Exploring and Accounting for Genetically Driven Effect Heterogeneity in Mendelian Randomization

This is the final version. Available on open access from Wiley via the DOI in this recordData Availability Statement: The data in ALSPAC is fully available, via managed systems, to any researchers. The managed system is a requirement of the study funders, but access is not restricted on the basis of overlap with other applications to use the data or on the basis of peer review of the proposed science. The ALSPAC data management plan describes in detail the policy regarding data sharing, which is through a system of managed open access. The following steps highlight how to apply for access to the data included in this paper and all other ALSPAC data. (1) Please read the ALSPAC access policy, which describes the process of accessing the data and samples in detail and outlines the costs associated with doing so. (2) You may also find it useful to browse the fully searchable ALSPAC research proposals database, which lists all research projects that have been approved since April 2011. (3) Please submit your research proposal for consideration by the ALSPAC Executive Committee. You will receive a response within 10 working days to advise you whether your proposal has been approved. If you have any questions about accessing data, please email [email protected] randomization (MR) is a framework to estimate the causal effect of a modifiable health exposure, drug target or pharmaceutical intervention on a downstream outcome by using genetic variants as instrumental variables. A crucial assumption allowing estimation of the average causal effect in MR, termed homogeneity, is that the causal effect does not vary across levels of any instrument used in the analysis. In contrast, the science of pharmacogenetics seeks to actively uncover and exploit genetically driven effect heterogeneity for the purposes of precision medicine. In this study, we consider a recently proposed method for performing pharmacogenetic analysis on observational data—the Triangulation WIthin a STudy (TWIST) framework—and explore how it can be combined with traditional MR approaches to properly characterise average causal effects and genetically driven effect heterogeneity. We propose two new methods which not only estimate the genetically driven effect heterogeneity but also enable the estimation of a causal effect in the genetic group with and without the risk allele separately. Both methods utilise homogeneity-respecting and homogeneity-violating genetic variants and rely on a different set of assumptions. Using data from the ALSPAC study, we apply our new methods to estimate the causal effect of smoking before and during pregnancy on offspring birth weight in mothers whose genetics mean they find it (relatively) easier or harder to quit smoking.Wellcome TrustNational Institutes of Health (NIH)Engineering and Physical Sciences Research Council (EPSRC

Smoking during pregnancy and its effect on placental weight: a Mendelian randomization study

This is the final version. Available on open access from BMC via the DOI in this recordAvailability of data and materials: The data in ALSPAC is fully available, via managed systems, to any researchers. The managed system is a requirement of the study funders, but access is not restricted on the basis of overlap with other applications to use the data or on the basis of peer review of the proposed science. The ALSPAC data management plan describes in detail the policy regarding data sharing, which is through a system of managed open access. The following steps highlight how to apply for access to the data included in this paper and all other ALSPAC data. (1) Please read the ALSPAC access policy, which describes the process of accessing the data and samples in detail and outlines the costs associated with doing so. (2) You may also find it useful to browse the fully searchable ALSPAC research proposals database, which lists all research projects that have been approved since April 2011. (3) Please submit your research proposal for consideration by the ALSPAC Executive Committee. You will receive a response within 10 working days to advise you whether your proposal has been approved. If you have any questions about accessing data, please email [email protected]. Data from the Norwegian Mother, Father and Child Cohort Study and the Medical Birth Registry of Norway used in this study are managed by the national health register holders in Norway (Norwegian Institute of public health) and can be made available to researchers, provided approval from the Regional Committees for Medical and Health Research Ethics (REC), compliance with the EU General Data Protection Regulation (GDPR) and approval from the data owners. The consent given by the participants does not open for storage of data on an individual level in repositories or journals. Researchers who want access to data sets for replication should apply through helsedata.no. Access to data sets requires approval from The Regional Committee for Medical and Health Research Ethics in Norway and an agreement with MoBa.Background The causal relationship between maternal smoking in pregnancy and reduced offspring birth weight is well established and is likely due to impaired placental function. However, observational studies have given conflicting results on the association between smoking and placental weight. We aimed to estimate the causal effect of newly pregnant mothers quitting smoking on their placental weight at the time of delivery. Methods We used one-sample Mendelian randomization, drawing data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (N = 690 to 804) and the Norwegian Mother, Father and Child Cohort Study (MoBa) (N = 4267 to 4606). The sample size depends on the smoking definition used for different analyses. The analysis was performed in pre-pregnancy smokers only, due to the specific role of the single-nucleotide polymorphism (SNP) rs1051730 (CHRNA5 – CHRNA3 – CHRNB4) in affecting smoking cessation but not initiation. Results Fixed effect meta-analysis showed a 182 g [95%CI: 29,335] higher placental weight for pre-pregnancy smoking mothers who continued smoking at the beginning of pregnancy, compared with those who stopped smoking. Using the number of cigarettes smoked per day in the first trimester as the exposure, the causal effect on placental weight was 11 g [95%CI: 1,21] per cigarette per day. Similarly, smoking at the end of pregnancy was causally associated with higher placental weight. Using the residuals of birth weight regressed on placental weight as the outcome, we showed evidence of lower offspring birth weight relative to the placental weight, both for continuing smoking at the start of pregnancy as well as continuing smoking throughout pregnancy (change in z-score birth weight adjusted for z-score placental weight: -0.8 [95%CI: -1.6,-0.1]). Conclusion Our results suggest that continued smoking during pregnancy causes higher placental weights

Sustained proliferation in cancer: mechanisms and novel therapeutic targets

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Increasing flexibility of employees in production processes using the differential learning approach – adaptation and validation of motor learning theories

© Springer International Publishing AG, part of Springer Nature 2019. International expanding markets and continuous development of new customer oriented products lead to an increasing product and process variety and complexity as well as shortened product lifecycles. According to these challenges, manufacturing companies have to enhance their process flexibility to remain sustainable competitive. Due to that, employees have to deal with high flexible work processes including continuous change of constellations and objectives. These in turn require a high employee’s flexibility, adaptability and occupational competence as well as new training concepts to enable them. In the academic literature and industrial practice, exists a variety of concepts for employee’s qualification and training. However, these concepts do only partially focus the employee’s occupational competence. Therefore, an innovative learning concept based on motor learning theories was developed and empirically validated. The description of the examination design as well as the result presentation and discussion are subject of the present contribution

Assistance system for individualization of work design [Assistenzsystem zur Individualisierung der Arbeitsgestaltung Einsatz von Smart Devices zur kontextsensitiven Arbeitsunterstützung]

To cope with increasing product and process diversification human labor is important for manufacturing companies. Furthermore, companies have to deal with the current demographic change including high inter-individual and intra-individual diversification of employee’s skills. In this context innovative assistance systems which individually support employees at work need to be discussed and developed

Thermodynamic and kinetic characterization of the interaction between the Ras binding domain of AF6 and members of the Ras subfamily

Cellular signaling downstream of Ras is highly diversified and may involve many different effector molecules. A potential candidate is AF6 which was originally identified as a fusion to ALL-1 in acute myeloid leukemia. In the present work the interaction between Ras and AF6 is characterized and compared with other effectors. The binding characteristics are quite similar to Raf and RalGEF, i.e. nucleotide dissociation as well as GTPase-activating protein activity are inhibited, whereas the intrinsic GTPase activity of Ras is unperturbed by AF6 binding. Particularly, the dynamics of interaction are similar to Raf and RalGEF with a lifetime of the Ras. AF6 complex in the millisecond range. As probed by 31P NMR spectroscopy one of two major conformational states of Ras is stabilized by the interaction with AF6. Looking at the affinities of AF6 to a number of Ras mutants in the effector region, a specificity profile emerges distinct from that of other effector molecules. This finding may be useful in defining the biological function of AF6 by selectively switching off other pathways downstream of Ras using the appropriate effector mutant. Notably, among the Ras-related proteins AF6 binds most tightly to Rap1A which could imply a role of Rap1A in AF6 regulation

The N'Dama cattle genetic improvement programme: A review

This paper reviews the successful N’Dama cattle genetic improvement programme implemented in a low input productions system at the International Trypanotolerance Centre (ITC) in 1994, in the Gambia. The first part of the paper presents the genetic improvement programme. The second part deals with the analysis of the genetic improvement programme expressed through genetic progress and the benefits for the farmers is encouraging. Recommendation process in the field are made

Structural variations within group 1 (Li-Cs)(+)(2,2,6,6-tetramethyl-1-piperidinyloxy)(-) complexes made via metallic reduction of the nitroxyl radical

Treatment of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) with a group 1 metal (Li, Na, K, Rb, or Cs), resulted in the reduction of this important radical to the TEMPO− anion-the first examples of elemental-metal single electron reduction of the radical to its anionic form. The synthesis and characterization of seven alkali metal TEMPO− complexes are reported. A variety of structural motifs are encountered depending on the choice of metal and/or solvent. (THF)2·[Li+(TEMPO−)]4 1 crystallized from THF as a cyclic (Li4O4) molecule. Two Li centers are stabilized by coordination to a THF molecule; the others by intramolecular coordination to NTEMPO atoms. [(THF)·Na+(TEMPO−)]4 2 exists as a distorted cubane where each Na center is coordinated to a THF molecule. No appreciable Na−NTEMPO coordination is observed. [(THF)2·Na+3(TEMPO−)2(OH)]2 3 was serendipitously prepared and exists as a distorted bis(cubane). It is envisaged that 3 is formed from 2 by insertion of a (Na-OH)2 double bridge into its framework. [Na+4(μ3-TEMPO−)2(μ2-TEMPO−)2(TMEDA)2] 4, adopts a four-runged ladder structure, whereby the two outer Na centers are coordinated to TMEDA, in addition to two μ2-O and a N atom. The inner metal atoms are bound to three μ3-O atoms and a N atom. [(THF)·K+(TEMPO−)]4 5 resembles the motif found for 2; however, presumably because of the larger size of the metal, K−NTEMPO interactions are present in 5. The asymmetric unit of [(TMEDA)·Rb+2(TEMPO−)2]2 6 comprises a Rb4O4 cubane with half a molecule of TMEDA coordinated to each metal. From a supramolecular perspective, 6 exists as a polymeric array of cubane units connected by TMEDA bridges. Completing the series, [Cs+(TEMPO)]∞ 7 crystallizes from hexane to form a donor-free polymeric complex. Complexes 1, 2, and 4−7 are soluble in D8-THF solution, and their NMR spectra are reported. The solution structures in donor solvent appear virtually identical