Effects Of Certain Combinations Research Articles

Complete effect decomposition for an arbitrary number of multiple ordered mediators with time-varying confounders: A method for generalized causal multi-mediation analysis.

Causal mediation analysis is advantageous for mechanism investigation. In settings with multiple causally ordered mediators, path-specific effects have been introduced to specify the effects of certain combinations of mediators. However, most path-specific effects are unidentifiable. An interventional analog of path-specific effects is adapted to address the non-identifiability problem. Moreover, previous studies only focused on cases with two or three mediators due to the complexity of the mediation formula in a large number of mediators. In this study, we provide a generalized definition of traditional path-specific effects and interventional path-specific effects with a recursive formula, along with the required assumptions for nonparametric identification. Subsequently, a general approach is developed with an arbitrary number of multiple ordered mediators and with time-varying confounders. All methods and software proposed in this study contribute to comprehensively decomposing a causal effect confirmed by data science and help disentangling causal mechanisms in the presence of complicated causal structures among multiple mediators.

Synergistic Effects of Weighted Genetic Risk Scores and Resistin and sST2 Levels on the Prognostication of Long-Term Outcomes in Patients with Coronary Artery Disease.

Resistin and soluble suppression of tumorigenicity 2 (sST2) are useful predictors in patients with coronary artery disease (CAD). Their serum levels are significantly attributed to variations in RETN and IL1RL1 loci. We investigated candidate variants in the RETN locus for resistin levels and those in the IL1RL1 locus for sST2 levels and evaluated the prognostication of these two biomarkers and the corresponding variants for long-term outcomes in the patients with CAD. We included 4652, 557, and 512 Chinese participants from the Taiwan Biobank (TWB), cardiovascular health examination (CH), and CAD cohorts, respectively. Candidate variants in RETN and IL1RL1 were investigated using whole-genome sequence (WGS) and genome-wide association study (GWAS) data in the TWB cohort. The weighted genetic risk scores (WGRS) of RETN and IL1RL1 with resistin and sST2 levels were calculated. Kaplan–Meier curves were used to analyze the prognostication of resistin and sST2 levels, WGRS of RETN and IL1RL1, and their combinations. Three RETN variants (rs3219175, rs370006313, and rs3745368) and two IL1RL1 variants (rs10183388 and rs4142132) were independently associated with resistin and sST2 levels as per the WGS and GWAS data in the TWB cohort and were further validated in the CH and CAD cohorts. In combination, these variants explained 53.7% and 28.0% of the variation in resistin and sST2 levels, respectively. In the CAD cohort, higher resistin and sST2 levels predicted higher rates of all-cause mortality and major adverse cardiac events (MACEs) during long-term follow-up, but WGRS of RETN and IL1RL1 variants had no impact on these outcomes. A synergistic effect of certain combinations of biomarkers with RETN and IL1RL1 variants was found on the prognostication of long-term outcomes: Patients with high resistin levels/low RETN WGRS and those with high sST2 levels/low IL1RL1 WGRS had significantly higher all-cause mortality and MACEs rates, and those with both these combinations had the poorest outcomes. Both higher resistin and sST2 levels, but not RETN and IL1RL1 variants, predict poor long-term outcomes in patients with CAD. Furthermore, combining resistin and sST2 levels with the WGRS of RETN and IL1RL1 genotyping exerts a synergistic effect on the prognostication of CAD outcomes. Future studies including a large sample size of participants with different ethnic populations are needed to verify this finding.

Abstract 4378: Contribution of ERα/PR crosstalk to endocrine therapy resistance in breast cancer

Abstract Half of estrogen receptor (ERα)-positive breast cancer patients treated with endocrine therapies display intrinsic or acquired therapy resistance. One-third of patients with acquired resistance present with metastatic tumors containing ERα-Y537S mutations. This mutation results in constitutive activity of ERα and altered ERα-associated gene expression. ERα/PR crosstalk, referring to the complex relationship of ERα and progesterone receptor (PR) interaction, offers therapeutic value in targeting both nuclear receptors simultaneously in ERα/PR-positive breast cancers. Previous research identified a synergistic effect of treating ERα-WT cancer cells with ERα/PR antagonism, where combined treatment results in tumor regression in vivo and increased cell death in vitro. Conversely, preliminary data suggests that treatment of ERα-Y537S-containing tumors with combined ERα and PR antagonists results in significantly increased proliferation in vivo and reduced cell death in vitro. My central hypothesis is that ERα-Y537S alters the transcription factor activity of ERα and PR, causing dysregulation of gene expression in SERM-resistant breast cancer. Using a three-dimensional culture system of patient-derived xenografts grown as organoids (PDxO), I have observed a synergistic effect of certain combinations of ERα/PR antagonists in the context of ERα-WT similar to previous results in two-dimensional cell culture. At the level of transcription, PR-associated transcriptional activity appears to be significantly altered in homozygous ERα-Y537S T47D cells compared to ERα-WT cells. Further understanding the role of ERα-Y537S in altering gene expression and reducing the response to SERM and SPRM treatment will provide understanding as to why these tumors are resistant to standard-of-care treatment and will suggest alternative targets for treatment as well. Citation Format: Rosemary J. Huggins. Contribution of ERα/PR crosstalk to endocrine therapy resistance in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4378.

Combinatorial Engineering of 1-Deoxy-D-Xylulose 5-Phosphate Pathway Using Cross-Lapping In Vitro Assembly (CLIVA) Method

The ability to assemble multiple fragments of DNA into a plasmid in a single step is invaluable to studies in metabolic engineering and synthetic biology. Using phosphorothioate chemistry for high efficiency and site specific cleavage of sequences, a novel ligase independent cloning method (cross-lapping in vitro assembly, CLIVA) was systematically and rationally optimized in E. coli. A series of 16 constructs combinatorially expressing genes encoding enzymes in the 1-deoxy-D-xylulose 5-phosphate (DXP) pathway were assembled using multiple DNA modules. A plasmid (21.6 kb) containing 16 pathway genes, was successfully assembled from 7 modules with high efficiency (2.0 x 103 cfu/ µg input DNA) within 2 days. Overexpressions of these constructs revealed the unanticipated inhibitory effects of certain combinations of genes on the production of amorphadiene. Interestingly, the inhibitory effects were correlated to the increase in the accumulation of intracellular methylerythritol cyclodiphosphate (MEC), an intermediate metabolite in the DXP pathway. The overexpression of the iron sulfur cluster operon was found to modestly increase the production of amorphadiene. This study demonstrated the utility of CLIVA in the assembly of multiple fragments of DNA into a plasmid which enabled the rapid exploration of biological pathways.

Deconstructing the semantics of big-step modelling languages

With the popularity of model-driven methodologies and the abundance of modelling languages, a major question for a requirements engineer is: which language is suitable for modelling a system under study? We address this question from a semantic point-of-view for big-step modelling languages (BSMLs). BSMLs are a class of popular behavioural modelling languages in which a model can respond to an input by executing multiple transitions, possibly concurrently. We deconstruct the operational semantics of a large class of BSMLs into eight high-level, mostly orthogonal semantic aspects and their common semantic options. We analyse the characteristics of each semantic option. We use feature diagrams to present the design space of BSML semantics that arises from our deconstruction, as well as to taxonomize the syntactic features of BSMLs that exhibit semantic variations. We enumerate the dependencies between syntactic and semantic features. We also discuss the effects of certain combinations of semantic options when used together in a BSML semantics. Our goal is to empower a requirements engineer to compare and choose an appropriate BSML from the plethora of existing BSMLs, or to articulate the semantic features of a new desired BSML when such a BSML does not exist.

A Program for Device Model Parameter Extraction from Gate Capacitance and Current of Ultrathin$hboxSiO_2$and High-$kappa$Gate Stacks

A modeling tool is demonstrated for fast and automatic gate dielectric characterization and parameter extraction for the 45-nm CMOS technology node and beyond. The model incorporates a nonlinear least squares fitting program with the ability to extract nanometer-scale equivalent oxide thicknesses (EOTs) SiO <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> and high-dielectric-constant (high-kappa) gate dielectrics from experimental gate capacitance (C <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">g</sub> -V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">g</sub> ) and gate leakage current (I <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">g</sub> -V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">g</sub> ) with high accuracy and efficiency. A modified Levenberg-Marquardt algorithm was used as the optimization approach. Improvements were made to reduce the chances of becoming stuck in local minima. A previously reported computationally efficient and accurate physically based compact model of self-consistent C <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">g</sub> -V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">g</sub> and I <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">g</sub> -V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">g</sub> model for both ultrathin SiO <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> and high-kappa gate stacks of EOT down to ~ 0.5 nm is used as the basis for translating experimental C <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">g </sub> -V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">g</sub> and I <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">g</sub> -V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">g</sub> data to material and device parameters. In just a few seconds, for single and double layer gate dielectrics, device parameters such as EOTs, surface substrate doping concentrations, flatband voltages, and polysilicon doping concentrations (if applicable) can be extracted from measured gate capacitance data, and parameters such as physical thickness, band offsets, dielectric constants, and tunneling masses for the gate dielectrics can be extracted from measured gate current data. It was found that significant correlation exists between the effects of certain combinations of model parameters, especially for gate tunneling current. Thus, in this program, parameters can be fixed selectively for those already obtained with high confidence from other measurements. Box constraints can also be imposed, at the price of somewhat longer extraction time (up to ~ 1-7 min), for parameters to be optimized to improve the possibility of finding the correct parameters

The effect of Russian Maternity Home routines on breastfeeding and neonatal weight loss with special reference to swaddling

Background Few investigations have considered evaluating the effects of certain combinations of ward routines like swaddling of the baby and separation of mother and baby on infant variables such as neonatal weight loss. Aims To study the effect of different ward routines in respect to proximity to mother and type of infant apparel, on breastfeeding parameters (amount of ingested milk, volume of supplements, number of breastfeeds, total duration of breastfeeding time) day 4 after birth as well as recovery from neonatal weight loss and infant's weight on day 5. Study design and subjects In a randomized trial with factorial design four treatment groups including 176 mother–infant dyads were studied 25–120 min after birth. Randomized treatments focused on care routines administered to the infants after delivery and later in the maternity ward as well as to the type of clothing the infants received. Group 1 infants were placed skin-to-skin with their mothers after delivery, and had rooming-in while in the maternity ward. Group 2 infants were dressed and placed in their mothers' arms after delivery, and roomed-in with mothers in the maternity ward. Group 3 infants were kept in the nursery both after birth and while their mothers were in the maternity ward. Group 4 infants were kept in the nursery after birth, but roomed-in with their mothers in the maternity ward. Equal numbers of infants were either swaddled or clothed in baby attire. Breastfeeding parameters were documented during day 4 after birth. Infant's weight was measured daily. Results Babies who were kept in the nursery received significantly more formula and significantly less breast-milk, than did babies who roomed-in with their mothers. Swaddling did not influence the breastfeeding parameters measured. However, swaddled babies who had experienced a 2-h separation period after birth and then were reunited with their mothers tended to have a delayed recovery of weight loss compared to those infants who were exposed to the same treatment but dressed in clothes. Furthermore, swaddled babies who were kept in the nursery and received breast-milk supplements had a significantly delayed recovery of weight loss after birth when compared to those infants ingesting only breast-milk. On day 5, regression analyses of predicted weight gain in the exclusively breastfed infants indicated a significant increase per 100 ml breast-milk (59 g), compared to the predicted weight gain on day 5 per 100 ml supplements in the swaddled babies (14 g) ( P = 0.001). Conclusion Supplements given to the infants in the nursery had a negative influence on the amount of milk ingested. In addition, supplement feeding or a short separation after birth when combined with swaddling was shown to have a negative consequence to infant weight gain.

Dietary Antioxidants for Prevention of Cardiovascular Disease

The traditional Japanese diet with its high intake of fruits and vegetables that are rich in antioxidants is believed to effectively ward off cardiovascular disease. Oxidative stress, related to reactive oxygen and nitrogen species produced by aerobic organisms, is responsible for the pathogenesis of most chronic diseases. Oxidative low density lipoprotein (LDL) is thought to play a key role in the pathogenesis of early atherosclerosis. There has been increasing interest in antioxidant substances derived from edible plants. It has been suggested that the measurement of LDL antioxidant activity is physiopathologically more important and informative for screening antioxidant activity to prevent atherosclerosis than other methods. We assessed by LDL oxidation assay the antioxidant characteristics of various edible plants from rural areas. The mulberry (Morus alba L.) leaf showed comparatively high antioxidant activity. We identified the antioxidant compounds and investigated compound levels in the mulberry leaf and found the antioxidant activity of mulberry leaves to be mainly attributable to quercetin 3-(6-malonylglucoside) (Q3MG). Dietary consumption of mulberry leaves and/or Q3MG may enhance resistance to oxidative modification of LDL and attenuated atherosclerotic lesion development. However, the outcome of intervention trials suggested that a single antioxidant had little effect on the risk of developing cardiovascular disease. The synergic effect of certain combinations may determine outcome. We need to widen our understanding of the synergic effect of diets and nutrient-gene interactions related to nutrient/disease risk.

Analysis of brick veneer walls on wood frame construction subjected to out-of-plane loads

Modern residential brick masonry veneer construction has been investigated by separate laboratory testing of corrugated sheet metal tie connections and full-scale solid brick veneer wall panels. Based on these experiments, detailed three-dimensional finite element (FE) models were developed, representing the full-scale brick veneer wall panel specimens, including nonlinear inelastic properties for the tie connections. Upon calibration, the FE wall panel models effectively captured the static and dynamic experimental brick veneer wall behaviors at different response levels (up to and including tie damage and even collapse). Some parametric studies were then carried out using the FE wall panel models to evaluate the effects of certain combinations of tie connections and layouts on the out-of-plane performance of brick veneer walls, subjected to static and dynamic loading.

Characterizations of Coronaviruscis-Acting RNA Elements and the Transcription Step Affecting Its Transcription Efficiency

Seven to eight species of viral subgenomic mRNAs are produced in coronavirus-infected cells. These mRNAs are produced in different quantities, and their molar ratios remain constant during viral replication. We studied RNA elements that affect coronavirus transcription efficiency by characterizing a series of cloned coronavirus mouse hepatitis virus (MHV) defective interfering (DI) RNAs containing an inserted intergenic sequence, from which subgenomic DI RNA is transcribed in MHV-infected cells. Certain combinations of upstream and downstream flanking sequences of the intergenic sequence suppressed subgenomic DI RNA transcription, yet changing one of the flanking sequences to a different sequence eliminated transcription suppression. The suppressive effect of certain combinations of flanking sequences, but not all combinations, could be counteracted by altering the intergenic sequence. Thus, the combination of intergenic sequence and flanking sequence affected transcription efficiency. We also characterized another set of DI RNAs designed to clarify which transcription step determines the relative molar ratios of coronavirus mRNAs. Our study indicated that if subgenomic mRNAs were exclusively synthesized from negative-strand genomic RNA, then the relative molar ratios of coronavirus mRNAs were most likely determined after synthesis of the genomic-sized template RNA. If negative-strand subgenomic RNAs were templates for subgenomic mRNAs, then the relative molar ratios of coronavirus mRNAs probably were determined after synthesis of the genomic-sized template RNA used for subgenomic-sized RNA transcription but prior to the completion of the synthesis of subgenomic-sized RNAs containing the leader sequence. The relative molar ratios of coronavirus mRNAs, therefore, seem to have been established prior to a putative replicon-type amplification of subgenomic mRNAs.