MSH6, and PMS2). For subjects with abnormal immunohistochemical staining, we performed microsatellite instability (MSI) analyses, and for tumors with a loss of MLH1 expression we also performed BRAF testing. In MSI high cases we searched further for germline mutations. Of the 24 patients enrolled, four subjects (16.7%) had MSI high tumors: one subject was found to harbor a biallelic PMS2 mutation, one subject had Lynch syndrome (LS) with MSH6 mutation and two subjects had a loss of MLH1/PMS2 proteins/BRAF wild type /normal MLH1 sequence. Ten patients (41.7%) were younger than 50 at the time of diagnosis and none had first degree relatives with CRC. In conclusion, in this cohort of 24 consecutive Arab Bedouins with CRC, one patient was found to harbor a constitutional mismatch repair deficiency, one patient had LS with MSH6 mutation, and two patients had unresolved loss of MLH1/PMS2 proteins/BRAF wild type phenotype.

Mismatch or cumulative stress: toward an integrated hypothesis of programming effects.

PubMed

Nederhof, Esther; Schmidt, Mathias V

2012-07-16

This paper integrates the cumulative stress hypothesis with the mismatch hypothesis, taking into account individual differences in sensitivity to programming. According to the cumulative stress hypothesis, individuals are more likely to suffer from disease as adversity accumulates. According to the mismatch hypothesis, individuals are more likely to suffer from disease if a mismatch occurs between the early programming environment and the later adult environment. These seemingly contradicting hypotheses are integrated into a new model proposing that the cumulative stress hypothesis applies to individuals who were not or only to a small extent programmed by their early environment, while the mismatch hypothesis applies to individuals who experienced strong programming effects. Evidence for the main effects of adversity as well as evidence for the interaction between adversity in early and later life is presented from human observational studies and animal models. Next, convincing evidence for individual differences in sensitivity to programming is presented. We extensively discuss how our integrated model can be tested empirically in animal models and human studies, inviting researchers to test this model. Furthermore, this integrated model should tempt clinicians and other intervenors to interpret symptoms as possible adaptations from an evolutionary biology perspective. Copyright © 2011 Elsevier Inc. All rights reserved.

Treatment of acute leukemia with unmanipulated HLA-mismatched/haploidentical blood and bone marrow transplantation.

PubMed

Huang, Xiao-Jun; Liu, Dai-Hong; Liu, Kai-Yan; Xu, Lan-Ping; Chen, Huan; Han, Wei; Chen, Yu-Hong; Zhang, Xiao-Hui; Lu, Dao-Pei

2009-02-01

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains one of the best therapeutic options to cure acute leukemia (AL). However, many patients have no human leukocyte antigen (HLA)-matched donor. Recently, we developed a new method for HLA-mismatched/haploidentical transplantation without in vitro T cell depletion (TCD). This method combined granulocyte-colony stimulating factor (G-CSF)-primed bone marrow and peripheral blood with intensive immunosuppression. We analyzed the outcome of 250 consecutive patients with AL who underwent HLA-mismatched/haploidentical transplantation with 1-3 mismatched loci of HLA-A, B, and DR from family donors via our new transplant protocol. Two hundred forty-nine patients achieved sustained, full donor chimerism. The incidence of grade 2-4 acute graft-versus-host disease (aGVHD) was 45.8%, and that of grades 3 and 4 was 13.4%, which was not associated with the extent of HLA disparity. The cumulative incidence of total chronic GVHD (cGVHD) was 53.9% and that of extensive cGVHD was 22.6% in 217 evaluable patients. One hundred forty-one of the 250 patients survived free of disease recurrence at a median of 1092 days (range: 442-2437 days) of follow-up. Seventeen patients received DLI as a treatment for relapse after transplantation and 7 patients achieved leukemia-free survival (LFS). The 3-year probability of LFS for acute myelogenous leukemia (AML) was 70.7% and 55.9%, and for acute lymphoblastic leukemia (ALL) it was 59.7% and 24.8% in standard-risk and high-risk groups, respectively. Lower LFS were associated with diagnosis of acute leukemia in the high-risk group (P= .001, relative risk [RR], 95% confidence interval [CI]: 2.94[1.535-5.631]) and the occurrence of aGVHD of grades 3 and 4 (P= .004). HLA-mismatched/haploidentical HSCT was feasible with unmanipulated blood and bone marrow harvest.

Shape forming by thermal expansion mismatch and shape memory locking in polymer/elastomer laminates

NASA Astrophysics Data System (ADS)

Yuan, Chao; Ding, Zhen; Wang, T. J.; Dunn, Martin L.; Qi, H. Jerry

2017-10-01

This paper studies a novel method to fabricate three-dimensional (3D) structure from 2D thermo-responsive shape memory polymer (SMP)/elastomer bilayer laminate. In this method, the shape change is actuated by the thermal mismatch strain between the SMP and the elastomer layers upon heating. However, the glass transition behavior of the SMP locks the material into a new 3D shape that is stable even upon cooling. Therefore, the second shape becomes a new permanent shape of the laminate. A theoretical model that accounts for the temperature-dependent thermomechanical behavior of the SMP material and thermal mismatch strain between the two layers is developed to better understand the underlying physics. Model predictions and experiments show good agreement and indicate that the theoretical model can well predict the bending behavior of the bilayer laminate. The model is then used in the optimal design of geometrical configuration and material selection. The latter also illustrates the requirement of thermomechanical behaviors of the SMP to lock the shape. Based on the fundamental understandings, several self-folding structures are demonstrated by the bilayer laminate design.

ABO incompatibility in mismatched unrelated donor allogeneic hematopoietic cell transplantation for acute myeloid leukemia: A report from the acute leukemia working party of the EBMT.

PubMed

Canaani, Jonathan; Savani, Bipin N; Labopin, Myriam; Michallet, Mauricette; Craddock, Charles; Socié, Gerard; Volin, Lisa; Maertens, Johan A; Crawley, Charles; Blaise, Didier; Ljungman, Per T; Cornelissen, Jan; Russell, Nigel; Baron, Frédéric; Gorin, Norbert; Esteve, Jordi; Ciceri, Fabio; Schmid, Christoph; Giebel, Sebastian; Mohty, Mohamad; Nagler, Arnon

2017-08-01

ABO incompatibility is commonly observed in stem cell transplantation and its impact in this setting has been extensively investigated. HLA-mismatched unrelated donors (MMURD) are often used as an alternative stem cell source but are associated with increased transplant related complications. Whether ABO incompatibility affects outcome in MMURD transplantation for acute myeloid leukemia (AML) patients is unknown. We evaluated 1,013 AML patients who underwent MMURD transplantation between 2005 and 2014. Engraftment rates were comparable between ABO matched and mismatched patients, as were relapse incidence [34%; 95% confidence interval (CI), 28-39; for ABO matched vs. 36%; 95% CI, 32-40; for ABO mismatched; P = .32], and nonrelapse mortality (28%; 95% CI, 23-33; for ABO matched vs. 25%; 95% CI, 21-29; for ABO mismatched; P = .2). Three year survival was 40% for ABO matched and 43% for ABO mismatched patients (P = .35), Leukemia free survival rates were also comparable between groups (37%; 95% CI, 32-43; for ABO matched vs. 38%; 95% CI, 33-42; for ABO mismatched; P = .87). Incidence of grade II-IV acute graft versus host disease was marginally lower in patients with major ABO mismatching (Hazard ratio of 0.7, 95% CI, 0.5-1; P = .049]. ABO incompatibility probably has no significant clinical implications in MMURD transplantation. © 2017 Wiley Periodicals, Inc.

High-performance, lattice-mismatched InGaAs/InP monolithic interconnected modules (MIMs)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fatemi, Navid S.; Wilt, David M.; Hoffman, Richard W., Jr.

1998-10-01

High performance, lattice-mismatched p/n InGaAs/lnP monolithic interconnected module (MIM) structures were developed for thermophotovoltaic (TPV) applications. A MIM device consists of several individual InGaAs photovoltaic (PV) cells series-connected on a single semi-insulating (S.I.) InP substrate. Both interdigitated and conventional (i.e., non-interdigitated) MIMs were fabricated. The energy bandgap (Eg) for these devices was 0.60 eV. A compositionally step-graded InPAs buffer was used to accommodate a lattice mismatch of 1.1% between the active InGaAs cell structure and the InP substrate. 1x1-cm, 15-cell, 0.60-eV MIMs demonstrated an open-circuit voltage (Voc) of 5.2 V (347 mV per cell) and a fill factor of 68.6%more » at a short-circuit current density (Jsc) of 2.0 A/cm{sup 2}, under flashlamp testing. The reverse saturation current density (Jo) was 1.6x10{sup {minus}6} A/cm{sup 2}. Jo values as low as 4.1x10{sup {minus}7} A/cm{sup 2} were also observed with a conventional planar cell geometry.« less

Impact of HLA mismatch direction on the outcome of unrelated bone marrow transplantation: a retrospective analysis from the Japan Society for Hematopoietic Cell Transplantation.

PubMed

Kanda, Junya; Ichinohe, Tatsuo; Fuji, Shigeo; Maeda, Yoshinobu; Ohashi, Kazuteru; Fukuda, Takahiro; Miyamura, Koichi; Iwato, Koji; Eto, Tetsuya; Nakamae, Hirohisa; Kobayashi, Naoki; Mori, Takehiko; Mori, Shin-Ichiro; Morishima, Yasuo; Atsuta, Yoshiko; Kanda, Yoshinobu

2015-02-01

The relative desirability of an unrelated donor with a bidirectional 1-locus mismatch (1MM-Bi), a 1-locus mismatch only in the graft-versus-host direction (1MM-GVH), or a 1-locus mismatch only in the host-versus-graft direction (1MM-HVG) is not yet clear. We analyzed adult patients with leukemia or myelodysplastic syndrome who received a first allogeneic stem cell transplant from an HLA-A, -B, -C, and -DRB1 matched or 1-allele mismatched unrelated donor in Japan. The effects of 1MM-Bi (n = 1020), 1MM-GVH (n = 83), and 1MM-HVG (n = 83) compared with a zero mismatch (0MM) (n = 2570) were analyzed after adjusting for other significant variables. The risk of grades III to IV acute graft-versus-host disease (GVHD) was higher with marginal significance in the 1MM-GVH group than in the 0MM group (hazard ratio, 1.85; P = .014). However, there was no significant difference in overall or nonrelapse mortality between the 1MM-GVH and 0MM groups. There was no significant difference in acute GVHD or overall or nonrelapse mortality between the 1MM-HVG and 0MM groups. The risks of acute GVHD and overall mortality were significantly higher in the 1MM-Bi group than in the 0MM group. These findings indicate that unrelated donors with 1MM-GVH and 1MM-HVG are both good candidates for patients without an HLA-matched unrelated donor in a Japanese cohort. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Thermal Protection Supplement for Reducing Interface Thermal Mismatch

NASA Technical Reports Server (NTRS)

Stewart, David A. (Inventor); Leiser, Daniel B. (Inventor)

2017-01-01

A thermal protection system that reduces a mismatch of thermal expansion coefficients CTE between a first material layer (CTE1) and a second material layer (CTE2) at a first layer-second layer interface. A portion of aluminum borosilicate (abs) or another suitable additive (add), whose CTE value, CTE(add), satisfies (CTE(add)-CTE1)(CTE(add)-CTE2)<0, is distributed with variable additive density,.rho.(z;add), in the first material layer and/or in the second material layer, with.rho.(z;add) near the materials interface being relatively high (alternatively, relatively low) and.rho.(z;add) in a region spaced apart from the interface being relatively low (alternatively, relatively high).

Receiver IQ mismatch estimation in PDM CO-OFDM system using training symbol

NASA Astrophysics Data System (ADS)

Peng, Dandan; Ma, Xiurong; Yao, Xin; Zhang, Haoyuan

2017-07-01

Receiver in-phase/quadrature (IQ) mismatch is hard to mitigate at the receiver via using conventional method in polarization division multiplexed (PDM) coherent optical orthogonal frequency division multiplexing (CO-OFDM) system. In this paper, a novel training symbol structure is proposed to estimate IQ mismatch and channel distortion. Combined this structure with Gram Schmidt orthogonalization procedure (GSOP) algorithm, we can get lower bit error rate (BER). Meanwhile, based on this structure one estimation method is deduced in frequency domain which can achieve the estimation of IQ mismatch and channel distortion independently and improve the system performance obviously. Numerical simulation shows that the proposed two methods have better performance than compared method at 100 Gb/s after 480 km fiber transmission. Besides, the calculation complexity is also analyzed.

Acoustic evidence for phonologically mismatched speech errors.

PubMed

Gormley, Andrea

2015-04-01

Speech errors are generally said to accommodate to their new phonological context. This accommodation has been validated by several transcription studies. The transcription methodology is not the best choice for detecting errors at this level, however, as this type of error can be difficult to perceive. This paper presents an acoustic analysis of speech errors that uncovers non-accommodated or mismatch errors. A mismatch error is a sub-phonemic error that results in an incorrect surface phonology. This type of error could arise during the processing of phonological rules or they could be made at the motor level of implementation. The results of this work have important implications for both experimental and theoretical research. For experimentalists, it validates the tools used for error induction and the acoustic determination of errors free of the perceptual bias. For theorists, this methodology can be used to test the nature of the processes proposed in language production.

Graft Growth and Podocyte Dedifferentiation in Donor-Recipient Size Mismatch Kidney Transplants.

PubMed

Müller-Deile, Janina; Bräsen, Jan Hinrich; Pollheimer, Marion; Ratschek, Manfred; Haller, Hermann; Pape, Lars; Schiffer, Mario

2017-10-01

Kidney transplantation is the treatment choice for patients with end-stage renal diseases. Because of good long-term outcome, pediatric kidney grafts are also accepted for transplantation in adult recipients despite a significant mismatch in body size and age between donor and recipient. These grafts show a remarkable ability of adaptation to the recipient body and increase in size in a very short period, presumably as an adaptation to hyperfiltration. We investigated renal graft growth as well as glomerular proliferation and differentiation markers Kiel-67, paired box gene 2 and Wilms tumor protein (WT1) expression in control biopsies from different transplant constellations: infant donor for infant recipient, infant donor for child recipient, infant donor for adult recipient, child donor for child recipient, child donor for adult recipient, and adult donor for an adult recipient. We detected a significant increase in kidney graft size after transplantation in all conditions with a body size mismatch, which was most prominent when an infant donated for a child. Podocyte WT1 expression was comparable in different transplant conditions, whereas a significant increase in WT1 expression could be detected in parietal epithelial cells, when a kidney graft from a child was transplanted into an adult. In kidney grafts that were relatively small for the recipients, we could detect reexpression of podocyte paired box gene 2. Moreover, the proliferation marker Kiel-67 was expressed in glomerular cells in grafts that increased in size after transplantation. Kidney grafts rapidly adapt to the recipient size after transplantation if they are transplanted in a body size mismatch constellation. The increase in transplant size is accompanied by an upregulation of proliferation and dedifferentiation markers in podocytes. The different examined conditions exclude hormonal factors as the key trigger for this growth so that most likely hyperfiltration is the key trigger inducing the

So little source, so much sink: requirements for afterdepolarizations to propagate in tissue.

PubMed

Xie, Yuanfang; Sato, Daisuke; Garfinkel, Alan; Qu, Zhilin; Weiss, James N

2010-09-08

How early (EADs) and delayed afterdepolarizations (DADs) overcome electrotonic source-sink mismatches in tissue to trigger premature ventricular complexes remains incompletely understood. To study this question, we used a rabbit ventricular action potential model to simulate tissues in which a central area of contiguous myocytes susceptible to EADs or DADs was surrounded by unsusceptible tissue. In 1D tissue with normal longitudinal conduction velocity (0.55 m/s), the numbers of contiguous susceptible myocytes required for an EAD and a barely suprathreshold DAD to trigger a propagating action potential were 70 and 80, respectively. In 2D tissue, these numbers increased to 6940 and 7854, and in 3D tissue to 696,910 and 817,280. These numbers were significantly decreased by reduced gap junction conductance, simulated fibrosis, reduced repolarization reserve and heart failure electrical remodeling. In conclusion, the source-sink mismatch in well-coupled cardiac tissue powerfully protects the heart from arrhythmias due to sporadic afterdepolarizations. Structural and electrophysiological remodeling decrease these numbers significantly but still require synchronization mechanisms for EADs and DADs to overcome the robust protective effects of source-sink mismatch. Copyright 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Seventeen-millimeter St. Jude Medical Regent valve in patients with small aortic annulus: dose moderate prosthesis-patient mismatch matter?

PubMed

Hu, Jia; Qian, Hong; Li, Ya-jiao; Gu, Jun; Zhao, Jing Janice; Zhang, Er-yong

2014-01-17

The study was designed to evaluate the effects of moderate prosthesis-patient mismatch (defined as 0.65 cm(2)/m(2) mismatch early after implantation of a 17-mm Regent valve at aortic position were included. Both clinical and echocardiographic assessments were performed preoperatively, at discharge and during follow-up period (mean follow-up time 52.6 ± 11.9 months). The prevalence of moderate prosthesis-patient mismatch was documented in 46 patients (43.4%) at discharge. During the follow-up period, no difference in the regression of left ventricular mass, decrease of transvalvular pressure gradients, mortality and prosthesis-related complications was observed between patients with and without moderate prosthesis-patient mismatch. After adjustment for several risk factors, moderate prosthesis-patient mismatch was associated with increased midterm mortality in patients with baseline left ventricular ejection fraction<50% (HR: 1.80, p=0.02), but with normal prognosis in those with preserved LV function. Younger age (cut off value=65 years) was not an independent predictor of increased midterm mortality and valve-related complications in patients with moderate prosthesis-patient mismatch. Moderate prosthesis-patient mismatch after aortic valve replacement with a small mechanical prosthesis is associated with increased mortality and adverse events in patients with pre-existing left ventricular dysfunction. Selected patients with small aortic annulus can experience satisfactory clinical improvements and midterm survival after aortic valve replacement with a 17-mm Regent valve.

Mlh2 Is an Accessory Factor for DNA Mismatch Repair in Saccharomyces cerevisiae

PubMed Central

Srivatsan, Anjana; Bowen, Nikki; Gries, Kerstin; Desai, Arshad; Putnam, Christopher D.; Kolodner, Richard D.

2014-01-01

In Saccharomyces cerevisiae, the essential mismatch repair (MMR) endonuclease Mlh1-Pms1 forms foci promoted by Msh2-Msh6 or Msh2-Msh3 in response to mispaired bases. Here we analyzed the Mlh1-Mlh2 complex, whose role in MMR has been unclear. Mlh1-Mlh2 formed foci that often colocalized with and had a longer lifetime than Mlh1-Pms1 foci. Mlh1-Mlh2 foci were similar to Mlh1-Pms1 foci: they required mispair recognition by Msh2-Msh6, increased in response to increased mispairs or downstream defects in MMR, and formed after induction of DNA damage by phleomycin but not double-stranded breaks by I-SceI. Mlh1-Mlh2 could be recruited to mispair-containing DNA in vitro by either Msh2-Msh6 or Msh2-Msh3. Deletion of MLH2 caused a synergistic increase in mutation rate in combination with deletion of MSH6 or reduced expression of Pms1. Phylogenetic analysis demonstrated that the S. cerevisiae Mlh2 protein and the mammalian PMS1 protein are homologs. These results support a hypothesis that Mlh1-Mlh2 is a non-essential accessory factor that acts to enhance the activity of Mlh1-Pms1. PMID:24811092

Mismatch removal via coherent spatial relations

NASA Astrophysics Data System (ADS)

Chen, Jun; Ma, Jiayi; Yang, Changcai; Tian, Jinwen

2014-07-01

We propose a method for removing mismatches from the given putative point correspondences in image pairs based on "coherent spatial relations." Under the Bayesian framework, we formulate our approach as a maximum likelihood problem and solve a coherent spatial relation between the putative point correspondences using an expectation-maximization (EM) algorithm. Our approach associates each point correspondence with a latent variable indicating it as being either an inlier or an outlier, and alternatively estimates the inlier set and recovers the coherent spatial relation. It can handle not only the case of image pairs with rigid motions but also the case of image pairs with nonrigid motions. To parameterize the coherent spatial relation, we choose two-view geometry and thin-plate spline as models for rigid and nonrigid cases, respectively. The mismatches could be successfully removed via the coherent spatial relations after the EM algorithm converges. The quantitative results on various experimental data demonstrate that our method outperforms many state-of-the-art methods, it is not affected by low initial correct match percentages, and is robust to most geometric transformations including a large viewing angle, image rotation, and affine transformation.

Localization by interaural time difference (ITD): Effects of interaural frequency mismatch

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bonham, B.H.; Lewis, E.R.

1999-07-01

A commonly accepted physiological model for lateralization of low-frequency sounds by interaural time delay (ITD) stipulates that binaural comparison neurons receive input from frequency-matched channels from each ear. Here, the effects of hypothetical interaural frequency mismatches on this model are reported. For this study, the cat{close_quote}s auditory system peripheral to the binaural comparison neurons was represented by a neurophysiologically derived model, and binaural comparison neurons were represented by cross-correlators. The results of the study indicate that, for binaural comparison neurons receiving input from one cochlear channel from each ear, interaural CF mismatches may serve to either augment or diminish themore » effective difference in ipsilateral and contralateral axonal time delays from the periphery to the binaural comparison neuron. The magnitude of this increase or decrease in the effective time delay difference can be up to 400 {mu}s for CF mismatches of 0.2 octaves or less for binaural neurons with CFs between 250 Hz and 2.5 kHz. For binaural comparison neurons with nominal CFs near 500 Hz, the 25-{mu}s effective time delay difference caused by a 0.012-octave CF mismatch is equal to the ITD previously shown to be behaviorally sufficient for the cat to lateralize a low-frequency sound source. {copyright} {ital 1999 Acoustical Society of America.}« less

78 FR 39062 - Group Lotus plc; Modification of a Temporary Exemption From an Advanced Air Bag Requirement of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-28

...-0086] Group Lotus plc; Modification of a Temporary Exemption From an Advanced Air Bag Requirement of... temporary exemption granted to Group Lotus plc (Lotus) on March 8, 2013. The agency granted Lotus an... Lotus Plc (Lotus) a temporary exemption from the higher maximum speed (56 km/h (35 mph)) belted test...

The effect of sociodemographic (mis)match between interviewers and respondents on unit and item nonresponse in Belgium.

PubMed

Vercruyssen, Anina; Wuyts, Celine; Loosveldt, Geert

2017-09-01

Interviewer characteristics affect nonresponse and measurement errors in face-to-face surveys. Some studies have shown that mismatched sociodemographic characteristics - for example gender - affect people's behavior when interacting with an interviewer at the door and during the survey interview, resulting in more nonresponse. We investigate the effect of sociodemographic (mis)matching on nonresponse in two successive rounds of the European Social Survey in Belgium. As such, we replicate the analyses of the effect of (mis)matching gender and age on unit nonresponse on the one hand, and of gender, age and education level (mis)matching on item nonresponse on the other hand. Recurring effects of sociodemographic (mis)match are found for both unit and item nonresponse. Copyright © 2017 Elsevier Inc. All rights reserved.

Structural studies of the 5'-phenazinium-tethered matched and G-A-mismatched DNA duplexes by NMR spectroscopy.

PubMed

Maltseva, T; Sandström, A; Ivanova, I M; Sergeyev, D S; Zarytova, V F; Chattopadhyaya, J

1993-05-01

The mechanism through which modified oligo-DNA analogues act as antisense repressors at the transcriptional and translational level of gene expression is based on the information content in the nucleotide sequence which is determined by the specific base pairing. The efficiency of such action is largely determined by the stability of the duplex formed between the oligonucleotide reagent and the target sequence and also by the mismatched base pairing, such as G-A, that occurs during replication or recombination. We herein report that the phenazinium (Pzn)-tethered matched duplex p(d(TGTTTGGC)):(Pzn)-p(d(CCAAACA)) (III) (Tm = 50 degrees C) has a much larger stability than the parent matched duplex p(d(TGTTTGGC)):p(d(CCAAACA)) (I) (Tm = 30 degrees C). On the other hand, the Pzn-tethered G-A-mismatched duplex p(d(TGTTTGGC)):(Pzn)-p(d(ACAAACA)) (IV) (Tm = 34 degrees C) is only slightly more stable than its parent mismatched duplex p(d(TGTTTGGC)):p(d(ACAAACA)) (Tm = 25 degrees C). A detailed 500 MHz NMR study and constrained MD refinements of NMR-derived structures have been undertaken for the DNA duplexes (I), (II), (III) and (IV) in order to understand the structural basis of stabilization of Pzn-tethered matched DNA duplex (delta Tm = 20 degrees C) compared to mismatched duplex (delta Tm = 9 degrees C). Assignment of the 1H-NMR (500 MHz) spectra of the duplexes has been carried out by 2D NOESY, HOHAHA and DQF-COSY experiments. The torsion angles have been extracted from the J-coupling constants obtained by simulation of most of the DQF-COSY cross-peaks using program SMART. The solution structure of the duplexes were assessed by an iterative hybride relaxation matrix method (MORASS) combined with NOESY distances and torsion angles restrained molecular dynamics (MD) using program Amber 4.0. The standard Amber 4.0 force-field parameters were used for the oligonucleotide in conjunction with the new parameters for Pzn residue which was obtained by full geometry

Immunohistochemistry for PMS2 and MSH6 alone can replace a four antibody panel for mismatch repair deficiency screening in colorectal adenocarcinoma.

PubMed

Hall, Geoffrey; Clarkson, Adele; Shi, Amanda; Langford, Eileen; Leung, Helen; Eckstein, Robert P; Gill, Anthony J

2010-01-01

Currently, testing for mismatch repair deficiency in colorectal cancers is initiated by performing immunohistochemistry with four antibodies (MLH1, PMS2, MSH2 and MSH6). If any one of these stains is negative the tumour is considered microsatellite unstable and, if clinical circumstances warrant it, the patient is offered genetic testing for Lynch's syndrome. Due to the binding properties of the mismatch repair heterodimer complexes, gene mutation and loss of MLH1 and MSH2 invariably result in the degradation of PMS2 and MSH6, respectively, but the converse is not true. We propose that staining for PMS2 and MSH6 alone will be sufficient to detect all cases of mismatch repair deficiency and should replace routine screening with all four antibodies. The electronic database of the department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia, was searched for all colorectal carcinomas on which a four panel immunohistochemical microsatellite instability screen was performed. An audit of the slides for concordant loss of MLH1-PMS2 and MSH2-MSH6 was then undertaken. Unusual or discordant cases were reviewed and, in some cases, re-stained to confirm the staining pattern. Of 344 cases of colorectal cancer which underwent four antibody immunohistochemistry, 104 displayed loss of at least one mismatch repair protein. Of these, 100 showed concordant mismatch repair loss (i.e., loss of MLH1 and PMS2 or loss of MSH2 and MSH6). The four discordant cases comprised two single negative cases (1 MSH6 negative/MSH2 positive case, 1 PMS2 negative/MLH1 positive) and two triple negative (both MLH1/PMS2/MSH6 negative). The microsatellite instability (MSI) group showed a relatively high median age (69.3 years) due to the departmental policy of testing all cases with possible MSI morphology regardless of age. The sensitivity and specificity of a two panel test comprised of PMS2 and MSH6, compared to a four panel test, is 100%. No false negatives or positives were

Complete wavelength mismatching effect in a Doppler broadened Y-type six-level EIT atomic medium

NASA Astrophysics Data System (ADS)

Bharti, Vineet; Wasan, Ajay

We present a theoretical study of the Doppler broadened Y-type six-level atomic system, using a density matrix approach, to investigate the effect of varying control field wavelengths and closely spaced hyperfine levels in the 5P state of 87Rb. The closely spaced hyperfine levels in our six-level system affect the optical properties of Y-type system and cause asymmetry in absorption profiles. Depending upon the choices of π-probe, σ+-control and σ--control fields transitions, we consider three regimes: (i) perfect wavelength matching regime (λp=λ=λ), (ii) partial wavelength mismatching regime (λp≠λ=λ), and (iii) complete wavelength mismatching regime (λp≠λ≠λ). The complete wavelength mismatching regime is further distinguished into two situations, i.e., λ<λ and λ>λ. We have shown that in the room temperature atomic vapor, the asymmetric transparency window gets broadened in the partial wavelength mismatching regime as compared to the perfect wavelength matching regime. This broad transparency window also splits at the line center in the complete wavelength mismatching regime.

Role of Cell Cycle Regulation and MLH1, A Key DNA Mismatch Repair Protein, In Adaptive Survival Responses. Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

David A. Boothman

1999-08-11

Due to several interesting findings on both adaptive survival responses (ASRs) and DNA mismatch repair (MMR), this grant was separated into two discrete Specific Aim sets (each with their own discrete hypotheses). The described experiments were simultaneously performed.

Graft and patient outcomes of zero-human leucocyte-antigen-mismatched deceased and live donor kidney transplant recipients.

PubMed

Lim, Wai H; Gray, Nicholas A; Chadban, Steven J; Pilmore, Helen; Wong, Germaine

2015-05-01

Greater compatibility of human leucocyte antigen (HLA) alleles between kidney donors and recipients may lead to improved graft outcomes. This study aimed to compare the incidence of acute rejection and graft failure in zero-HLA-mismatched recipients of living-related (LD) and deceased donor (DD) kidney transplants. Using data from the Australia and New Zealand Dialysis and Transplant Registry, we compared the risk of any acute rejection and biopsy-proven acute rejection (BPAR) and graft failure in recipients of zero-HLA-mismatched kidneys between LD and DD using logistic and Cox regression models. Of the 931 zero-HLA-mismatched recipients transplanted between 1990 and 2012, 19 (2.0%) received kidneys from monozygotic/dizygotic twins (twin), 500 (53.7%) from nontwin LD and 412 (44.3%) from DD. Twin kidney transplant recipients did not experience rejection. Compared to DD transplant recipients, the risk of any acute rejection (adjusted odds ratio 0.52, 95%CI 0.34-0.79, P = 0.002) and overall graft failure (adjusted hazard ratio 0.55, 95%CI 0.41-0.73, P < 0.001) was significantly lower in LD recipients independent of initial immunosuppression, but not for BPAR (adjusted odds ratio 0.52, 95%CI 0.16-1.64, P = 0.263). Zero-HLA-mismatched DD kidney transplant recipients have a significantly higher risk of any acute rejection episodes and graft loss compared to zero-HLA-mismatched LD kidney transplant recipients. A cautious and careful approach in reducing immunosuppression appears to be warranted in this group of transplant recipients. © 2015 Steunstichting ESOT.

Detecting mismatches of bird migration stopover and tree phenology in response to changing climate

USGS Publications Warehouse

Kellermann, Jherime L.; van Riper, Charles

2015-01-01

Migratory birds exploit seasonal variation in resources across latitudes, timing migration to coincide with the phenology of food at stopover sites. Differential responses to climate in phenology across trophic levels can result in phenological mismatch; however, detecting mismatch is sensitive to methodology. We examined patterns of migrant abundance and tree flowering, phenological mismatch, and the influence of climate during spring migration from 2009 to 2011 across five habitat types of the Madrean Sky Islands in southeastern Arizona, USA. We used two metrics to assess phenological mismatch: synchrony and overlap. We also examined whether phenological overlap declined with increasing difference in mean event date of phenophases. Migrant abundance and tree flowering generally increased with minimum spring temperature but depended on annual climate by habitat interactions. Migrant abundance was lowest and flowering was highest under cold, snowy conditions in high elevation montane conifer habitat while bird abundance was greatest and flowering was lowest in low elevation riparian habitat under the driest conditions. Phenological synchrony and overlap were unique and complementary metrics and should both be used when assessing mismatch. Overlap declined due to asynchronous phenologies but also due to reduced migrant abundance or flowering when synchrony was actually maintained. Overlap declined with increasing difference in event date and this trend was strongest in riparian areas. Montane habitat specialists may be at greatest risk of mismatch while riparian habitat could provide refugia during dry years for phenotypically plastic species. Interannual climate patterns that we observed match climate change projections for the arid southwest, altering stopover habitat condition.

Emotional Intelligence and Mismatching Expressive and Verbal Messages: A Contribution to Detection of Deception

PubMed Central

Wojciechowski, Jerzy; Stolarski, Maciej; Matthews, Gerald

2014-01-01

Processing facial emotion, especially mismatches between facial and verbal messages, is believed to be important in the detection of deception. For example, emotional leakage may accompany lying. Individuals with superior emotion perception abilities may then be more adept in detecting deception by identifying mismatch between facial and verbal messages. Two personal factors that may predict such abilities are female gender and high emotional intelligence (EI). However, evidence on the role of gender and EI in detection of deception is mixed. A key issue is that the facial processing skills required to detect deception may not be the same as those required to identify facial emotion. To test this possibility, we developed a novel facial processing task, the FDT (Face Decoding Test) that requires detection of inconsistencies between facial and verbal cues to emotion. We hypothesized that gender and ability EI would be related to performance when cues were inconsistent. We also hypothesized that gender effects would be mediated by EI, because women tend to score as more emotionally intelligent on ability tests. Data were collected from 210 participants. Analyses of the FDT suggested that EI was correlated with superior face decoding in all conditions. We also confirmed the expected gender difference, the superiority of high EI individuals, and the mediation hypothesis. Also, EI was more strongly associated with facial decoding performance in women than in men, implying there may be gender differences in strategies for processing affective cues. It is concluded that integration of emotional and cognitive cues may be a core attribute of EI that contributes to the detection of deception. PMID:24658500

Total variation-based method for radar coincidence imaging with model mismatch for extended target

NASA Astrophysics Data System (ADS)

Cao, Kaicheng; Zhou, Xiaoli; Cheng, Yongqiang; Fan, Bo; Qin, Yuliang

2017-11-01

Originating from traditional optical coincidence imaging, radar coincidence imaging (RCI) is a staring/forward-looking imaging technique. In RCI, the reference matrix must be computed precisely to reconstruct the image as preferred; unfortunately, such precision is almost impossible due to the existence of model mismatch in practical applications. Although some conventional sparse recovery algorithms are proposed to solve the model-mismatch problem, they are inapplicable to nonsparse targets. We therefore sought to derive the signal model of RCI with model mismatch by replacing the sparsity constraint item with total variation (TV) regularization in the sparse total least squares optimization problem; in this manner, we obtain the objective function of RCI with model mismatch for an extended target. A more robust and efficient algorithm called TV-TLS is proposed, in which the objective function is divided into two parts and the perturbation matrix and scattering coefficients are updated alternately. Moreover, due to the ability of TV regularization to recover sparse signal or image with sparse gradient, TV-TLS method is also applicable to sparse recovering. Results of numerical experiments demonstrate that, for uniform extended targets, sparse targets, and real extended targets, the algorithm can achieve preferred imaging performance both in suppressing noise and in adapting to model mismatch.

Si Complies with GaN to Overcome Thermal Mismatches for the Heteroepitaxy of Thick GaN on Si.

PubMed

Tanaka, Atsunori; Choi, Woojin; Chen, Renjie; Dayeh, Shadi A

2017-10-01

Heteroepitaxial growth of lattice mismatched materials has advanced through the epitaxy of thin coherently strained layers, the strain sharing in virtual and nanoscale substrates, and the growth of thick films with intermediate strain-relaxed buffer layers. However, the thermal mismatch is not completely resolved in highly mismatched systems such as in GaN-on-Si. Here, geometrical effects and surface faceting to dilate thermal stresses at the surface of selectively grown epitaxial GaN layers on Si are exploited. The growth of thick (19 µm), crack-free, and pure GaN layers on Si with the lowest threading dislocation density of 1.1 × 10 7 cm -2 achieved to date in GaN-on-Si is demonstrated. With these advances, the first vertical GaN metal-insulator-semiconductor field-effect transistors on Si substrates with low leakage currents and high on/off ratios paving the way for a cost-effective high power device paradigm on an Si CMOS platform are demonstrated. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Impact of mismatched and misaligned laser light sheet profiles on PIV performance

NASA Astrophysics Data System (ADS)

Grayson, K.; de Silva, C. M.; Hutchins, N.; Marusic, I.

2018-01-01

The effect of mismatched or misaligned laser light sheet profiles on the quality of particle image velocimetry (PIV) results is considered in this study. Light sheet profiles with differing widths, shapes, or alignment can reduce the correlation between PIV images and increase experimental errors. Systematic PIV simulations isolate these behaviours to assess the sensitivity and implications of light sheet mismatch on measurements. The simulations in this work use flow fields from a turbulent boundary layer; however, the behaviours and impacts of laser profile mismatch are highly relevant to any fluid flow or PIV application. Experimental measurements from a turbulent boundary layer facility are incorporated, as well as additional simulations matched to experimental image characteristics, to validate the synthetic image analysis. Experimental laser profiles are captured using a modular laser profiling camera, designed to quantify the distribution of laser light sheet intensities and inform any corrective adjustments to an experimental configuration. Results suggest that an offset of just 1.35 standard deviations in the Gaussian light sheet intensity distributions can cause a 40% reduction in the average correlation coefficient and a 45% increase in spurious vectors. Errors in measured flow statistics are also amplified when two successive laser profiles are no longer well matched in alignment or intensity distribution. Consequently, an awareness of how laser light sheet overlap influences PIV results can guide faster setup of an experiment, as well as achieve superior experimental measurements.

Doublethink and scale mismatch polarize policies for an invasive tree

PubMed Central

Roberts, Caleb P.; Uden, Daniel R.; Allen, Craig R.; Twidwell, Dirac

2018-01-01

Mismatches between invasive species management policies and ecological knowledge can lead to profound societal consequences. For this reason, natural resource agencies have adopted the scientifically-based density-impact invasive species curve to guide invasive species management. We use the density-impact model to evaluate how well management policies for a native invader (Juniperus virginiana) match scientific guidelines. Juniperus virginiana invasion is causing a sub-continental regime shift from grasslands to woodlands in central North America, and its impacts span collapses in endemic diversity, heightened wildfire risk, and crashes in grazing land profitability. We (1) use land cover data to identify the stage of Juniperus virginiana invasion for three ecoregions within Nebraska, USA, (2) determine the range of invasion stages at individual land parcel extents within each ecoregion based on the density-impact model, and (3) determine policy alignment and mismatches relative to the density-impact model in order to assess their potential to meet sustainability targets and avoid societal impacts as Juniperus virginiana abundance increases. We found that nearly all policies evidenced doublethink and policy-ecology mismatches, for instance, promoting spread of Juniperus virginiana regardless of invasion stage while simultaneously managing it as a native invader in the same ecoregion. Like other invasive species, theory and literature for this native invader indicate that the consequences of invasion are unlikely to be prevented if policies fail to prioritize management at incipient invasion stages. Theory suggests a more realistic approach would be to align policy with the stage of invasion at local and ecoregion management scales. There is a need for scientists, policy makers, and ecosystem managers to move past ideologies governing native versus non-native invader classification and toward a framework that accounts for the uniqueness of native species invasions

Doublethink and scale mismatch polarize policies for an invasive tree

USGS Publications Warehouse

Roberts, Caleb P.; Uden, Daniel R.; Allen, Craig R.; Twidwell, Dirac

2018-01-01

Mismatches between invasive species management policies and ecological knowledge can lead to profound societal consequences. For this reason, natural resource agencies have adopted the scientifically-based density-impact invasive species curve to guide invasive species management. We use the density-impact model to evaluate how well management policies for a native invader (Juniperus virginiana) match scientific guidelines. Juniperus virginiana invasion is causing a sub-continental regime shift from grasslands to woodlands in central North America, and its impacts span collapses in endemic diversity, heightened wildfire risk, and crashes in grazing land profitability. We (1) use land cover data to identify the stage of Juniperus virginiana invasion for three ecoregions within Nebraska, USA, (2) determine the range of invasion stages at individual land parcel extents within each ecoregion based on the density-impact model, and (3) determine policy alignment and mismatches relative to the density-impact model in order to assess their potential to meet sustainability targets and avoid societal impacts as Juniperus virginiana abundance increases. We found that nearly all policies evidenced doublethink and policy-ecology mismatches, for instance, promoting spread of Juniperus virginiana regardless of invasion stage while simultaneously managing it as a native invader in the same ecoregion. Like other invasive species, theory and literature for this native invader indicate that the consequences of invasion are unlikely to be prevented if policies fail to prioritize management at incipient invasion stages. Theory suggests a more realistic approach would be to align policy with the stage of invasion at local and ecoregion management scales. There is a need for scientists, policy makers, and ecosystem managers to move past ideologies governing native versus non-native invader classification and toward a framework that accounts for the uniqueness of native species

High-performance, lattice-mismatched InGaAs/InP monolithic interconnected modules (MIMs)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fatemi, Navid S.; Wilt, David M.; Hoffman, Richard W.

1999-03-01

High performance, lattice-mismatched p/n InGaAs/InP monolithic interconnected module (MIM) structures were developed for thermophotovoltaic (TPV) applications. A MIM device consists of several individual InGaAs photovoltaic (PV) cells series-connected on a single semi-insulating (S.I.) InP substrate. Both interdigitated and conventional (i.e., non-interdigitated) MIMs were fabricated. The energy bandgap (Eg) for these devices was 0.60 eV. A compositionally step-graded InPAs buffer was used to accommodate a lattice mismatch of 1.1{percent} between the active InGaAs cell structure and the InP substrate. 1{times}1-cm, 15-cell, 0.60-eV MIMs demonstrated an open-circuit voltage (Voc) of 5.2 V (347 mV per cell) and a fill factor of 68.6{percent}more » at a short-circuit current density (Jsc) of 2.0 A/cm{sup 2}, under flashlamp testing. The reverse saturation current density (Jo) was 1.6{times}10{sup {minus}6}&hthinsp;A/cm{sup 2}. Jo values as low as 4.1{times}10{sup {minus}7}&hthinsp;A/cm{sup 2} were also observed with a conventional planar cell geometry. {copyright} {ital 1999 American Institute of Physics.}« less

Decadal declines in avian herbivore reproduction: density-dependent nutrition and phenological mismatch in the Arctic.

PubMed

Ross, Megan V; Alisauskas, Ray T; Douglas, David C; Kellett, Dana K

2017-07-01

A full understanding of population dynamics depends not only on estimation of mechanistic contributions of recruitment and survival, but also knowledge about the ecological processes that drive each of these vital rates. The process of recruitment in particular may be protracted over several years, and can depend on numerous ecological complexities until sexually mature adulthood is attained. We addressed long-term declines (23 breeding seasons, 1992-2014) in the per capita production of young by both Ross's Geese (Chen rossii) and Lesser Snow Geese (Chen caerulescens caerulescens) nesting at Karrak Lake in Canada's central Arctic. During this period, there was a contemporaneous increase from 0.4 to 1.1 million adults nesting at this colony. We evaluated whether (1) density-dependent nutritional deficiencies of pre-breeding females or (2) phenological mismatch between peak gosling hatch and peak forage quality, inferred from NDVI on the brood-rearing areas, may have been behind decadal declines in the per capita production of goslings. We found that, in years when pre-breeding females arrived to the nesting grounds with diminished nutrient reserves, the proportional composition of young during brood-rearing was reduced for both species. Furthermore, increased mismatch between peak gosling hatch and peak forage quality contributed additively to further declines in gosling production, in addition to declines caused by delayed nesting with associated subsequent negative effects on clutch size and nest success. The degree of mismatch increased over the course of our study because of advanced vegetation phenology without a corresponding advance in Goose nesting phenology. Vegetation phenology was significantly earlier in years with warm surface air temperatures measured in spring (i.e., 25 May-30 June). We suggest that both increased phenological mismatch and reduced nutritional condition of arriving females were behind declines in population-level recruitment, leading

Auditory mismatch impairments are characterized by core neural dysfunctions in schizophrenia

PubMed Central

Gaebler, Arnim Johannes; Mathiak, Klaus; Koten, Jan Willem; König, Andrea Anna; Koush, Yury; Weyer, David; Depner, Conny; Matentzoglu, Simeon; Edgar, James Christopher; Willmes, Klaus; Zvyagintsev, Mikhail

2015-01-01

Major theories on the neural basis of schizophrenic core symptoms highlight aberrant salience network activity (insula and anterior cingulate cortex), prefrontal hypoactivation, sensory processing deficits as well as an impaired connectivity between temporal and prefrontal cortices. The mismatch negativity is a potential biomarker of schizophrenia and its reduction might be a consequence of each of these mechanisms. In contrast to the previous electroencephalographic studies, functional magnetic resonance imaging may disentangle the involved brain networks at high spatial resolution and determine contributions from localized brain responses and functional connectivity to the schizophrenic impairments. Twenty-four patients and 24 matched control subjects underwent functional magnetic resonance imaging during an optimized auditory mismatch task. Haemodynamic responses and functional connectivity were compared between groups. These data sets further entered a diagnostic classification analysis to assess impairments on the individual patient level. In the control group, mismatch responses were detected in the auditory cortex, prefrontal cortex and the salience network (insula and anterior cingulate cortex). Furthermore, mismatch processing was associated with a deactivation of the visual system and the dorsal attention network indicating a shift of resources from the visual to the auditory domain. The patients exhibited reduced activation in all of the respective systems (right auditory cortex, prefrontal cortex, and the salience network) as well as reduced deactivation of the visual system and the dorsal attention network. Group differences were most prominent in the anterior cingulate cortex and adjacent prefrontal areas. The latter regions also exhibited a reduced functional connectivity with the auditory cortex in the patients. In the classification analysis, haemodynamic responses yielded a maximal accuracy of 83% based on four features; functional connectivity

Nuclear import of human MLH1, PMS2, and MutLalpha: redundancy is the key.

PubMed

Leong, Vivian; Lorenowicz, Jessica; Kozij, Natalie; Guarné, Alba

2009-08-01

DNA mismatch repair maintains genomic stability by correcting errors that have escaped polymerase proofreading. Defects on mismatch repair genes lead to an increased mutation rate, microsatellite instability and predisposition to human non-polyposis colorectal cancer (HNPCC). Human MutLalpha is a heterodimer formed by the interaction of MLH1 and PMS2 that coordinates a series of key events in mismatch repair. It has been proposed that nuclear import of MutLalpha may be the first regulatory step on the activation of the mismatch repair pathway. Using confocal microscopy and mismatch repair deficient cells, we have identified the sequence determinants that drive nuclear import of human MLH1, PMS2, and MutLalpha. Transient transfection of the individual proteins reveals that MLH1 has a bipartite and PMS2 has a single monopartite nuclear localization signal. Although dimerization is not required for nuclear localization, the MutLalpha heterodimer is imported more efficiently than the MLH1 or PMS2 monomers. Interestingly, the bipartite localization signal of MLH1 can direct import of MutLalpha even when PMS2 encompasses a mutated localization signal. Hence we conclude that the presence of redundant nuclear localization signals guarantees nuclear transport of MutLalpha and, consequently, efficient mismatch repair.

The Scientist and the Educational Development Team: An Impedance Mismatch?

NASA Astrophysics Data System (ADS)

Pompea, S. M.

2001-05-01

This talk describes my experiences and those of several other scientists who have worked on teams to develop new instructional materials and programs. At each stage of the development process we try to communicate our skills and experiences to the rest of the development team. In turn, the experiences of non-scientist educators on the team must be communicated to us. However, in many cases there is an "impedance mismatch" which makes communication difficult. One primary source of this mismatch is the scientist's lack of experience with schools, students, teachers, school administrators, museums, and the public. The result of this mismatch can leave the scientist in one limited, but useful role: proofreader and critic. Unfortunately, this can hardly be described as a partnership. This talk gives some advice, based on 25 years of educational materials and program development work, on how to avoid such a limited role. The talk would be appropriate for those scientists who want to lead, inspire, or significantly contribute to educational initiatives and to share in the frustration and the rewards enjoyed by professional educators and professional educational developers. S. Pompea is an adjunct faculty member of Steward Observatory of the University of Arizona.

Selenium compounds activate ATM-dependent DNA damage responses via the mismatch repair protein hMLH1 in colorectal cancer cells

USDA-ARS?s Scientific Manuscript database

Epidemiological and animal studies indicate that selenium supplementation suppresses risk of colorectal and other cancers. The majority of colorectal cancers are characterized by a defective DNA mismatch repair (MMR) process. Here, we have employed the MMR-deficient HCT 116 colorectal cancer cells ...

A Multicenter, Open-Label Trial to Evaluate the Quality of Life in Adults with ADHD Treated with Long-Acting Methylphenidate (OROS MPH): Concerta Quality of Life (CONQoL) Study

ERIC Educational Resources Information Center

Mattos, Paulo; Rodrigues Louza, Mario; Fernandes Palmini, Andre Luis; de Oliveira, Irismar Reis; Lopes Rocha, Fabio

2013-01-01

The available literature provides few studies on the effectiveness of methylphenidate in improving quality of life in individuals with ADHD. Objective: To assess the effectiveness of Methyphenidate OROS formulation (OROS MPH) through QoL in adults with ADHD. Method: A 12-week, multicenter, open-label trial involving 60 patients was used. The…

The c15 ring of the Spirulina platensis F-ATP synthase: F1/F0 symmetry mismatch is not obligatory

PubMed Central

Pogoryelov, Denys; Yu, Jinshu; Meier, Thomas; Vonck, Janet; Dimroth, Peter; Muller, Daniel J

2005-01-01

The oligomeric c ring of the F-ATP synthase from the alkaliphilic cyanobacterium Spirulina platensis was isolated and characterized. Mass spectroscopy analysis indicated a mass of 8,210 Da, reflecting that of a c monomer. The mass increased by 206 Da after treatment with the c-subunit-specific inhibitor dicyclohexylcarbodiimide (DCCD), which indicated modification of the ion-binding carboxylate by DCCD. Atomic force microscopy topographs of c rings from S. platensis showed 15 symmetrically assembled subunits. The c15-mer reported here is the largest c ring that is isolated and does not show the classical c-ring mismatch to the three-fold symmetry of the F1 domain. PMID:16170308

Minimizing the effect of process mismatch in a neuromorphic system using spike-timing-dependent adaptation.

PubMed

Cameron, Katherine; Murray, Alan

2008-05-01

This paper investigates whether spike-timing-dependent plasticity (STDP) can minimize the effect of mismatch within the context of a depth-from-motion algorithm. To improve noise rejection, this algorithm contains a spike prediction element, whose performance is degraded by analog very large scale integration (VLSI) mismatch. The error between the actual spike arrival time and the prediction is used as the input to an STDP circuit, to improve future predictions. Before STDP adaptation, the error reflects the degree of mismatch within the prediction circuitry. After STDP adaptation, the error indicates to what extent the adaptive circuitry can minimize the effect of transistor mismatch. The circuitry is tested with static and varying prediction times and chip results are presented. The effect of noisy spikes is also investigated. Under all conditions the STDP adaptation is shown to improve performance.

Evidence supporting the match/mismatch hypothesis of psychiatric disorders.

PubMed

Santarelli, Sara; Lesuis, Sylvie L; Wang, Xiao-Dong; Wagner, Klaus V; Hartmann, Jakob; Labermaier, Christiana; Scharf, Sebastian H; Müller, Marianne B; Holsboer, Florian; Schmidt, Mathias V

2014-06-01

Chronic stress is one of the predominant environmental risk factors for a number of psychiatric disorders, particularly for major depression. Different hypotheses have been formulated to address the interaction between early and adult chronic stress in psychiatric disease vulnerability. The match/mismatch hypothesis of psychiatric disease states that the early life environment shapes coping strategies in a manner that enables individuals to optimally face similar environments later in life. We tested this hypothesis in female Balb/c mice that underwent either stress or enrichment early in life and were in adulthood further subdivided in single or group housed, in order to provide aversive or positive adult environments, respectively. We studied the effects of the environmental manipulation on anxiety-like, depressive-like and sociability behaviors and gene expression profiles. We show that continuous exposure to adverse environments (matched condition) is not necessarily resulting in an opposite phenotype compared to a continuous supportive environment (matched condition). Rather, animals with mismatched environmental conditions behaved differently from animals with matched environments on anxious, social and depressive like phenotypes. These results further support the match/mismatch hypothesis and illustrate how mild or moderate aversive conditions during development can shape an individual to be optimally adapted to similar conditions later in life. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

Educational Mismatch and the Careers of Scientists

ERIC Educational Resources Information Center

Bender, Keith A.; Heywood, John S.

2011-01-01

Previous research confirms that many employees work in jobs not well matched to their skills and education, resulting in lower pay and job satisfaction. While this literature typically uses cross-sectional data, we examine the evolution of mismatch and its consequences over a career, by using a panel data set of scientists in the USA. The results…

C-Terminal Fluorescent Labeling Impairs Functionality of DNA Mismatch Repair Proteins

PubMed Central

Brieger, Angela; Plotz, Guido; Hinrichsen, Inga; Passmann, Sandra; Adam, Ronja; Zeuzem, Stefan

2012-01-01

The human DNA mismatch repair (MMR) process is crucial to maintain the integrity of the genome and requires many different proteins which interact perfectly and coordinated. Germline mutations in MMR genes are responsible for the development of the hereditary form of colorectal cancer called Lynch syndrome. Various mutations mainly in two MMR proteins, MLH1 and MSH2, have been identified so far, whereas 55% are detected within MLH1, the essential component of the heterodimer MutLα (MLH1 and PMS2). Most of those MLH1 variants are pathogenic but the relevance of missense mutations often remains unclear. Many different recombinant systems are applied to filter out disease-associated proteins whereby fluorescent tagged proteins are frequently used. However, dye labeling might have deleterious effects on MutLα's functionality. Therefore, we analyzed the consequences of N- and C-terminal fluorescent labeling on expression level, cellular localization and MMR activity of MutLα. Besides significant influence of GFP- or Red-fusion on protein expression we detected incorrect shuttling of single expressed C-terminal GFP-tagged PMS2 into the nucleus and found that C-terminal dye labeling impaired MMR function of MutLα. In contrast, N-terminal tagged MutLαs retained correct functionality and can be recommended both for the analysis of cellular localization and MMR efficiency. PMID:22348133

The mismatch repair and meiotic recombination endonuclease Mlh1-Mlh3 is activated by polymer formation and can cleave DNA substrates in trans.

PubMed

Manhart, Carol M; Ni, Xiaodan; White, Martin A; Ortega, Joaquin; Surtees, Jennifer A; Alani, Eric

2017-04-01

Crossing over between homologs is initiated in meiotic prophase by the formation of DNA double-strand breaks that occur throughout the genome. In the major interference-responsive crossover pathway in baker's yeast, these breaks are resected to form 3' single-strand tails that participate in a homology search, ultimately forming double Holliday junctions (dHJs) that primarily include both homologs. These dHJs are resolved by endonuclease activity to form exclusively crossovers, which are critical for proper homolog segregation in Meiosis I. Recent genetic, biochemical, and molecular studies in yeast are consistent with the hypothesis of Mlh1-Mlh3 DNA mismatch repair complex acting as the major endonuclease activity that resolves dHJs into crossovers. However, the mechanism by which the Mlh1-Mlh3 endonuclease is activated is unknown. Here, we provide evidence that Mlh1-Mlh3 does not behave like a structure-specific endonuclease but forms polymers required to generate nicks in DNA. This conclusion is supported by DNA binding studies performed with different-sized substrates that contain or lack polymerization barriers and endonuclease assays performed with varying ratios of endonuclease-deficient and endonuclease-proficient Mlh1-Mlh3. In addition, Mlh1-Mlh3 can generate religatable double-strand breaks and form an active nucleoprotein complex that can nick DNA substrates in trans. Together these observations argue that Mlh1-Mlh3 may not act like a canonical, RuvC-like Holliday junction resolvase and support a novel model in which Mlh1-Mlh3 is loaded onto DNA to form an activated polymer that cleaves DNA.

Dominant phonon polarization conversion across dimensionally mismatched interfaces: Carbon-nanotube-graphene junction

NASA Astrophysics Data System (ADS)

Shi, Jingjing; Lee, Jonghoon; Dong, Yalin; Roy, Ajit; Fisher, Timothy S.; Ruan, Xiulin

2018-04-01

Dimensionally mismatched interfaces are emerging for thermal management applications, but thermal transport physics remains poorly understood. Here we consider the carbon-nanotube-graphene junction, which is a dimensionally mismatched interface between one- and two-dimensional materials and is the building block for carbon-nanotube (CNT)-graphene three-dimensional networks. We predict the transmission function of individual phonon modes using the wave packet method; surprisingly, most incident phonon modes show predominantly polarization conversion behavior. For instance, longitudinal acoustic (LA) polarizations incident from CNTs transmit mainly into flexural transverse (ZA) polarizations in graphene. The frequency stays the same as the incident mode, indicating elastic transmission. Polarization conversion is more significant as the phonon wavelength increases. We attribute such unique phonon polarization conversion behavior to the dimensional mismatch across the interface, and it opens significantly new phonon transport channels as compared to existing theories where polarization conversion is neglected.

Contingency blindness: location-identity binding mismatches obscure awareness of spatial contingencies and produce profound interference in visual working memory.

PubMed

Fiacconi, Chris M; Milliken, Bruce

2012-08-01

The purpose of the present study was to highlight the role of location-identity binding mismatches in obscuring explicit awareness of a strong contingency. In a spatial-priming procedure, we introduced a high likelihood of location-repeat trials. Experiments 1, 2a, and 2b demonstrated that participants' explicit awareness of this contingency was heavily influenced by the local match in location-identity bindings. In Experiment 3, we sought to determine why location-identity binding mismatches produce such low levels of contingency awareness. Our results suggest that binding mismatches can interfere substantially with visual-memory performance. We attribute the low levels of contingency awareness to participants' inability to remember the critical location-identity binding in the prime on a trial-to-trial basis. These results imply a close interplay between object files and visual working memory.

Reactivity of cytosine and thymine in single-base-pair mismatches with hydroxylamine and osmium tetroxide and its application to the study of mutations.

PubMed Central

Cotton, R G; Rodrigues, N R; Campbell, R D

1988-01-01

The chemical reactivity of thymine (T), when mismatched with the bases cytosine, guanine, and thymine, and of cytosine (C), when mismatched with thymine, adenine, and cytosine, has been examined. Heteroduplex DNAs containing such mismatched base pairs were first incubated with osmium tetroxide (for T and C mismatches) or hydroxylamine (for C mismatches) and then incubated with piperidine to cleave the DNA at the modified mismatched base. This cleavage was studied with an internally labeled strand containing the mismatched T or C, such that DNA cleavage and thus reactivity could be detected by gel electrophoresis. Cleavage at a total of 13 T and 21 C mismatches isolated (by at least three properly paired bases on both sides) single-base-pair mismatches was identified. All T or C mismatches studied were cleaved. By using end-labeled DNA probes containing T or C single-base-pair mismatches and conditions for limited cleavage, we were able to show that cleavage was at the base predicted by sequence analysis and that mismatches in a length of DNA could be readily detected by such an approach. This procedure may enable detection of all single-base-pair mismatches by use of sense and antisense probes and thus may be used to identify the mutated base and its position in a heteroduplex. Images PMID:3260032

Phenological mismatch and the effectiveness of assisted gene flow.

PubMed

Wadgymar, Susana M; Weis, Arthur E

2017-06-01

The persistence of narrowly adapted species under climate change will depend on their ability to migrate apace with their historical climatic envelope or to adapt in place to maintain fitness. This second path to persistence can only occur if there is sufficient genetic variance for response to new selection regimes. Inadequate levels of genetic variation can be remedied through assisted gene flow (AGF), that is the intentional introduction of individuals genetically adapted to localities with historic climates similar to the current or future climate experienced by the resident population. However, the timing of reproduction is frequently adapted to local conditions. Phenological mismatch between residents and migrants can reduce resident × migrant mating frequencies, slowing the introgression of migrant alleles into the resident genetic background and impeding evolutionary rescue efforts. Focusing on plants, we devised a method to estimate the frequency of resident × migrant matings based on flowering schedules and applied it in an experiment that mimicked the first generation of an AGF program with Chamaecrista fasciculata, a prairie annual, under current and expected future temperature regimes. Phenological mismatch reduced the potential for resident × migrant matings by 40-90%, regardless of thermal treatment. The most successful migrant sires were the most resident like in their flowering time, further biasing the genetic admixture between resident and migrant populations. Other loci contributing to local adaptation-heat-tolerance genes, for instance-may be in linkage disequilibrium with phenology when residents and migrants are combined into a single mating pool. Thus, introgression of potentially adaptive migrant alleles into the resident genetic background is slowed when selection acts against migrant phenology. Successful AGF programs may require sustained high immigration rates or preliminary breeding programs when phenologically matched migrant

Graft Growth and Podocyte Dedifferentiation in Donor-Recipient Size Mismatch Kidney Transplants

PubMed Central

Müller-Deile, Janina; Bräsen, Jan Hinrich; Pollheimer, Marion; Ratschek, Manfred; Haller, Hermann; Pape, Lars; Schiffer, Mario

2017-01-01

Background Kidney transplantation is the treatment choice for patients with end-stage renal diseases. Because of good long-term outcome, pediatric kidney grafts are also accepted for transplantation in adult recipients despite a significant mismatch in body size and age between donor and recipient. These grafts show a remarkable ability of adaptation to the recipient body and increase in size in a very short period, presumably as an adaptation to hyperfiltration. Methods We investigated renal graft growth as well as glomerular proliferation and differentiation markers Kiel-67, paired box gene 2 and Wilms tumor protein (WT1) expression in control biopsies from different transplant constellations: infant donor for infant recipient, infant donor for child recipient, infant donor for adult recipient, child donor for child recipient, child donor for adult recipient, and adult donor for an adult recipient. Results We detected a significant increase in kidney graft size after transplantation in all conditions with a body size mismatch, which was most prominent when an infant donated for a child. Podocyte WT1 expression was comparable in different transplant conditions, whereas a significant increase in WT1 expression could be detected in parietal epithelial cells, when a kidney graft from a child was transplanted into an adult. In kidney grafts that were relatively small for the recipients, we could detect reexpression of podocyte paired box gene 2. Moreover, the proliferation marker Kiel-67 was expressed in glomerular cells in grafts that increased in size after transplantation. Conclusions Kidney grafts rapidly adapt to the recipient size after transplantation if they are transplanted in a body size mismatch constellation. The increase in transplant size is accompanied by an upregulation of proliferation and dedifferentiation markers in podocytes. The different examined conditions exclude hormonal factors as the key trigger for this growth so that most likely

Measuring DNA hybridization using fluorescent DNA-stabilized silver clusters to investigate mismatch effects on therapeutic oligonucleotides.

PubMed

de Bruin, Donny; Bossert, Nelli; Aartsma-Rus, Annemieke; Bouwmeester, Dirk

2018-04-06

Short nucleic acid oligomers have found a wide range of applications in experimental physics, biology and medicine, and show potential for the treatment of acquired and genetic diseases. These applications rely heavily on the predictability of hybridization through Watson-Crick base pairing to allow positioning on a nanometer scale, as well as binding to the target transcripts, but also off-target binding to transcripts with partial homology. These effects are of particular importance in the development of therapeutic oligonucleotides, where off-target effects caused by the binding of mismatched sequences need to be avoided. We employ a novel method of probing DNA hybridization using optically active DNA-stabilized silver clusters (Ag-DNA) to measure binding efficiencies through a change in fluorescence intensity. In this way we can determine their location-specific sensitivity to individual mismatches in the sequence. The results reveal a strong dependence of the hybridization on the location of the mismatch, whereby mismatches close to the edges and center show a relatively minor impact. In parallel, we propose a simple model for calculating the annealing ratios of mismatched DNA sequences, which supports our experimental results. The primary result shown in this work is a demonstration of a novel technique to measure DNA hybridization using fluorescent Ag-DNA. With this technique, we investigated the effect of mismatches on the hybridization efficiency, and found a significant dependence on the location of individual mismatches. These effects are strongly influenced by the length of the used oligonucleotides. The novel probe method based on fluorescent Ag-DNA functions as a reliable tool in measuring this behavior. As a secondary result, we formulated a simple model that is consistent with the experimental data.

Label-free optical detection of single-base mismatches by the combination of nuclease and gold nanoparticles.

PubMed

Liu, Meiying; Yuan, Min; Lou, Xinhui; Mao, Hongju; Zheng, Dongmei; Zou, Ruxing; Zou, Nengli; Tang, Xiangrong; Zhao, Jianlong

2011-07-15

We report here an optical approach that enables highly selective and colorimetric single-base mismatch detection without the need of target modification, precise temperature control or stringent washes. The method is based on the finding that nucleoside monophosphates (dNMPs), which are digested elements of DNA, can better stabilize unmodified gold nanoparticles (AuNPs) than single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with the same base-composition and concentration. The method combines the exceptional mismatch discrimination capability of the structure-selective nucleases with the attractive optical property of AuNPs. Taking S1 nuclease as one example, the perfectly matched 16-base synthetic DNA target was distinctively differentiated from those with single-base mutation located at any position of the 16-base synthetic target. Single-base mutations present in targets with varied length up to 80-base, located either in the middle or near to the end of the targets, were all effectively detected. In order to prove that the method can be potentially used for real clinic samples, the single-base mismatch detections with two HBV genomic DNA samples were conducted. To further prove the generality of this method and potentially overcome the limitation on the detectable lengths of the targets of the S1 nuclease-based method, we also demonstrated the use of a duplex-specific nuclease (DSN) for color reversed single-base mismatch detection. The main limitation of the demonstrated methods is that it is limited to detect mutations in purified ssDNA targets. However, the method coupled with various convenient ssDNA generation and purification techniques, has the potential to be used for the future development of detector-free testing kits in single nucleotide polymorphism screenings for disease diagnostics and treatments. Copyright © 2011 Elsevier B.V. All rights reserved.

Differential Influences of Ethanol on Early Exposure to Racemic Methylphenidate Compared with Dexmethylphenidate in Humans

PubMed Central

Straughn, Arthur B.; Reeves, Owen T.; Bernstein, Hilary; Bell, Guinevere H.; Anderson, Erica R.; Malcolm, Robert J.

2013-01-01

Enantioselective hydrolysis of oral racemic methylphenidate (dl-MPH) by carboxylesterase 1 (CES1) limits the absolute bioavailability of the pharmacologically active d-MPH isomer to approximately 30% and that of the inactive l-MPH to only 1–2%. Coadministration of dl-MPH with ethanol results in elevated d-MPH plasma concentrations accompanied by CES1-mediated enantioselective transesterification of l-MPH to l-ethylphenidate (EPH). The present study tested the hypothesis that administration of the pure isomer dexmethylphenidate (d-MPH) will overcome the influence of ethanol on d-MPH absorption by eliminating competitive CES1-mediated presystemic metabolism of l-MPH to l-EPH. Twenty-four healthy volunteers received dl-MPH (0.3 mg/kg) or d-MPH (0.15 mg/kg), with or without ethanol (0.6 g/kg). During the absorption phase of dl-MPH, concomitant ethanol significantly elevated d-MPH plasma concentrations (44–99%; P < 0.005). Furthermore, immediately following the ethanol drink the subjective effects of “high,” “good,” “like,” “stimulated,” and overall “effect” were significantly potentiated (P ≤ 0.01). Plasma l-EPH concentrations exceeded those of l-MPH. Ethanol combined with pure d-MPH did not elevate plasma d-MPH concentrations during the absorption phase, and the ethanol-induced potentiation of subjective effects was delayed relative to dl-MPH-ethanol. These findings are consistent with l-MPH competitively inhibiting presystemic CES1 metabolism of d-MPH. Ethanol increased the d-MPH area under the curve (AUC)0-inf by 21% following dl-MPH (P < 0.001) and 14% for d-MPH (P = 0.001). In men receiving d-MPH-ethanol, the d-MPH absorption partial AUC0.5–2 hours was 2.1 times greater and the time to maximum concentration (Tmax) occurred 1.1 hours earlier than in women, consistent with an increased rate of d-MPH absorption reducing hepatic extraction. More rapid absorption of d-MPH carries implications for increased abuse liability. PMID:23104969

GLI1 interferes with the DNA mismatch repair system in pancreatic cancer through BHLHE41-mediated suppression of MLH1.

PubMed

Inaguma, Shingo; Riku, Miho; Hashimoto, Mitsuyoshi; Murakami, Hideki; Saga, Shinsuke; Ikeda, Hiroshi; Kasai, Kenji

2013-12-15

The mismatch repair (MMR) system is indispensable for the fidelity of DNA replication, the impairment of which predisposes to the development and progression of many types of cancers. To date, GLI1 transcription factor, a key molecule of the Hedgehog signaling pathway, has been shown to regulate the expression of several genes crucial for a variety of cancer cell properties in many types of cancers, including pancreatic ductal adenocarcinoma (PDAC), but whether GLI1 could control the MMR system was not known. Here, we showed that GLI1 and GLI2 indirectly suppressed the expression of MLH1 in PDAC cells. Through GLI1 target gene screening, we found that GLI1 and GLI2 activated the expression of a basic helix-loop-helix type suppressor BHLHE41/DEC2/SHARP1 through a GLI-binding site in the promoter. Consistent with a previous report that BHLHE41 suppresses the MLH1 promoter activity, we found that the activation of GLI1 led to the BHLHE41-dependent suppression of MLH1, and a double knockdown of GLI1 and GLI2 conversely increased the MLH1 protein in PDAC cells. Using TALEN-based modification of the MLH1 gene, we further showed that GLI1 expression was indeed associated with an increased tolerance to a methylating agent, methylnitrosourea cooperatively with a lower copy number status of MLH1. Finally, GLI1 expression was immunohistochemically related positively with BHLHE41 and inversely with MLH1 in PDAC cells and precancerous lesions of the pancreas. On the basis of these results, we propose that GLI1 depresses the MMR activity and might contribute to the development and progression of PDAC. ©2013 AACR.

Evaluation of Isotopic Data Mismatches on DOE-STD-1027 Facility Categorization Inventories for the K-1065 Complex and the Above Grade Storage Facility (AGSF)

DOE Office of Scientific and Technical Information (OSTI.GOV)

McHugh, M.G.; Coleman, G.H.

2006-07-01

The contents of a safety basis (SB) are based upon the facility's purpose of operation, radiological inventory, and safety systems in place to mitigate any releases to the employees, general public and environment. Specifically, the radiological inventory is used for facility categorizations (e.g., Category 2, Category 3) and determining the material at risk used in the associated nuclear safety analysis calculations. Radiological inventory discrepancies, referred to as 'mismatches', have the potential to adversely impact the SB. This paper summarizes a process developed to: 1) identify these 'mismatches' based on a facility's radiological inventory, 2) categorize these 'mismatches' according to availablemore » data, and then 3) determine if these 'mismatches' yield either trivial or significant cumulative impacts on credited assumptions associated with a particular facility's SB. The two facilities evaluated for 'mismatches' were the K-1065 Complex and the Above Grade Storage Facility (AGSF). The randomly selected containers from each facility were obtained along with screening the radiological inventories found in the Waste Information Tracking System (WITS) database and the Request for Disposal (RFD) forms. Ideally, the radiological inventory, which is comprised of isotopic data for each container, is maintained in the WITS database. However, the RFD is the official repository record for isotopic data for each container. Historically, neither WITS nor the RFDs were required to contain isotopic data. Based on the WITS and RFD data, the containers were then categorized into five (5) separate conditions: Condition 1) Isotopic data in the RFD matches the isotopic data in WITS; Condition 2) Isotopic data in the RFD does not match the isotopic data in WITS; Condition 3) Isotopic data are in the RFD, but are not in WITS; Condition 4) No isotopic data in the RFD, but isotopic data are found in WITS; Condition 5) No isotopic data found in either the RFD or WITS. The

Highly mismatched GaN1-x Sb x alloys: synthesis, structure and electronic properties

NASA Astrophysics Data System (ADS)

Yu, K. M.; Sarney, W. L.; Novikov, S. V.; Segercrantz, N.; Ting, M.; Shaw, M.; Svensson, S. P.; Martin, R. W.; Walukiewicz, W.; Foxon, C. T.

2016-08-01

Highly mismatched alloys (HMAs) is a class of semiconductor alloys whose constituents are distinctly different in terms of size, ionicity and/or electronegativity. Electronic properties of the alloys deviate significantly from an interpolation scheme based on small deviations from the virtual crystal approximation. Most of the HMAs were only studied in a dilute composition limit. Recent advances in understanding of the semiconductor synthesis processes allowed growth of thin films of HMAs under non-equilibrium conditions. Thus reducing the growth temperature allowed synthesis of group III-N-V HMAs over almost the entire composition range. This paper focuses on the GaN x Sb1-x HMA which has been suggested as a potential material for solar water dissociation devices. Here we review our recent work on the synthesis, structural and optical characterization of GaN1-x Sb x HMA. Theoretical modeling studies on its electronic structure based on the band anticrossing (BAC) model are also reviewed. In particular we discuss the effects of growth temperature, Ga flux and Sb flux on the incorporation of Sb, film microstructure and optical properties of the alloys. Results obtained from two separate MBE growths are directly compared. Our work demonstrates that a large range of direct bandgap energies from 3.4 eV to below 1.0 eV can be achieved for this alloy grown at low temperature. We show that the electronic band structure of GaN1-x Sb x HMA over the entire composition range is well described by a modified BAC model which includes the dependence of the host matrix band edges as well as the BAC model coupling parameters on composition. We emphasize that the modified BAC model of the electronic band structure developed for the full composition of GaN x Sb1-x is general and is applicable to any HMA.

Tuning quadratic nonlinear photonic crystal fibers for zero group-velocity mismatch.

PubMed

Bache, Morten; Nielsen, Hanne; Laegsgaard, Jesper; Bang, Ole

2006-06-01

We consider an index-guiding silica photonic crystal fiber with a triangular hole pattern and a periodically poled quadratic nonlinearity. By tuning the pitch and the relative hole size, second-harmonic generation with zero group-velocity mismatch is found for any fundamental wavelength above 780 nm. The nonlinear strength is optimized when the fundamental has maximum confinement in the core. The conversion bandwidth allows for femtosecond-pulse conversion, and 4%-180%W(-1)cm(-2) relative efficiencies were found.

Temperature-dependent spectral mismatch corrections

DOE PAGES

Osterwald, Carl R.; Campanelli, Mark; Moriarty, Tom; ...

2015-11-01

This study develops the mathematical foundation for a translation of solar cell short-circuit current from one thermal and spectral irradiance operating condition to another without the use of ill-defined and error-prone temperature coefficients typically employed in solar cell metrology. Using the partial derivative of quantum efficiency with respect to temperature, the conventional isothermal expression for spectral mismatch corrections is modified to account for changes of current due to temperature; this modification completely eliminates the need for short-circuit-current temperature coefficients. An example calculation is provided to demonstrate use of the new translation.

An Index-Mismatch Scattering Approach to Optical Limiting

DOE Office of Scientific and Technical Information (OSTI.GOV)

Exarhos, Gregory J.; Ferris, Kim F.; Windisch, Charles F.

A densely packed bed of alkaline earth fluoride particles percolated by a fluid medium has been investigated as a potential index-matched optical limiter in the spirit of a Christiansen-Shelyubskii filter. Marked optical limiting was observed through this transparent medium under conditions where the focused second-harmonic output of a Q-swtiched Nd: YAG laser was on the order of about 1 J/cm2. An open-aperture Z-scan technique was used to quantify the limiting behavior. In this case, the mechanism of optical limiting is thought to be a nonlinear shift in the fluid index of refraction, resulting in an index mismatch between the disparatemore » phases at high laser fluence.« less

KENNEDY SPACE CENTER, FLA. - The crawler transporter slowly moves the Mobile Launcher Platform (MLP), carrying a set of twin solid rocket boosters, away from the Vehicle Assembly Building (VAB) in support of engineering analysis vibration tests on the crawler and MLP. The crawler is moving at various speeds up to 1 mph in an effort to achieve vibration data gathering goals as it leaves the VAB and then returns. The boosters are braced at the top for stability. The primary purpose of these rollout tests is to gather data to develop future maintenance requirements on the transport equipment and the flight hardware. Various parts of the MLP and crawler transporter have been instrumented with vibration data collection equipment.

NASA Image and Video Library

2003-11-17

KENNEDY SPACE CENTER, FLA. - The crawler transporter slowly moves the Mobile Launcher Platform (MLP), carrying a set of twin solid rocket boosters, away from the Vehicle Assembly Building (VAB) in support of engineering analysis vibration tests on the crawler and MLP. The crawler is moving at various speeds up to 1 mph in an effort to achieve vibration data gathering goals as it leaves the VAB and then returns. The boosters are braced at the top for stability. The primary purpose of these rollout tests is to gather data to develop future maintenance requirements on the transport equipment and the flight hardware. Various parts of the MLP and crawler transporter have been instrumented with vibration data collection equipment.

KENNEDY SPACE CENTER, FLA. - The crawler transporter has slowly moved the Mobile Launcher Platform (MLP), carrying a set of twin solid rocket boosters, out of the Vehicle Assembly Building (VAB) in support of engineering analysis vibration tests on the crawler and MLP. The crawler is moving at various speeds up to 1 mph in an effort to achieve vibration data gathering goals as it leaves the VAB and then returns. The boosters are braced at the top for stability. The primary purpose of these rollout tests is to gather data to develop future maintenance requirements on the transport equipment and the flight hardware. Various parts of the MLP and crawler transporter have been instrumented with vibration data collection equipment.

NASA Image and Video Library

2003-11-17

KENNEDY SPACE CENTER, FLA. - The crawler transporter has slowly moved the Mobile Launcher Platform (MLP), carrying a set of twin solid rocket boosters, out of the Vehicle Assembly Building (VAB) in support of engineering analysis vibration tests on the crawler and MLP. The crawler is moving at various speeds up to 1 mph in an effort to achieve vibration data gathering goals as it leaves the VAB and then returns. The boosters are braced at the top for stability. The primary purpose of these rollout tests is to gather data to develop future maintenance requirements on the transport equipment and the flight hardware. Various parts of the MLP and crawler transporter have been instrumented with vibration data collection equipment.

KENNEDY SPACE CENTER, FLA. - The crawler transporter slowly moves the Mobile Launcher Platform (MLP), carrying a set of twin solid rocket boosters, along the crawlerway in support of engineering analysis vibration tests on the crawler and MLP. The crawler is moving at various speeds up to 1 mph in an effort to achieve vibration data gathering goals as it leaves the VAB and then returns. The boosters are braced at the top for stability. The primary purpose of these rollout tests is to gather data to develop future maintenance requirements on the transport equipment and the flight hardware. Various parts of the MLP and crawler transporter have been instrumented with vibration data collection equipment.

NASA Image and Video Library

2003-11-17

KENNEDY SPACE CENTER, FLA. - The crawler transporter slowly moves the Mobile Launcher Platform (MLP), carrying a set of twin solid rocket boosters, along the crawlerway in support of engineering analysis vibration tests on the crawler and MLP. The crawler is moving at various speeds up to 1 mph in an effort to achieve vibration data gathering goals as it leaves the VAB and then returns. The boosters are braced at the top for stability. The primary purpose of these rollout tests is to gather data to develop future maintenance requirements on the transport equipment and the flight hardware. Various parts of the MLP and crawler transporter have been instrumented with vibration data collection equipment.

KENNEDY SPACE CENTER, FLA. - The crawler transporter is slowly moving the Mobile Launcher Platform (MLP), carrying a set of twin solid rocket boosters, out of the Vehicle Assembly Building (VAB) in support of engineering analysis vibration tests on the crawler and MLP. The crawler is moving at various speeds up to 1 mph in an effort to achieve vibration data gathering goals as it leaves the VAB and then returns. The boosters are braced at the top for stability. The primary purpose of these rollout tests is to gather data to develop future maintenance requirements on the transport equipment and the flight hardware. Various parts of the MLP and crawler transporter have been instrumented with vibration data collection equipment.

NASA Image and Video Library

2003-11-17

KENNEDY SPACE CENTER, FLA. - The crawler transporter is slowly moving the Mobile Launcher Platform (MLP), carrying a set of twin solid rocket boosters, out of the Vehicle Assembly Building (VAB) in support of engineering analysis vibration tests on the crawler and MLP. The crawler is moving at various speeds up to 1 mph in an effort to achieve vibration data gathering goals as it leaves the VAB and then returns. The boosters are braced at the top for stability. The primary purpose of these rollout tests is to gather data to develop future maintenance requirements on the transport equipment and the flight hardware. Various parts of the MLP and crawler transporter have been instrumented with vibration data collection equipment.

KENNEDY SPACE CENTER, FLA. - The crawler transporter slowly moves the Mobile Launcher Platform (MLP), carrying a set of twin solid rocket boosters, out of the Vehicle Assembly Building (VAB) in support of engineering analysis vibration tests on the crawler and MLP. The crawler is moving at various speeds up to 1 mph in an effort to achieve vibration data gathering goals as it leaves the VAB and then returns. The boosters are braced at the top for stability. The primary purpose of these rollout tests is to gather data to develop future maintenance requirements on the transport equipment and the flight hardware. Various parts of the MLP and crawler transporter have been instrumented with vibration data collection equipment.

NASA Image and Video Library

2003-11-17

KENNEDY SPACE CENTER, FLA. - The crawler transporter slowly moves the Mobile Launcher Platform (MLP), carrying a set of twin solid rocket boosters, out of the Vehicle Assembly Building (VAB) in support of engineering analysis vibration tests on the crawler and MLP. The crawler is moving at various speeds up to 1 mph in an effort to achieve vibration data gathering goals as it leaves the VAB and then returns. The boosters are braced at the top for stability. The primary purpose of these rollout tests is to gather data to develop future maintenance requirements on the transport equipment and the flight hardware. Various parts of the MLP and crawler transporter have been instrumented with vibration data collection equipment.

Comorbidities in ADHD children treated with methylphenidate: a database study

PubMed Central

2013-01-01

Background Methylphenidate (MPH) is the most common drug treatment of attention deficit / hyperactivity disorder (ADHD) in children. Treatment with MPH is contraindicated in the presence of certain psychiatric, cerebro- and cardiovascular conditions. We assessed MPH treatment prevalence and incidence and the frequency of comorbid conditions related to these contraindications in new MPH users compared to a control group without ADHD and ADHD medication. Methods We used health care data for the years 2004 to 2006 from the German Pharmacoepidemiological Research Database (GePaRD) which includes about 18% of the German population. MPH treatment prevalence and incidence was assessed based on at least one MPH prescription in the given year. In MPH users, the prevalence of psychiatric and other comorbidities was assessed in the quarter of the first MPH prescription and the three preceding quarters, whereas in controls it was assessed in the earliest four quarters of continuous insurance time starting at 01.01.2004 or the start of insurance if this was later. Differences in the presence of comorbid diagnoses between MPH users and controls were tested by logistic regression. Results In 2005, 1.5% of all children and adolescents aged 3 to 17 years (2.3% of males and 0.6% of females) received MPH in Germany. The proportion of children with a record of a psychiatric comorbidity in any of the nine ICD categories of diagnoses was substantially higher in new MPH users (83%) compared to controls (20%). Cerebro- and cardiovascular comorbidities were rare in general. Still, among new MPH users, 2% of males and females had a diagnosis of a pre-existing cardiovascular disorder but only 1.2% of controls. Conclusions Besides MPH treatment prevalence we first publish age-specific incidence rates for Germany. A high proportion of children who were started on MPH had a record of a psychiatric comorbidity preceding the first prescription. Cerebro- and cardiovascular conditions were rare

Evaluation of primer and probe mismatches in sensitivity of select RRT-PCR tests for avian influenza

USDA-ARS?s Scientific Manuscript database

The recent outbreak of pH1N1 in animals highlighted an imperfection of the matrix real-time reverse transcriptase-polymerase chain reaction (RRT-PCR) that has become the primary screening test for avian and swine influenza viruses. Four mismatches in one primer resulted in an important loss of sens...

Mismatch repair gene MSH3 polymorphism is associated with the risk of sporadic prostate cancer.

PubMed

Hirata, Hiroshi; Hinoda, Yuji; Kawamoto, Ken; Kikuno, Nobuyuki; Suehiro, Yutaka; Okayama, Naoko; Tanaka, Yuichiro; Dahiya, Rajvir

2008-05-01

The mismatch repair system is a DNA repair mechanism that corrects mispaired bases during DNA replication errors. Cancer cells deficient in MMR proteins have a 10(2) to 10(3)-fold increase in the mutation rate. Single nucleotide polymorphisms of mismatch repair genes have been shown to cause a decrease in DNA repair activity. We hypothesized that mismatch repair gene polymorphism could be a risk factor for prostate cancer and p53 Pro/Pro genotype carriers could influence MSH3 and MSH6 polymorphisms. DNA samples from 110 patients with prostate cancer and 110 healthy controls were analyzed by single strand conformational polymorphism and polymerase chain reaction-restriction fragment length polymorphism to determine the genotypic frequency of 5 polymorphic loci on 2 MMR genes (MSH3 and MSH6) and p53 codon72. The chi-square test was applied to compare genotype frequency between patients and controls. A significant increase in the G/A+A/A genotype of MSH3 Pro222Pro was observed in patients compared to controls (OR 1.87, 95% CI 1.0-3.5). The frequency of A/G + G/G genotypes of MSH3 exon23 Thr1036Ala also tended to increase in patients (OR 1.57, 95% CI 0.92-2.72). In p53 codon72 Arg/Pro + Pro/Pro carriers the frequency of the AG + GG genotype of MSH3 exon23 was significantly increased in patients compared to controls (OR 2.1, 95% CI 1.05-4.34). To our knowledge this is the first report of the association of MSH3 gene polymorphisms in prostate cancer. These results suggest that the MSH3 polymorphism may be a risk factor for prostate cancer.

Identification of miR-31-5p, miR-141-3p, miR-200c-3p, and GLT1 as human liver aging markers sensitive to donor-recipient age-mismatch in transplants.

PubMed

Capri, Miriam; Olivieri, Fabiola; Lanzarini, Catia; Remondini, Daniel; Borelli, Vincenzo; Lazzarini, Raffaella; Graciotti, Laura; Albertini, Maria Cristina; Bellavista, Elena; Santoro, Aurelia; Biondi, Fiammetta; Tagliafico, Enrico; Tenedini, Elena; Morsiani, Cristina; Pizza, Grazia; Vasuri, Francesco; D'Errico, Antonietta; Dazzi, Alessandro; Pellegrini, Sara; Magenta, Alessandra; D'Agostino, Marco; Capogrossi, Maurizio C; Cescon, Matteo; Rippo, Maria Rita; Procopio, Antonio Domenico; Franceschi, Claudio; Grazi, Gian Luca

2017-04-01

To understand why livers from aged donors are successfully used for transplants, we looked for markers of liver aging in 71 biopsies from donors aged 12-92 years before transplants and in 11 biopsies after transplants with high donor-recipient age-mismatch. We also assessed liver function in 36 age-mismatched recipients. The major findings were the following: (i) miR-31-5p, miR-141-3p, and miR-200c-3p increased with age, as assessed by microRNAs (miRs) and mRNA transcript profiling in 12 biopsies and results were validated by RT-qPCR in a total of 58 biopsies; (ii) telomere length measured by qPCR in 45 samples showed a significant age-dependent shortage; (iii) a bioinformatic approach combining transcriptome and miRs data identified putative miRs targets, the most informative being GLT1, a glutamate transporter expressed in hepatocytes. GLT1 was demonstrated by luciferase assay to be a target of miR-31-5p and miR-200c-3p, and both its mRNA (RT-qPCR) and protein (immunohistochemistry) significantly decreased with age in liver biopsies and in hepatic centrilobular zone, respectively; (iv) miR-31-5p, miR-141-3p and miR-200c-3p expression was significantly affected by recipient age (older environment) as assessed in eleven cases of donor-recipient extreme age-mismatch; (v) the analysis of recipients plasma by N-glycans profiling, capable of assessing liver functions and biological age, showed that liver function recovered after transplants, independently of age-mismatch, and recipients apparently 'rejuvenated' according to their glycomic age. In conclusion, we identified new markers of aging in human liver, their relevance in donor-recipient age-mismatches in transplantation, and offered positive evidence for the use of organs from old donors. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Motif mismatches in microsatellites: insights from genome-wide investigation among 20 insect species.

PubMed

Behura, Susanta K; Severson, David W

2015-02-01

We present a detailed genome-wide comparative study of motif mismatches of microsatellites among 20 insect species representing five taxonomic orders. The results show that varying proportions (∼15-46%) of microsatellites identified in these species are imperfect in motif structure, and that they also vary in chromosomal distribution within genomes. It was observed that the genomic abundance of imperfect repeats is significantly associated with the length and number of motif mismatches of microsatellites. Furthermore, microsatellites with a higher number of mismatches tend to have lower abundance in the genome, suggesting that sequence heterogeneity of repeat motifs is a key determinant of genomic abundance of microsatellites. This relationship seems to be a general feature of microsatellites even in unrelated species such as yeast, roundworm, mouse and human. We provide a mechanistic explanation of the evolutionary link between motif heterogeneity and genomic abundance of microsatellites by examining the patterns of motif mismatches and allele sequences of single-nucleotide polymorphisms identified within microsatellite loci. Using Drosophila Reference Genetic Panel data, we further show that pattern of allelic variation modulates motif heterogeneity of microsatellites, and provide estimates of allele age of specific imperfect microsatellites found within protein-coding genes. © The Author 2014. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.

Comparative treatment patterns, healthcare resource utilization and costs of atomoxetine and long-acting methylphenidate among children and adolescents with attention-deficit/hyperactivity disorder in Germany.

PubMed

Greven, Peter; Sikirica, Vanja; Chen, Yaozhu J; Curtice, Tammy G; Makin, Charles

2017-09-01

Attention-deficit/hyperactivity disorder (ADHD) imposes a substantial burden on patients and their families. A retrospective, propensity score-matched cohort study compared treatment patterns, healthcare resource utilization (HRU) and costs among children/adolescents with ADHD aged 6-17 years at treatment initiation (index) in Germany who received atomoxetine (ATX) or long-acting methylphenidate (LA-MPH) monotherapy. Patients received at least one prescription for their index medication (ATX/LA-MPH) during 2006-2010; the first prescription marked the index date. ATX- and LA-MPH-indexed cohorts were matched 1:1 (n = 737); a patient subset was identified that had not received ADHD-indicated medications in 12 months prior to index (novel initiators: ATX, n = 486; LA-MPH, n = 488). Treatment patterns were evaluated among novel initiators, and HRU and costs among the matched cohorts in the 12 months after index. No significant differences in baseline characteristics were found between the novel initiator patient subsets. ATX-indexed novel initiators had significantly longer persistence to index medication [mean (standard deviation; SD) days: 222.0 (133.9) vs 203.2 (135.0), P = 0.029) but higher switching rates (8.8 vs 5.5 %, P = 0.045) than LA-MPH-indexed novel initiators. The total ATX-indexed cohort required more prescriptions [any medication; mean (SD): 20.9 (11.5) vs 15.7 (9.0), P < 0.001] and outpatient visits [mean (SD): 10.1 (6.3) vs 8.3 (5.3), P < 0.001], and incurred significantly higher total median healthcare costs (€1144 vs €541, P < 0.001) versus matched LA-MPH patients. These real-world data indicate that, among children/adolescents with ADHD in Germany, ATX-indexed patients may require more prescriptions and physician visits, and incur higher total healthcare costs, than matched LA-MPH patients.

On compensation of mismatched recording conditions in the Bayesian approach for forensic automatic speaker recognition.

PubMed

Botti, F; Alexander, A; Drygajlo, A

2004-12-02

This paper deals with a procedure to compensate for mismatched recording conditions in forensic speaker recognition, using a statistical score normalization. Bayesian interpretation of the evidence in forensic automatic speaker recognition depends on three sets of recordings in order to perform forensic casework: reference (R) and control (C) recordings of the suspect, and a potential population database (P), as well as a questioned recording (QR) . The requirement of similar recording conditions between suspect control database (C) and the questioned recording (QR) is often not satisfied in real forensic cases. The aim of this paper is to investigate a procedure of normalization of scores, which is based on an adaptation of the Test-normalization (T-norm) [2] technique used in the speaker verification domain, to compensate for the mismatch. Polyphone IPSC-02 database and ASPIC (an automatic speaker recognition system developed by EPFL and IPS-UNIL in Lausanne, Switzerland) were used in order to test the normalization procedure. Experimental results for three different recording condition scenarios are presented using Tippett plots and the effect of the compensation on the evaluation of the strength of the evidence is discussed.

Investigating a memory-based account of negative priming: support for selection-feature mismatch.

PubMed

MacDonald, P A; Joordens, S

2000-08-01

Using typical and modified negative priming tasks, the selection-feature mismatch account of negative priming was tested. In the modified task, participants performed selections on the basis of a semantic feature (e.g., referent size). This procedure has been shown to enhance negative priming (P. A. MacDonald, S. Joordens, & K. N. Seergobin, 1999). Across 3 experiments, negative priming occurred only when the repeated item mismatched in terms of the feature used as the basis for selections. When the repeated item was congruent on the selection feature across the prime and probe displays, positive priming arose. This pattern of results appeared in both the ignored- and the attended-repetition conditions. Negative priming does not result from previously ignoring an item. These findings strongly support the selection-feature mismatch account of negative priming and refute both the distractor inhibition and the episodic-retrieval explanations.

Individual characteristics associated with mismatches between self-reported and accelerometer-measured physical activity.

PubMed

Tully, Mark A; Panter, Jenna; Ogilvie, David

2014-01-01

Accurate assessment tools are required for the surveillance of physical activity (PA) levels and the assessment of the effect of interventions. In addition, increasing awareness of PA is often used as the first step in pragmatic behavioural interventions, as discrepancies between the amount of activity an individual perceives they do and the amount actually undertaken may act as a barrier to change. Previous research has demonstrated differences in the amount of activity individuals report doing, compared to their level of physical activity when measured with an accelerometer. Understanding the characteristics of those whose PA level is ranked differently when measured with either self-report or accelerometry is important as it may inform the choice of instrument for future research. The aim of this project was to determine which individual characteristics are associated with differences between self-reported and accelerometer measured physical activity. Participant data from the 2009 wave of the Commuting and Health in Cambridge study were used. Quartiles of self-reported and accelerometer-measured PA were derived by ranking each measure from lowest to highest. These quartiles were compared to determine whether individuals' physical activity was ranked higher by either method. Multinomial logistic regression models were used to investigate the individual characteristics associated with different categories of mismatch. Data from 486 participants (70% female) were included in the analysis. In adjusted analyses, the physical activity of overweight or obese individuals was significantly more likely to be ranked higher by self-report than by accelerometer than that of normal-weight individuals (OR = 2.07, 95%CI = 1.28-3.34), particularly among women (OR = 3.97, 95%CI = 2.11-7.47). There was a greater likelihood of mismatch between self-reported and accelerometer measured physical activity levels in overweight or obese adults. Future studies in overweight or obese

Log-layer mismatch and modeling of the fluctuating wall stress in wall-modeled large-eddy simulations

NASA Astrophysics Data System (ADS)

Yang, Xiang I. A.; Park, George Ilhwan; Moin, Parviz

2017-10-01

Log-layer mismatch refers to a chronic problem found in wall-modeled large-eddy simulation (WMLES) or detached-eddy simulation, where the modeled wall-shear stress deviates from the true one by approximately 15 % . Many efforts have been made to resolve this mismatch. The often-used fixes, which are generally ad hoc, include modifying subgrid-scale stress models, adding a stochastic forcing, and moving the LES-wall-model matching location away from the wall. An analysis motivated by the integral wall-model formalism suggests that log-layer mismatch is resolved by the built-in physics-based temporal filtering. In this work we investigate in detail the effects of local filtering on log-layer mismatch. We show that both local temporal filtering and local wall-parallel filtering resolve log-layer mismatch without moving the LES-wall-model matching location away from the wall. Additionally, we look into the momentum balance in the near-wall region to provide an alternative explanation of how LLM occurs, which does not necessarily rely on the numerical-error argument. While filtering resolves log-layer mismatch, the quality of the wall-shear stress fluctuations predicted by WMLES does not improve with our remedy. The wall-shear stress fluctuations are highly underpredicted due to the implied use of LES filtering. However, good agreement can be found when the WMLES data are compared to the direct numerical simulation data filtered at the corresponding WMLES resolutions.

40 CFR 86.161-00 - Air conditioning environmental test facility ambient requirements.

Code of Federal Regulations, 2010 CFR

2010-07-01

... each point of a 0.5 meter grid over the entire footprint of the test vehicle at the elevation of one... impractical, air flow of 2 mph or less will be allowed at 0 mph vehicle speed. (3) The fan air flow velocity..., within the test cell, during all phases of the air conditioning test sequence to 95 ±2 °F on average and...

The development of estimated methodology for interfacial adhesion of semiconductor coatings having an enormous mismatch extent

NASA Astrophysics Data System (ADS)

Lee, Chang-Chun; Huang, Pei-Chen

2018-05-01

The long-term reliability of multi-stacked coatings suffering the bending or rolling load was a severe challenge to extend the lifespan of foregoing structure. In addition, the adhesive strength of dissimilar materials was regarded as the major mechanical reliability concerns among multi-stacked films. However, the significant scale-mismatch from several nano-meter to micro-meter among the multi-stacked coatings causing the numerical accuracy and converged capability issues on fracture-based simulation approach. For those reasons, this study proposed the FEA-based multi-level submodeling and multi-point constraint (MPC) technique to conquer the foregoing scale-mismatch issue. The results indicated that the decent region of first and second-order submodeling can achieve the small error of 1.27% compared with the experimental result and significantly reduced the mesh density and computing time. Moreover, the MPC method adopted in FEA simulation also shown only 0.54% error when the boundary of selected local region was away the concerned critical region following the Saint-Venant principle. In this investigation, two FEA-based approaches were used to conquer the evidently scale mismatch issue when the adhesive strengths of micro and nano-scale multi-stacked coating were taken into account.

Efficient engineering of chromosomal ribosome binding site libraries in mismatch repair proficient Escherichia coli.

PubMed

Oesterle, Sabine; Gerngross, Daniel; Schmitt, Steven; Roberts, Tania Michelle; Panke, Sven

2017-09-26

Multiplexed gene expression optimization via modulation of gene translation efficiency through ribosome binding site (RBS) engineering is a valuable approach for optimizing artificial properties in bacteria, ranging from genetic circuits to production pathways. Established algorithms design smart RBS-libraries based on a single partially-degenerate sequence that efficiently samples the entire space of translation initiation rates. However, the sequence space that is accessible when integrating the library by CRISPR/Cas9-based genome editing is severely restricted by DNA mismatch repair (MMR) systems. MMR efficiency depends on the type and length of the mismatch and thus effectively removes potential library members from the pool. Rather than working in MMR-deficient strains, which accumulate off-target mutations, or depending on temporary MMR inactivation, which requires additional steps, we eliminate this limitation by developing a pre-selection rule of genome-library-optimized-sequences (GLOS) that enables introducing large functional diversity into MMR-proficient strains with sequences that are no longer subject to MMR-processing. We implement several GLOS-libraries in Escherichia coli and show that GLOS-libraries indeed retain diversity during genome editing and that such libraries can be used in complex genome editing operations such as concomitant deletions. We argue that this approach allows for stable and efficient fine tuning of chromosomal functions with minimal effort.

Tuning thermal mismatch between turbine rotor parts with a thermal medium

DOEpatents

Schmidt, Mark Christopher

2001-01-01

In a turbine rotor, an aft shaft wheel and the final-stage wheel of the rotor are coupled together, including by a rabbeted joint. During shutdown and startup of the turbine, a thermal mismatch between the aft shaft wheel and final-stage wheel is avoided by respectively heating and cooling the aft shaft wheel to maintain the thermal mismatch within acceptable limits, thereby avoiding opening of the rabbeted joint and the potential for unbalancing the rotor and rotor vibration. The thermal medium may be supplied by piping in the aft bearing cavity into the cavity between the forward closure plate and the aft shaft wheel.

IFN-γ Blocks CD4+CD25+ Tregs and Abolishes Immune Privilege of Minor Histocompatibility Mismatched Corneal Allografts

PubMed Central

Cunnusamy, Khrishen; Niederkorn, Jerry Y.

2014-01-01

Th1 CD4+ cells are believed to be the primary mediators of corneal allograft rejection. However, rejection of fully allogeneic C57BL/6 corneal allografts soared from 50% to 90% in both INF-γ−/− and anti-IFN-γ-treated BALB/c mice. In contrast, similar deficits in IFN-γ in BALB/c hosts enhanced immune privilege of BALB.B (minor histocompatibility antigen-matched, MHC-mismatched) and NZB (major histocompatibility complex-matched, minor histocompatibility antigen-mismatched) corneal allografts – decreasing rejection from 80% to ~20%. This effect of IFN-γ was independent of CD4+ T cell lineage commitment as both anti-IFN-γ-treated acceptor and rejector mice displayed a Th2 cytokine profile. The presence of IFN-γ prevented the generation of alloantigen-specific CD4+CD25+ Tregs in hosts receiving either MHC only mismatched BALB.B or minor only histocompatibility (minor H)-mismatched NZB corneal allografts. Tregs in these hosts, promoted corneal allograft survival by suppressing Th2 effector cells. By contrast, IFN-γ was necessary for the generation of CD4+CD25+ Tregs that prevented rejection of fully allogeneic C57BL/6 corneal allografts in BALB/c hosts. These findings suggest that MHC-matching in combination with blockade of IFN-γ holds promise as a means of enhancing corneal allograft survival. PMID:24119152

Thickness dependent properties of CMR Manganite thin films on lattice mismatched substrates: Distinguishing Strain and Interface Effects

NASA Astrophysics Data System (ADS)

Davidson, Anthony, III; Kolagani, Rajeswari; Bacharova, Ellisaveta; Yong, Grace; Smolyaninova, Vera; Schaefer, David; Mundle, Rajeh

2007-03-01

Epitaxial thin films of CMR manganite materials have been known to show thickness dependent electrical and magnetic properties on lattice mismatched substrates. Below a critical thickness, insulator-metal transition is suppressed. These effects have been largely attributed to the role of bi-axial lattice mismatch strain. Our recent results of epitaxial thin films of La0.67Ca0.33MnO3 (LCMO) on two substrates with varying degrees of compressive lattice mismatch indicate that, in addition to the effect of lattice mismatch strain, the thickness dependence of the properties are influenced by other factors possibly related to the nature of the film substrate interface and defects such as twin boundaries. We have compared the properties of LCMO films on (100) oriented LaAlO3 and (001) oriented NdCaAlO4 both of which induce compressive bi-axial strain. Interestingly, the suppression of the insulator-metal transition is less in films on NCAO which has a larger lattice mismatch. We will present results correlating the electrical and magneto transport properties with the structure and morphology of the films.

Animal model of methylphenidate's long-term memory-enhancing effects.

PubMed

Carmack, Stephanie A; Howell, Kristin K; Rasaei, Kleou; Reas, Emilie T; Anagnostaras, Stephan G

2014-01-16

Methylphenidate (MPH), introduced more than 60 years ago, accounts for two-thirds of current prescriptions for attention deficit hyperactivity disorder (ADHD). Although many studies have modeled MPH's effect on executive function, almost none have directly modeled its effect on long-term memory (LTM), even though improvement in LTM is a critical target of therapeutic intervention in ADHD. We examined the effects of a wide range of doses of MPH (0.01-10 mg/kg, i.p.) on Pavlovian fear learning, a leading model of memory. MPH's effects were then compared to those of atomoxetine (0.1-10 mg/kg, i.p.), bupropion (0.5-20 mg/kg, i.p.), and citalopram (0.01-10 mg/kg, i.p.). At low, clinically relevant doses, MPH enhanced fear memory; at high doses it impaired memory. MPH's memory-enhancing effects were not confounded by its effects on locomotion or anxiety. Further, MPH-induced memory enhancement seemed to require both dopamine and norepinephrine transporter inhibition. Finally, the addictive potential of MPH (1 mg/kg and 10 mg/kg) was compared to those of two other psychostimulants, amphetamine (0.005 mg/kg and 1.5 mg/kg) and cocaine (0.15 mg/kg and 15 mg/kg), using a conditioned place preference and behavioral sensitization paradigm. We found that memory-enhancing effects of psychostimulants observed at low doses are readily dissociable from their reinforcing and locomotor activating effects at high doses. Together, our data suggest that fear conditioning will be an especially fruitful platform for modeling the effects of psychostimulants on LTM in drug development.

The mismatch repair and meiotic recombination endonuclease Mlh1-Mlh3 is activated by polymer formation and can cleave DNA substrates in trans

PubMed Central

Manhart, Carol M.; Ni, Xiaodan; White, Martin A.; Ortega, Joaquin; Surtees, Jennifer A.

2017-01-01

Crossing over between homologs is initiated in meiotic prophase by the formation of DNA double-strand breaks that occur throughout the genome. In the major interference-responsive crossover pathway in baker’s yeast, these breaks are resected to form 3' single-strand tails that participate in a homology search, ultimately forming double Holliday junctions (dHJs) that primarily include both homologs. These dHJs are resolved by endonuclease activity to form exclusively crossovers, which are critical for proper homolog segregation in Meiosis I. Recent genetic, biochemical, and molecular studies in yeast are consistent with the hypothesis of Mlh1-Mlh3 DNA mismatch repair complex acting as the major endonuclease activity that resolves dHJs into crossovers. However, the mechanism by which the Mlh1-Mlh3 endonuclease is activated is unknown. Here, we provide evidence that Mlh1-Mlh3 does not behave like a structure-specific endonuclease but forms polymers required to generate nicks in DNA. This conclusion is supported by DNA binding studies performed with different-sized substrates that contain or lack polymerization barriers and endonuclease assays performed with varying ratios of endonuclease-deficient and endonuclease-proficient Mlh1-Mlh3. In addition, Mlh1-Mlh3 can generate religatable double-strand breaks and form an active nucleoprotein complex that can nick DNA substrates in trans. Together these observations argue that Mlh1-Mlh3 may not act like a canonical, RuvC-like Holliday junction resolvase and support a novel model in which Mlh1-Mlh3 is loaded onto DNA to form an activated polymer that cleaves DNA. PMID:28453523

Hippocampal Mismatch Signals Are Modulated by the Strength of Neural Predictions and Their Similarity to Outcomes.

PubMed

Long, Nicole M; Lee, Hongmi; Kuhl, Brice A

2016-12-14

The hippocampus is thought to compare predicted events with current perceptual input, generating a mismatch signal when predictions are violated. However, most prior studies have only inferred when predictions occur without measuring them directly. Moreover, an important but unresolved question is whether hippocampal mismatch signals are modulated by the degree to which predictions differ from outcomes. Here, we conducted a human fMRI study in which subjects repeatedly studied various word-picture pairs, learning to predict particular pictures (outcomes) from the words (cues). After initial learning, a subset of cues was paired with a novel, unexpected outcome, whereas other cues continued to predict the same outcome. Critically, when outcomes changed, the new outcome was either "near" to the predicted outcome (same visual category as the predicted picture) or "far" from the predicted outcome (different visual category). Using multivoxel pattern analysis, we indexed cue-evoked reactivation (prediction) within neocortical areas and related these trial-by-trial measures of prediction strength to univariate hippocampal responses to the outcomes. We found that prediction strength positively modulated hippocampal responses to unexpected outcomes, particularly when unexpected outcomes were close, but not identical, to the prediction. Hippocampal responses to unexpected outcomes were also associated with a tradeoff in performance during a subsequent memory test: relatively faster retrieval of new (updated) associations, but relatively slower retrieval of the original (older) associations. Together, these results indicate that hippocampal mismatch signals reflect a comparison between active predictions and current outcomes and that these signals are most robust when predictions are similar, but not identical, to outcomes. Although the hippocampus is widely thought to signal "mismatches" between memory-based predictions and outcomes, previous research has not linked

A Bulky Rhodium Complex Bound to an Adenosine-Adenosine DNA Mismatch: General Architecture of the Metalloinsertion Binding Mode†

PubMed Central

Zeglis, Brian M.; Pierre, Valérie C.; Kaiser, Jens T.; Barton, Jacqueline K.

2009-01-01

Two crystal structures are determined for Δ-Rh(bpy)2(chrysi)3+ (chrysi = 5,6-chrysenequinone diimine) bound to the oligonucleotide duplex 5′-CGGAAATTACCG-3′ containing two adenosine-adenosine mismatches (italics) through metalloinsertion. Diffraction quality crystals with two different space groups (P3221 and P43212) were obtained under very similar crystallization conditions. In both structures, the bulky rhodium complex inserts into the two mismatched sites from the minor groove side, ejecting the mismatched bases into the major groove. The conformational changes are localized to the mismatched site; the metal complex replaces the mismatched base pair without an increase in base pair rise. The expansive metal complex is accommodated in the duplex by a slight opening in the phosphodiester backbone; all sugars retain a C2′-endo puckering, and flanking base pairs neither stretch nor shear. The structures differ, however, in that in one of the structures, an additional metal complex is bound by intercalation from the major groove at the central 5′-AT-3′ step. We conclude that this additional metal complex is intercalated into this central step because of crystal packing forces. The structures described here of Δ-Rh(bpy)2(chrysi)3+ bound to thermodynamically destabilized AA mismatches share critical features with binding by metalloinsertion in two other oligonucleotides containing different single base mismatches. These results underscore the generality of the metalloinsertion as a new mode of non-covalent binding by small molecules with a DNA duplex. PMID:19374348

Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation.

PubMed

Leventhal, Joseph; Abecassis, Michael; Miller, Joshua; Gallon, Lorenzo; Ravindra, Kadiyala; Tollerud, David J; King, Bradley; Elliott, Mary Jane; Herzig, Geoffrey; Herzig, Roger; Ildstad, Suzanne T

2012-03-07

The toxicity of chronic immunosuppressive agents required for organ transplant maintenance has prompted investigators to pursue approaches to induce immune tolerance. We developed an approach using a bioengineered mobilized cellular product enriched for hematopoietic stem cells (HSCs) and tolerogenic graft facilitating cells (FCs) combined with nonmyeloablative conditioning; this approach resulted in engraftment, durable chimerism, and tolerance induction in recipients with highly mismatched related and unrelated donors. Eight recipients of human leukocyte antigen (HLA)-mismatched kidney and FC/HSC transplants underwent conditioning with fludarabine, 200-centigray total body irradiation, and cyclophosphamide followed by posttransplant immunosuppression with tacrolimus and mycophenolate mofetil. Subjects ranged in age from 29 to 56 years. HLA match ranged from five of six loci with related donors to one of six loci with unrelated donors. The absolute neutrophil counts reached a nadir about 1 week after transplant, with recovery by 2 weeks. Multilineage chimerism at 1 month ranged from 6 to 100%. The conditioning was well tolerated, with outpatient management after postoperative day 2. Two subjects exhibited transient chimerism and were maintained on low-dose tacrolimus monotherapy. One subject developed viral sepsis 2 months after transplant and experienced renal artery thrombosis. Five subjects experienced durable chimerism, demonstrated immunocompetence and donor-specific tolerance by in vitro proliferative assays, and were successfully weaned off all immunosuppression 1 year after transplant. None of the recipients produced anti-donor antibody or exhibited engraftment syndrome or graft-versus-host disease. These results suggest that manipulation of a mobilized stem cell graft and nonmyeloablative conditioning represents a safe, practical, and reproducible means of inducing durable chimerism and donor-specific tolerance in solid organ transplant recipients.

1 CFR 10.1 - Publication required.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 1 General Provisions 1 2011-01-01 2011-01-01 false Publication required. 10.1 Section 10.1 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER PRESIDENTIAL PAPERS Regular Publication § 10.1 Publication required. The Director publishes a special edition...

1 CFR 10.1 - Publication required.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 1 General Provisions 1 2010-01-01 2010-01-01 false Publication required. 10.1 Section 10.1 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER PRESIDENTIAL PAPERS Regular Publication § 10.1 Publication required. The Director publishes a special edition...

1 CFR 10.1 - Publication required.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 1 General Provisions 1 2013-01-01 2012-01-01 true Publication required. 10.1 Section 10.1 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER PRESIDENTIAL PAPERS Regular Publication § 10.1 Publication required. The Director publishes a special edition...

1 CFR 10.1 - Publication required.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 1 General Provisions 1 2012-01-01 2012-01-01 false Publication required. 10.1 Section 10.1 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER PRESIDENTIAL PAPERS Regular Publication § 10.1 Publication required. The Director publishes a special edition...

1 CFR 10.1 - Publication required.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 1 General Provisions 1 2014-01-01 2012-01-01 true Publication required. 10.1 Section 10.1 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER PRESIDENTIAL PAPERS Regular Publication § 10.1 Publication required. The Director publishes a special edition...

Detection of single base mismatches of thymine and cytosine residues by potassium permanganate and hydroxylamine in the presence of tetralkylammonium salts.

PubMed Central

Gogos, J A; Karayiorgou, M; Aburatani, H; Kafatos, F C

1990-01-01

In the presence of tetramethylammonium chloride, potassium permanganate specifically modifies mismatched thymines. Similarly, the modification of mismatched cytosines by hydroxylamine was enhanced by tetraethylammonium chloride. Modification followed by piperidine cleavage permits specific identification of the T and C mismatches and by extension, when the opposite DNA strand is analyzed, of A and G mismatches as well. These reactions can be performed conveniently with DNA immobilized on Hybond M-G paper. We describe conditions that exploit these reactions to detect mismatches, e.g. point mutations or genetic polymorphisms, using either synthetic oligonucleotide probes or PCR amplification of specific genomic DNA sequences. Images PMID:2263445

Effect of deep cryogenic temperature on silicon-on-insulator CMOS mismatch: A circuit designer’s perspective

NASA Astrophysics Data System (ADS)

Das, Kushal; Lehmann, Torsten

2014-07-01

The effect of ultra low operating temperature on mismatch among identically designed Silicon-on-Sapphire CMOS devices is investigated in detail from a circuit design view point. The evolution of transistor matching properties for different operating conditions at both room and 4.2 K temperature are presented. The statistical analysis reveals that mismatch at low temperature is effectively unrelated to that at room temperature, which disagrees with previously published literature. The measurement data was used to extract key transistor parameters and the consequence of temperature lowering on their respective variance is estimated. We find that standard deviation of the threshold-voltage mismatch deteriorates by a factor ∼2 at 4.2 K temperature. Similar to room temperature operation, mismatch at 4.2 K is bias point dependent and the degradation of matching at very low temperature depends to some extent on how the bias point shifts upon cooling.

Mismatch repair proteins recruited to ultraviolet light-damaged sites lead to degradation of licensing factor Cdt1 in the G1 phase.

PubMed

Tanaka, Miyuki; Takahara, Michiyo; Nukina, Kohei; Hayashi, Akiyo; Sakai, Wataru; Sugasawa, Kaoru; Shiomi, Yasushi; Nishitani, Hideo

2017-04-03

Cdt1 is rapidly degraded by CRL4 Cdt2 E3 ubiquitin ligase after UV (UV) irradiation. Previous reports revealed that the nucleotide excision repair (NER) pathway is responsible for the rapid Cdt1-proteolysis. Here, we show that mismatch repair (MMR) proteins are also involved in the degradation of Cdt1 after UV irradiation in the G1 phase. First, compared with the rapid (within ∼15 min) degradation of Cdt1 in normal fibroblasts, Cdt1 remained stable for ∼30 min in NER-deficient XP-A cells, but was degraded within ∼60 min. The delayed degradation was also dependent on PCNA and CRL4 Cdt2 . The MMR proteins Msh2 and Msh6 were recruited to the UV-damaged sites of XP-A cells in the G1 phase. Depletion of these factors with small interfering RNAs prevented Cdt1 degradation in XP-A cells. Similar to the findings in XP-A cells, depletion of XPA delayed Cdt1 degradation in normal fibroblasts and U2OS cells, and co-depletion of Msh6 further prevented Cdt1 degradation. Furthermore, depletion of Msh6 alone delayed Cdt1 degradation in both cell types. When Cdt1 degradation was attenuated by high Cdt1 expression, repair synthesis at the damaged sites was inhibited. Our findings demonstrate that UV irradiation induces multiple repair pathways that activate CRL4 Cdt2 to degrade its target proteins in the G1 phase of the cell cycle, leading to efficient repair of DNA damage.

NRP-1 Receptor Expression Mismatch in Skin of Subjects with Experimental and Diabetic Small Fiber Neuropathy

PubMed Central

Van Acker, Nathalie; Ragé, Michael; Vermeirsch, Hilde; Schrijvers, Dorien; Nuydens, Rony; Byttebier, Geert; Timmers, Maarten; De Schepper, Stefanie; Streffer, Johannes; Andries, Luc; Plaghki, Léon; Cras, Patrick; Meert, Theo

2016-01-01

The in vivo cutaneous nerve regeneration model using capsaicin is applied extensively to study the regenerative mechanisms and therapeutic efficacy of disease modifying molecules for small fiber neuropathy (SFN). Since mismatches between functional and morphological nerve fiber recovery are described for this model, we aimed at determining the capability of the capsaicin model to truly mimic the morphological manifestations of SFN in diabetes. As nerve and blood vessel growth and regenerative capacities are defective in diabetes, we focused on studying the key regulator of these processes, the neuropilin-1 (NRP-1)/semaphorin pathway. This led us to the evaluation of NRP-1 receptor expression in epidermis and dermis of subjects presenting experimentally induced small fiber neuropathy, diabetic polyneuropathy and of diabetic subjects without clinical signs of small fiber neuropathy. The NRP-1 receptor was co-stained with CD31 vessel-marker using immunofluorescence and analyzed with Definiens® technology. This study indicates that capsaicin application results in significant loss of epidermal NRP-1 receptor expression, whereas diabetic subjects presenting small fiber neuropathy show full epidermal NRP-1 expression in contrast to the basal expression pattern seen in healthy controls. Capsaicin induced a decrease in dermal non-vascular NRP-1 receptor expression which did not appear in diabetic polyneuropathy. We can conclude that the capsaicin model does not mimic diabetic neuropathy related changes for cutaneous NRP-1 receptor expression. In addition, our data suggest that NRP-1 might play an important role in epidermal nerve fiber loss and/or defective regeneration and that NRP-1 receptor could change the epidermal environment to a nerve fiber repellant bed possibly through Sem3A in diabetes. PMID:27598321

Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair

PubMed Central

Campbell, Brittany B; Ungerleider, Nathan; Light, Nicholas; Wu, Tong; LeCompte, Kimberly G; Goksenin, A Yasemin; Bunnell, Bruce A; Tabori, Uri; Shlien, Adam

2018-01-01

Tumors defective for DNA polymerase (Pol) ε proofreading have the highest tumor mutation burden identified. A major unanswered question is whether loss of Pol ε proofreading by itself is sufficient to drive this mutagenesis, or whether additional factors are necessary. To address this, we used a combination of next generation sequencing and in vitro biochemistry on human cell lines engineered to have defects in Pol ε proofreading and mismatch repair. Absent mismatch repair, monoallelic Pol ε proofreading deficiency caused a rapid increase in a unique mutation signature, similar to that observed in tumors from patients with biallelic mismatch repair deficiency and heterozygous Pol ε mutations. Restoring mismatch repair was sufficient to suppress the explosive mutation accumulation. These results strongly suggest that concomitant suppression of mismatch repair, a hallmark of colorectal and other aggressive cancers, is a critical force for driving the explosive mutagenesis seen in tumors expressing exonuclease-deficient Pol ε. PMID:29488881

Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair.

PubMed

Hodel, Karl P; de Borja, Richard; Henninger, Erin E; Campbell, Brittany B; Ungerleider, Nathan; Light, Nicholas; Wu, Tong; LeCompte, Kimberly G; Goksenin, A Yasemin; Bunnell, Bruce A; Tabori, Uri; Shlien, Adam; Pursell, Zachary F

2018-02-28

Tumors defective for DNA polymerase (Pol) ε proofreading have the highest tumor mutation burden identified. A major unanswered question is whether loss of Pol ε proofreading by itself is sufficient to drive this mutagenesis, or whether additional factors are necessary. To address this, we used a combination of next generation sequencing and in vitro biochemistry on human cell lines engineered to have defects in Pol ε proofreading and mismatch repair. Absent mismatch repair, monoallelic Pol ε proofreading deficiency caused a rapid increase in a unique mutation signature, similar to that observed in tumors from patients with biallelic mismatch repair deficiency and heterozygous Pol ε mutations. Restoring mismatch repair was sufficient to suppress the explosive mutation accumulation. These results strongly suggest that concomitant suppression of mismatch repair, a hallmark of colorectal and other aggressive cancers, is a critical force for driving the explosive mutagenesis seen in tumors expressing exonuclease-deficient Pol ε. © 2018, Hodel et al.

1 CFR 9.1 - Publication required.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 1 General Provisions 1 2011-01-01 2011-01-01 false Publication required. 9.1 Section 9.1 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER THE UNITED STATES GOVERNMENT MANUAL § 9.1 Publication required. The Director of the Federal Register shall...

1 CFR 9.1 - Publication required.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 1 General Provisions 1 2012-01-01 2012-01-01 false Publication required. 9.1 Section 9.1 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER THE UNITED STATES GOVERNMENT MANUAL § 9.1 Publication required. (a) The Director publishes a special edition...

1 CFR 9.1 - Publication required.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 1 General Provisions 1 2014-01-01 2012-01-01 true Publication required. 9.1 Section 9.1 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER THE UNITED STATES GOVERNMENT MANUAL § 9.1 Publication required. (a) The Director publishes a special edition...

1 CFR 9.1 - Publication required.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 1 General Provisions 1 2013-01-01 2012-01-01 true Publication required. 9.1 Section 9.1 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER SPECIAL EDITIONS OF THE FEDERAL REGISTER THE UNITED STATES GOVERNMENT MANUAL § 9.1 Publication required. (a) The Director publishes a special edition...

Toward a phenological mismatch in estuarine pelagic food web?

PubMed

Chevillot, Xavier; Drouineau, Hilaire; Lambert, Patrick; Carassou, Laure; Sautour, Benoit; Lobry, Jérémy

2017-01-01

Alterations of species phenology in response to climate change are now unquestionable. Until now, most studies have reported precocious occurrence of life cycle events as a major phenological response. Desynchronizations of biotic interactions, in particular predator-prey relationships, are however assumed to strongly impact ecosystems' functioning, as formalized by the Match-Mismatch Hypothesis (MMH). Temporal synchronicity between juvenile fish and zooplankton in estuaries is therefore of essential interest since estuaries are major nursery grounds for many commercial fish species. The Gironde estuary (SW France) has suffered significant alterations over the last three decades, including two Abrupt Ecosystem Shifts (AES), and three contrasted intershift periods. The main objective of this study was to depict modifications in fish and zooplankton phenology among inter-shift periods and discuss the potential effects of the resulting mismatches at a community scale. A flexible Bayesian method was used to estimate and compare yearly patterns of species abundance in the estuary among the three pre-defined periods. Results highlighted (1) an earlier peak of zooplankton production and entrance of fish species in the estuary and (2) a decrease in residence time of both groups in the estuary. Such species-specific phenological changes led to changes in temporal overlap between juvenile fish and their zooplanktonic prey. This situation questions the efficiency and potentially the viability of nursery function of the Gironde estuary, with potential implications for coastal marine fisheries of the Bay of Biscay.

Toward a phenological mismatch in estuarine pelagic food web?

PubMed Central

Chevillot, Xavier; Drouineau, Hilaire; Lambert, Patrick; Carassou, Laure; Sautour, Benoit; Lobry, Jérémy

2017-01-01

Alterations of species phenology in response to climate change are now unquestionable. Until now, most studies have reported precocious occurrence of life cycle events as a major phenological response. Desynchronizations of biotic interactions, in particular predator-prey relationships, are however assumed to strongly impact ecosystems’ functioning, as formalized by the Match-Mismatch Hypothesis (MMH). Temporal synchronicity between juvenile fish and zooplankton in estuaries is therefore of essential interest since estuaries are major nursery grounds for many commercial fish species. The Gironde estuary (SW France) has suffered significant alterations over the last three decades, including two Abrupt Ecosystem Shifts (AES), and three contrasted intershift periods. The main objective of this study was to depict modifications in fish and zooplankton phenology among inter-shift periods and discuss the potential effects of the resulting mismatches at a community scale. A flexible Bayesian method was used to estimate and compare yearly patterns of species abundance in the estuary among the three pre-defined periods. Results highlighted (1) an earlier peak of zooplankton production and entrance of fish species in the estuary and (2) a decrease in residence time of both groups in the estuary. Such species-specific phenological changes led to changes in temporal overlap between juvenile fish and their zooplanktonic prey. This situation questions the efficiency and potentially the viability of nursery function of the Gironde estuary, with potential implications for coastal marine fisheries of the Bay of Biscay. PMID:28355281

The mismatch between conventional house price modeling and regulated markets: insights from The Netherlands.

PubMed

Tu, Qi; de Haan, Jan; Boelhouwer, Peter

2017-01-01

House price modeling has been frequently used to investigate the dynamics of housing markets, especially competitive markets; yet less attention has been given to markets that have experienced considerable interventions. The aim of this study is to demonstrate a mismatch between conventional house price models and the case of the Netherlands and to provide reasons of such mismatch. We first describe and classify the conventional house price models into asset-pricing house price model, stock-flow model, multi-period utility model, and repayment model. These models are subsequently applied to the Netherlands, where considerable government interventions took place. As expected, the empirical results are unsatisfactory to explain the Dutch house price development. The degree of mismatch of the repayment model and the multi-period utility model, however, seems to be fairly limited.

An Efficient Modulation Strategy for Cascaded Photovoltaic Systems Suffering From Module Mismatch

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Cheng; Zhang, Kai; Xiong, Jian

Modular multilevel cascaded converter (MMCC) is a promising technique for medium/high-voltage high-power photovoltaic systems due to its modularity, scalability, and capability of distributed maximum power point tracking (MPPT) etc. However, distributed MPPT under module-mismatch might polarize the distribution of ac output voltages as well as the dc-link voltages among the modules, distort grid currents, and even cause system instability. For the better acceptance in practical applications, such issues need to be well addressed. Based on mismatch degree that is defined to consider both active power distribution and maximum modulation index, this paper presents an efficient modulation strategy for a cascaded-H-bridge-basedmore » MMCC under module mismatch. It can operate in loss-reducing mode or range-extending mode. By properly switching between the two modes, performance indices such as system efficiency, grid current quality, and balance of dc voltages, can be well coordinated. In this way, the MMCC system can maintain high-performance over a wide range of operating conditions. As a result, effectiveness of the proposed modulation strategy is proved with experiments.« less

An Efficient Modulation Strategy for Cascaded Photovoltaic Systems Suffering From Module Mismatch

DOE PAGES

Wang, Cheng; Zhang, Kai; Xiong, Jian; ...

2017-09-26

Modular multilevel cascaded converter (MMCC) is a promising technique for medium/high-voltage high-power photovoltaic systems due to its modularity, scalability, and capability of distributed maximum power point tracking (MPPT) etc. However, distributed MPPT under module-mismatch might polarize the distribution of ac output voltages as well as the dc-link voltages among the modules, distort grid currents, and even cause system instability. For the better acceptance in practical applications, such issues need to be well addressed. Based on mismatch degree that is defined to consider both active power distribution and maximum modulation index, this paper presents an efficient modulation strategy for a cascaded-H-bridge-basedmore » MMCC under module mismatch. It can operate in loss-reducing mode or range-extending mode. By properly switching between the two modes, performance indices such as system efficiency, grid current quality, and balance of dc voltages, can be well coordinated. In this way, the MMCC system can maintain high-performance over a wide range of operating conditions. As a result, effectiveness of the proposed modulation strategy is proved with experiments.« less

The effect of methylphenidate on postural stability under single and dual task conditions in children with attention deficit hyperactivity disorder - a double blind randomized control trial.

PubMed

Jacobi-Polishook, Talia; Shorer, Zamir; Melzer, Itshak

2009-05-15

To investigate the effects of Methylphenidate (MPH) on postural stability in attention deficit hyperactivity disorder (ADHD) children in single and dual task conditions. A randomized controlled double-blind study analyzing postural stability in 24 ADHD children before and after MPH vs. placebo treatments, in three task conditions: (1) Single task, standing still; (2) dual task, standing still performing a memory-attention demanding task; (3) standing still listening to music. MPH resulted in a significant improvement in postural stability during the dual task condition and while listening to music, with no equivalent improvement in placebo controls. MPH improves postural stability in ADHD, especially when an additional task is performed. This is probably due to enhanced attention abilities, thus contributing to improved balance control during performance of tasks that require attention. MPH remains to be studied as a potential drug treatment to improve balance control and physical functioning in other clinical populations.

Index mismatch aberration correction over long working distances using spatial light modulation.

PubMed

Gjonaj, Bergin; Johnson, Patrick; Bonn, Mischa; Domke, Katrin F

2012-11-20

For many microscopy applications, millimeters-long free working distances (LWD) are required. However, the high resolution and contrast of LWD objectives operated in air are lost when introducing glass and/or liquid with the sample. We propose to use spatial light modulation to correct for such beam aberrations caused by refractive index mismatches. Focusing a monochromatic laser beam with a 10 mm working distance air objective (50×, 0.5 NA) through air, glass, and water, we manage to restore a sharp, intense focus (FWHM<2λ) by adaptive beam phase shaping. Our approach offers a practical and cost-effective route to high resolution and contrast microscopy using LWD air objectives, extending their usage beyond applications in air.

1.3 micrometers Wavelength Vertical Cavity Surface Emitting Laser Fabricated by Orientation-Mismatched Wafer Bonding: A Prospect for Polarization Control

DTIC Science & Technology

2005-06-01

mismatched wafer bonding: A prospect for polarization control Yae L. Okuno,a) Jon Geske , Kian-Giap Gan, Yi-Jen Chiu, Steven P. DenBaars, and John E. Bowers...Uomi, M. Aoki, and T. Tsuchiya, IEEE J. Quantum Electron. 33, 959 ~1997!. 20 Y. L. Okuno, J. Geske , Y.-J. Chiu, S. P. DenBaars, and J. E. Bowers, Proc

Topoisomerase-1 and -2A gene copy numbers are elevated in mismatch repair-proficient colorectal cancers.

PubMed

Sønderstrup, Ida Marie Heeholm; Nygård, Sune Boris; Poulsen, Tim Svenstrup; Linnemann, Dorte; Stenvang, Jan; Nielsen, Hans Jørgen; Bartek, Jiri; Brünner, Nils; Nørgaard, Peter; Riis, Lene

2015-06-01

Topoisomerase 1 (TOP1) and 2A (TOP2A) are potential predictive biomarkers for irinotecan and anthracycline treatment, respectively, in colorectal cancer (CRC), and we have recently reported a high frequency of gene gain of the TOP1 and TOP2A genes in CRC. Furthermore, Mismatch Repair (MMR) subtypes of CRC have been associated with benefit from adjuvant chemotherapy of primary CRC. Given the involvement of the topoisomerase enzymes in DNA replication and repair, we raised the hypothesis that an association may exist between TOP gene copy numbers and MMR proficiency/deficiency in CRC. Test cohort: FISH analysis with an in-house TOP1/CEN20 probe mix and a commercially available TOP2A/CEN17 (Dako, Glostrup, Denmark) probe mix was performed on archival formalin fixed paraffin embedded (FFPE) tissue samples from 18 patients with proficient MMR (pMMR) CRC and 18 patients with deficient MMR (dMMR) CRC. TOP1 and TOP2A gene copy numbers and their ratios per nucleus were correlated with MMR status using the Mann-Whitney test. Validation cohort: FFPE samples from 154 patients with primary stage III CRC (originally included in the RANX05 study) were classified according to MMR status by immunohistochemical analysis using validated antibodies for MLH1, MLH2, MSH6 and PMS2, and information on TOP1, CEN20, TOP2A and CEN17 status was previously published for this cohort. The observed TOP1 gene copy numbers in the 36 CRC test cohort were significantly greater (p < 0.01) in the pMMR subgroup (mean: 3.84, SD: 2.03) than in the dMMR subgroup (mean: 1.50, SD: 0.12). Similarly, the TOP2A copy numbers were significantly greater (p < 0.01) in the pMMR subgroup (mean: 1.99, SD: 0.52) than in the dMMR subgroup (mean: 1.52, SD: 0.10). These findings were confirmed in the validation cohort, where in the pMMR subgroup 51% had ≥2 extra TOP1 copies per cell, while all tumors classified as dMMR had diploid TOP1 status and mean TOP2A copy numbers were 2.30 (SD: 1.36) and 1.80 (SD: 0.31) (p = 0

Expression of DNA mismatch repair proteins MLH1, MSH2, and MSH6 in recurrent glioblastoma.

PubMed

Stark, Andreas M; Doukas, Alexander; Hugo, Heinz-Herrmann; Hedderich, Jürgen; Hattermann, Kirsten; Maximilian Mehdorn, H; Held-Feindt, Janka

2015-02-01

Methylated O6-methylguanin-DNA-methytransferase (MGMT) promoter methylation is associated with survival in patients with glioblastoma. Current evidence suggests that further mismatch repair genes play a pivotal role in the tumor response to treatment. Candidate genes are MLH1, MSH2, and MSH6. Formerly, we found evidence of prognostic impact of MLH1 and MSH6 immunohistochemical expression in a small series of patients with initial glioblastoma. Two hundred and eleven patients were included who underwent macroscopically total removal of primary glioblastoma and at least one re-craniotomy for recurrence. Immunohistochemical staining was performed on paraffin-embedded specimens of initial tumors with specific antibodies against MLH1, MSH2, and MSH6. RESULTS were compared to the Ki67 proliferation index and patient survival. Additionally, fresh frozen samples from 16 paired initial and recurrent specimens were examined using real-time reverse transcription polymerase chain reaction (RT-PCR) with specific primers against MLH1, MSH2, and MSH6. RESULTS were compared to MGMT status and survival. (1) Immunohistochemical expression of MSH6 was significantly associated with the Ki67 proliferation index (P<0.001) but not with survival. (2) PCR revealed two patients with increasing expression of MLH1, MLH2, and MSH6 over treatment combined with lacking MGMT methylation. In another two patients, decreased MLH1, MSH2, and MSH6 expression was observed in combination with MGMT promoter methylation. Our data indicate that there may be glioblastoma patient subgroups characterized by MMR-expression changes beyond MGMT promoter methylation. The immunohistochemical expression of MLH1, MSH2, and MSH6 in initial glioblastoma is not associated with patient survival.

Genomic amplification of the human DHFR/MSH3 locus remodels mismatch recognition and repair activities.

PubMed

Drummond, J T

1999-01-01

Mismatch recognition in human cells is mediated by two heterodimers, MutS alpha and MutS beta. MutS alpha appears to shoulder primary responsibility for mismatch correction during replication, based on its relative abundance and ability to recognize a broad spectrum of base-base and base-insertion mismatches. Because MutS alpha and MutS beta share a common component, MSH2, conditions that influence the expression or degradation of MSH3 or MSH6 can redistribute the profile of mismatch recognition and repair. MSH3 is linked by a shared promoter with DHFR, connecting two pathways with key roles in DNA metabolism. In a classic example of gene amplification, the DHFR (and MSH3) locus can become amplified to several hundred copies in the presence of methotrexate. Under these conditions, MutS beta forms at the expense of MutS alpha, and the mutation rate in these tumor cells rises more than 100-fold. The implications for cancer chemotherapy include a potential increase in mutability when tumors are treated with methotrexate, which could increase the frequency of subsequent mutations that influence the tumor's drug sensitivity or aggressiveness. Because processing certain types of DNA damage by the mismatch repair pathway has also been implicated in tumor sensitivity to agents such as cisplatin, changes in expression at the DHFR/MSH3 locus may have further relevance to the outcome of multi-drug treatment regimens.

Effects of Prosthetic Mismatch and Subscapularis Tear on Glenohumeral Contact Patterns in Total Shoulder Arthroplasty: A Numerical Musculoskeletal Analysis.

PubMed

Sins, Lauranne; Tétreault, Patrice; Nuño, Natalia; Hagemeister, Nicola

2016-12-01

Prosthetic components' mismatch and subscapularis (SC) tear are determining factors for glenoid failure complication in nonconforming total shoulder arthroplasty (NC-TSA). Risk factors are linked to glenoid prosthetic loading. However, the mechanisms underlying the clinical observations remain unclear. This study assessed the combined impact of mismatch and subscapularis tear on glenoid loading. It was assumed that adequate glenoid loading was associated with minimal, but non-null, humeral head translations and contact pressure, as well as with maximal glenoid contact area, and that the center of pressure (COP) on the glenoid would have a centered displacement pattern. A numerical model was used to achieve two objectives. The first was to verify whether an optimum mismatch existed, for which failure risk would be minimal. The second was to explore the effect of subscapularis tear on the position of applied forces on the glenoid. A shoulder AnyBody musculoskeletal model was adapted to the arthroplasty context by introducing humeral head translations and contact between implants. Ten simulations were computed to compare combinations of varying mismatches (1.4 mm, 3.4 mm, 6.4 mm, 8.6 mm, and 9 mm) with two shoulder conditions (intact-muscle or subscapularis tear). Humeral head translations, center-of-pressure, contact area, contact pressure, and glenohumeral joint contact forces were numerically estimated. Mismatches between 3.4 mm and 6.4 mm were associated with the most minimal humeral translations and contact pressure, as well as with maximal contact area. Center of pressure displacement pattern differed according to shoulder condition, with an outward anterior tendency in presence of tear.

Idiopathic pulmonary fibrosis. A rare cause of scintigraphic ventilation-perfusion mismatch

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pochis, W.T.; Krasnow, A.Z.; Collier, B.D.

1990-05-01

A case of idiopathic pulmonary fibrosis with multiple areas of mismatch on ventilation-perfusion lung imaging in the absence of pulmonary embolism is presented. Idiopathic pulmonary fibrosis is one of the few nonembolic diseases producing a pulmonary ventilation-perfusion mismatch. In this condition, chest radiographs may not detect the full extent of disease, and xenon-133 ventilation imaging may be relatively insensitive to morbid changes in small airways. Thus, when examining patients with idiopathic pulmonary fibrosis, one should be aware that abnormal perfusion imaging patterns without matching ventilation abnormalities are not always due to embolism. In this setting, contrast pulmonary angiography is oftenmore » needed for accurate differential diagnosis.« less

Influence of oxidized purine processing on strand directionality of mismatch repair.

PubMed

Repmann, Simone; Olivera-Harris, Maite; Jiricny, Josef

2015-04-17

Replicative DNA polymerases are high fidelity enzymes that misincorporate nucleotides into nascent DNA with a frequency lower than [1/10(5)], and this precision is improved to about [1/10(7)] by their proofreading activity. Because this fidelity is insufficient to replicate most genomes without error, nature evolved postreplicative mismatch repair (MMR), which improves the fidelity of DNA replication by up to 3 orders of magnitude through correcting biosynthetic errors that escaped proofreading. MMR must be able to recognize non-Watson-Crick base pairs and excise the misincorporated nucleotides from the nascent DNA strand, which carries by definition the erroneous genetic information. In eukaryotes, MMR is believed to be directed to the nascent strand by preexisting discontinuities such as gaps between Okazaki fragments in the lagging strand or breaks in the leading strand generated by the mismatch-activated endonuclease of the MutL homologs PMS1 in yeast and PMS2 in vertebrates. We recently demonstrated that the eukaryotic MMR machinery can make use also of strand breaks arising during excision of uracils or ribonucleotides from DNA. We now show that intermediates of MutY homolog-dependent excision of adenines mispaired with 8-oxoguanine (G(O)) also act as MMR initiation sites in extracts of human cells or Xenopus laevis eggs. Unexpectedly, G(O)/C pairs were not processed in these extracts and failed to affect MMR directionality, but extracts supplemented with exogenous 8-oxoguanine DNA glycosylase (OGG1) did so. Because OGG1-mediated excision of G(O) might misdirect MMR to the template strand, our findings suggest that OGG1 activity might be inhibited during MMR. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Methylphenidate DAT binding in adolescents with Attention-Deficit/ Hyperactivity Disorder comorbid with Substance Use Disorder--a single photon emission computed tomography with [Tc(99m)]TRODAT-1 study.

PubMed

Szobot, Claudia M; Shih, Ming Chi; Schaefer, Thais; Júnior, Neivo; Hoexter, Marcelo Q; Fu, Ying Kai; Pechansky, Flávio; Bressan, Rodrigo A; Rohde, Luis A P

2008-04-15

Attention-Deficit/Hyperactivity Disorder (ADHD) is highly prevalent among adolescents with Substance Use Disorders (SUD). Effects of methylphenidate (MPH) on ADHD are attributed to its properties of blocking the dopamine transporter (DAT) in the striatum. However, it has been demonstrated that drug addiction is associated with dopaminergic system changes that may affect MPH brain effects, emphasizing the need to better understand MPH actions in subjects with ADHD+SUD. To evaluate the effect of an extended release formulation of MPH (MPH-SODAS) on DAT availability in 17 stimulant-naive ADHD adolescents with comorbid SUD (cannabis and cocaine). Subjects underwent two single photon emission computed tomography (SPECT) scans with [Tc(99m)]TRODAT-1, at baseline and after 3 weeks on MPH-SODAS. Clinical assessment for ADHD relied on the Swanson, Nolan and Pelham Scale - version IV (SNAP-IV). Caudate and putamen DAT binding potential (BP) was calculated. After 3 weeks on MPH-SODAS, there was a significant reduction of SNAP-IV total scores (p<0.001), and approximately 52% reductions of DAT BP at the left and right caudate. Similar decreases were found at the left and right putamen (p<0.001 for all analyses). This study shows that the magnitude of DAT blockade induced by MPH in this population is similar to what is found in ADHD patients without SUD comorbidity, providing neurobiological support for trials with stimulants in adolescents with ADHD+SUD, an important population excluded from studies.

Education-to-job mismatch and the risk of work injury.

PubMed

Premji, Stephanie; Smith, Peter M

2013-04-01

To examine the association between education-to-job mismatch and work injury. Cross-sectional data from the 2003 and 2005 Canadian Community Health Surveys (n=63,462) were used to examine the relationship between having an educational level that is incongruent with occupational skills requirements and the risk of sustaining a work injury requiring medical attention or a work-related repetitive movement injury (RMI). The effect on injury of the interaction of overeducation with recent immigrant status was also examined. Models were stratified by sex and adjusted for possible confounders. Occupational physical demands were conceptualised as a potential mediating variable. After adjustment for covariates, over-education was associated with work injury and RMI for both sexes. Adjustment for occupational demands attenuated the impact on work injury but did not eliminate the effect on RMI among men. The interaction of over-education and recent immigrant status resulted among men in a fourfold increase in the odds of work injury compared with non-recent immigrants who were not over-educated. After adjustment for occupational demands, over-educated recent immigrant men still had more than a twofold increase in the odds of injury. The risk of sustaining a work injury is higher among those whose education exceeds that of job requirements. These findings highlight the need to address barriers to suitable employment, particularly among recent immigrants.

DNA conformations in mismatch repair probed in solution by X-ray scattering from gold nanocrystals

PubMed Central

Hura, Greg L.; Tsai, Chi-Lin; Claridge, Shelley A.; Mendillo, Marc L.; Smith, Jessica M.; Williams, Gareth J.; Mastroianni, Alexander J.; Alivisatos, A. Paul; Putnam, Christopher D.; Kolodner, Richard D.; Tainer, John A.

2013-01-01

DNA metabolism and processing frequently require transient or metastable DNA conformations that are biologically important but challenging to characterize. We use gold nanocrystal labels combined with small angle X-ray scattering to develop, test, and apply a method to follow DNA conformations acting in the Escherichia coli mismatch repair (MMR) system in solution. We developed a neutral PEG linker that allowed gold-labeled DNAs to be flash-cooled and stored without degradation in sample quality. The 1,000-fold increased gold nanocrystal scattering vs. DNA enabled investigations at much lower concentrations than otherwise possible to avoid concentration-dependent tetramerization of the MMR initiation enzyme MutS. We analyzed the correlation scattering functions for the nanocrystals to provide higher resolution interparticle distributions not convoluted by the intraparticle distribution. We determined that mispair-containing DNAs were bent more by MutS than complementary sequence DNA (csDNA), did not promote tetramer formation, and allowed MutS conversion to a sliding clamp conformation that eliminated the DNA bends. Addition of second protein responder MutL did not stabilize the MutS-bent forms of DNA. Thus, DNA distortion is only involved at the earliest mispair recognition steps of MMR: MutL does not trap bent DNA conformations, suggesting migrating MutL or MutS/MutL complexes as a conserved feature of MMR. The results promote a mechanism of mismatch DNA bending followed by straightening in initial MutS and MutL responses in MMR. We demonstrate that small angle X-ray scattering with gold labels is an enabling method to examine protein-induced DNA distortions key to the DNA repair, replication, transcription, and packaging. PMID:24101514

Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg?

PubMed

Wimmer, Katharina; Etzler, Julia

2008-09-01

Heterozygous mutations in one of the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause the dominant adult cancer syndrome termed Lynch syndrome or hereditary non-polyposis colorectal cancer. During the past 10 years, some 35 reports have delineated the phenotype of patients with biallelic inheritance of mutations in one of these MMR genes. The patients suffer from a condition that is characterised by the development of childhood cancers, mainly haematological malignancies and/or brain tumours, as well as early-onset colorectal cancers. Almost all patients also show signs reminiscent of neurofibromatosis type 1, mainly café au lait spots. Alluding to the underlying mechanism, this condition may be termed as "constitutional mismatch repair-deficiency (CMMR-D) syndrome". To give an overview of the current knowledge and its implications of this recessively inherited cancer syndrome we summarise here the genetic, clinical and pathological findings of the so far 78 reported patients of 46 families suffering from this syndrome.

The Impact of Major-Job Mismatch on College Graduates' Early Career Earnings: Evidence from China

ERIC Educational Resources Information Center

Zhu, Rong

2014-01-01

This paper assesses the impact of the mismatch between a college major and job on college graduates' early career earnings using a sample from China. On average, a major-job mismatched college graduate is found to suffer from an income loss that is much lower than the penalty documented in previous studies. The income losses are also found to be…

Recognition of T·G mismatched base pairs in DNA by stacked imidazole-containing polyamides: surface plasmon resonance and circular dichroism studies

PubMed Central

Lacy, Eilyn R.; Cox, Kari K.; Wilson, W. David; Lee, Moses

2002-01-01

An imidazole-containing polyamide trimer, f-ImImIm, where f is a formamido group, was recently found using NMR methods to recognize T·G mismatched base pairs. In order to characterize in detail the T·G recognition affinity and specificity of imidazole-containing polyamides, f-ImIm, f-ImImIm and f-PyImIm were synthesized. The kinetics and thermodynamics for the polyamides binding to Watson–Crick and mismatched (containing one or two T·G, A·G or G·G mismatched base pairs) hairpin oligonucleotides were determined by surface plasmon resonance and circular dichroism (CD) methods. f-ImImIm binds significantly more strongly to the T·G mismatch-containing oligonucleotides than to the sequences with other mismatched or with Watson–Crick base pairs. Compared with the Watson–Crick CCGG sequence, f-ImImIm associates more slowly with DNAs containing T·G mismatches in place of one or two C·G base pairs and, more importantly, the dissociation rate from the T·G oligonucleotides is very slow (small kd). These results clearly demonstrate the binding selectivity and enhanced affinity of side-by-side imidazole/imidazole pairings for T·G mismatches and show that the affinity and specificity increase arise from much lower kd values with the T·G mismatched duplexes. CD titration studies of f-ImImIm complexes with T·G mismatched sequences produce strong induced bands at ∼330 nm with clear isodichroic points, in support of a single minor groove complex. CD DNA bands suggest that the complexes remain in the B conformation. PMID:11937638

Mismatch Negativity in Children with Autism and Typical Development

ERIC Educational Resources Information Center

Dunn, Michelle A.; Gomes, Hilary; Gravel, Judith

2008-01-01

Children with autism are often characterized as having abnormalities in auditory processing. This study examined automatic and active processing of simple auditory stimuli in children using a component of event related potentials, the mismatch negativity (MMN). Amplitude of MMN in children with autism was significantly smaller than in children…

Results of baseline tests of the Lucas Limousine

NASA Technical Reports Server (NTRS)

Soltis, R. F.; Dustin, M. O.; Sargent, N. B.

1977-01-01

The Lucas Limousine, an electric vehicle, was tested to assess the state-of-the-art of electric vehicles. All tests were made without the regenerative braking system and were conducted at the gross vehicle weight of 7,700 pounds. Over a 30 mph stop and go driving cycle the vehicle went 48.4 miles. The vehicle was able to accelerate to 30 mph in about 15 seconds with a gradeability limit of 16.5 percent. As determined by coast down tests the road power and road energy consumption for the vehicle were 2.92 kilowatts and 0.146 kWh/mi, respectively, at 20 mph. At 40 mph the road power requirement was 11.12 kilowatts and the road energy requirement was 0.278 kWh/mi. The maximum energy economy measured 0.45 kilowatt hours per mile at 30 mph and increased to 0.76 kilowatt hours per mile at 50 mph. Over the 30 mph stop and go driving cycle the energy economy was 0.92 kilowatt hours per mile.