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At least 1,639 records · Page 91Linked to original sources
PubMed2005

Inhibition of multidrug resistance proteins MRP1 and MRP2 by a series of alpha,beta-unsaturated carbonyl compounds.

To study the possible interplay between glutathione metabolism of and MRP inhibition by thiol reactive compounds, the interactions of a series of alpha,beta-unsaturated carbonyl compounds with multidrug resistance proteins 1 and 2 (MRP1/ABCC1 and MRP2/ABCC2) were studied. Alpha,beta-unsaturated carbonyl compounds react with glutathione, and therefore either their parent compound or their intracellularly formed glutathione metabolite(s) can modulate MRP-activity. Inhibition was studied in Madin-Darby canine kidney cells stably expressing MRP1 or MRP2, and isolated Sf9-MRP1 or Sf9-MRP2 membrane vesicles. In the latter model system metabolism is not an issue. Of the series tested, three distinct groups could be discriminated based on differences in interplay of glutathione metabolism with MRP1 inhibition. Curcumin inhibited MRP1 transport only in the vesicle model pointing at inhibition by the parent compound. The glutathione conjugates of curcumin also inhibit MRP1 mediated transport, but to a much lesser extent than the parent compound curcumin. In the cellular model system, it was demonstrated that glutathione conjugation of curcumin leads to inactivation of its inhibitory potential. Demethoxycurcumin and bisdemethoxycurcumin inhibited MRP1 in both the vesicle and cellular model pointing at inhibitory potency of at least the parent compound and possibly their metabolites. A second group, including caffeic acid phenethyl ester inhibited MRP1-mediated calcein transport only in the MDCKII-MRP1 cells, and not in the vesicle model indicating that metabolism appeared a prerequisite to generate the active inhibitor. Finally cinnamaldehyde, crotonaldehyde, trans-2-hexanal, citral, and acrolein did not inhibit MRP1. For MRP2, inhibition was much less in both model systems, with the three curcuminoids being the most effective. The results of this study show the importance to study the complex interplay between MRP-inhibitors and their cellular metabolism, the latter affecting the ultimate potential of a compound for cellular MRP-inhibition.

Aldehydes↗
PubMed2004

Paternal alcohol dependence and offspring suicidal behaviors in a children-of-twins study.

INTRODUCTION: In substance abusing families, sources of familial comorbidity are potentially confounded by genetic-environmental (GE) interplays. The children-of-twins (COT) design can be used to elucidate the association of a parental trait and an offspring outcome such as the association of parental alcoholism and offspring suicidality. METHODS: We examined the association of paternal alcoholism and offspring suicidal behaviors in an adolescent and young adult COT sample of 'Vietnam Era Twins' offspring who had completed an interview including a comprehensive assessment of lifetime suicidal behaviors. We stratified the COT sample into four groups contingent upon paternal zygosity, MZ versus DZ, and lifetime paternal alcohol dependence history (AD), positive versus negative. We examined whether the relationship of paternal alcoholism and offspring suicidality was best explained by genetic predispositions common to alcoholism and suicidality or by GE interplay--environmental influences correlated with parental alcoholism or the interaction of genetic and environmental factors. RESULTS: Our results suggest a main effect of paternal alcoholism on offspring suicide attempt; COT analyses do not support a purely genetic explanation for this association. DISCUSSION: Suicide attempts probably result from GE interplays and must be studied in genetically informative samples of offspring of substance abusing parents.

Adolescent↗
PubMed2004

[Modulatory effect of antimicrobial agents or aminoacids on the oxidative burst of polymorphonuclear neutrophils triggered by formylmethionyl-leucyl-phenylalanine (fMLP)].

We have compared the interplay of several antimicrobial agents and aminoacids on the neutrophil respiratory burst in response to formylmethionyl-leucyl-phenylalanine (fMLP), a chemoattractant. Mainly, an inhibitory effect has been observed in the penicillin family of agents and an enhancing effect in the cephalosporin family of agents. The molecules in which the sulfur numbered 1 in the 6-APA or 7-ACA nucleus was replaced by a carbon or an oxygen, had a different effect as compared with the other members of the family. The modulatory effects of ampicillin and cephalothine were not significant at a concentration lower than 10 mg/l and the effect of cephalothine looked maximum at 20-40 mg/l. If studies in cell-free systems demonstrated that the inhibitory effect of some antimicrobials could be due to a direct oxidant-scavenger activity mainly of HOCl, only hypotheses are proposed to explain the enhancing activity of the others. It could be in relation with (i) a synergistic effect upon fMLP receptor leading to an increase in H(2)O(2)/HOCl production or (ii) the generation of new oxydant products originating in cephalosporin lysis under HOCl attack, which would be able to react with luminol. The interplay of antimicrobial agents with the respiratory burst measured outside the cells probably has no therapeutic consequences because the bactericidal activity of neutrophils is achieved inside phagosomes where few agents are known to come into and where chemical conditions are different. On the opposite, in clinical use, this interplay could be interesting to study for a prevention of side effects.

Amino Acids↗
PubMed2002

Computing an organism: on the interface between informatic and dynamic processes.

The importance of interactions between processes at diverse space and time scales in biological information processing is a recurrent theme in the work of Michael Conrad (BioSystems, 1995: 35, 157-160; BioSystems, 1999: 52, 99-100). In this paper I present some results of explicit computational models that aim to capture and exploit some of the essential features of such multi-level processes. In the model formulation, I try to minimize the explicit definition of inter-level interactions, while providing the possibility of such interactions to develop. As often argued by Conrad inter-level interactions limit programmability. Indeed, we use an evolutionary process to derive the specific models. We study morphogenesis. We show that the interplay between cell adhesion and cell differentiation provides interesting mechanisms for morphogenesis. We also show that the interplay can both reduce and enhance small random fluctuations. We show that unequal cell cleavage in the early embryo-genesis reduces inter-individual variation of the morphemes developed from the same 'genome'. Our results suggest that, during evolution, the interplay between levels is exploited while it is at the same time reduced so as to give a certain primacy to inherited information.

Animals↗
PubMed2000

Interactions between androgen and estrogen receptors and the effects on their transactivational properties.

The physiological interplay of androgen and estrogen action in endocrine tissues is well recognized. The biochemical processes responsible for this interplay have yet to be fully defined. We have demonstrated that the androgen receptor (AR) and estrogen receptor-alpha (ERalpha) can interact directly using the yeast and mammalian two-hybrid systems. These interactions occurred between the C-terminal ERalpha ligand-binding domain and either the N-terminal AR transactivational domain or the full-length AR. Estrogen receptor-beta (ERbeta) did not interact with the AR. DNA cotransfection studies employing AR, ERalpha and ERbeta expression vectors and AR- or ER-reporter gene constructs were used to identify and measure potential functional effects of AR-ER interaction. Coexpression of ERalpha with AR decreased AR transactivation by 35%; coexpression of AR with ERalpha decreased ERalpha transactivation by 74%. Coexpression of AR and ERbeta did not significantly modulate AR or ERbeta transactivation. In summary, we have shown that specific domains of AR and ERalpha physically interact and have demonstrated the functional consequences of such interaction. These results may help explain the nature of the physiological interplay between androgens and estrogens.

Animals↗
PubMed1997

Integrating nature and nurture: implications of person-environment correlations and interactions for developmental psychopathology.

The developmental interplay between nature and nurture is discussed, with particular reference to implications for research in developmental psychopathology. The general principles include individual differences in reactivity to the environment, two-way interplay between intraindividual biology and environmental influences, and the need to consider broader social contextual features. Individuals actively process their experiences; they also act on their environment to shape and select their experiences, and individual characteristics change over time. Key findings on genetic effects include their ubiquitous influence, the multifactorial origin of most psychopathology, the involvement of several genes in most mental disorders, some genetic effects operate through dimensional risk features rather than directly on disorder, some genetic effects are dependent on gene-environment correlations and interactions, and genetic effects increase with age. Key findings on environmental effects include their ubiquitous influence, the genetic mediation of some supposed environmental effects, the importance of passive gene-environment correlations, the paucity of evidence regarding environmental effects on lifetime liability to psychopathology, the lack of understanding of environmental effects on the organism, and the importance of nonshared environmental effects. Research strategies to investigate environmental risk mediation include the range of genetically sensitive designs, migration studies, secular trend investigations, studies of nonfamilial environments, and examination of intraindividual change in relation to measured environmental alterations. Proximal processes involved in person-environment interplay are discussed in relation to person-environment interactions and evocative and active person-environment correlations.

Adaptation, Psychological↗
PubMedDate not supplied

A public health genetic approach for schizophrenia.

BACKGROUND: Schizophrenia is a complex disease resulting from the interplay of genetic and environmental factors. However, psychiatric genetics and epidemiology have often worked as independent research fields. AIMS: To review the evidence about the gene-environment interplay involved in the development of schizophrenia. METHODS: Systematic review of medical and psychological databases. RESULTS: On one hand, quantitative and molecular genetics showed high heritability for schizophrenia and identified genes likely to be involved in its pathophysiology. The strength of the association between candidate genes and schizophrenia is however modest, and the need for a more appropriate conceptualization of the genetic risk has been claimed. On the other hand, psychiatric epidemiology described several environmental factors liked with the onset or the course of schizophrenia. The observational nature of epidemiology, however, may hamper inference on causation. Gene-environment correlations and interactions influence the exposure and the vulnerability to the environment, respectively. Current findings suggest that gene-environment correlations and interactions may be common phenomena in the pathophysiology of schizophrenia. The consideration of gene-environment interplay may help to overcome many limitations of genetic and epidemiological studies in psychiatry and suggest innovative preventive and therapeutic strategies. CONCLUSIONS: Taking into account the complexity of schizophrenia pathophysiology, mental health genetics may provide a comprehensive and heuristic model of disease.

Emigration and Immigration↗
PubMed2004

Effects of motion on the total dose distribution.

The success of highly target-conformal treatments such as intensity-modulated radiotherapy (IMRT) can be compromised by motion of the inner organs and random patient setup errors. This article gives an overview of different studies that looked at the effect of organ motion and setup errors on radiation therapy dose distributions, both from a qualitative and quantitative point of view. The qualitative findings are generally applicable (ie, case independent). It is found that motion always leads to a blurring of the dose distribution. In addition, there are so-called interplay effects if the treatment delivery involves moving parts, such as multileaf collimators. After a large number of fractions, the interplay effects lead to a normal distribution of the dose value around the average blurred value. Thirdly, organ motion can also cause a spatial deformation of the dose distribution. Quantitatively it has been found that both deformation and interplay effects appear to be small (in the order of 1%-2%) in many typical clinical cases. The dominant effect is the blurring of the dose distribution, which is, in essence, independent of the treatment technique, and is not more pronounced in IMRT than in more conventional treatment techniques. However, because in IMRT there is a tendency to reduce or compromise target margins, the blurring has potentially a bigger effect on the outcome of IMRT, unless precision dose delivery techniques (such as gated or motion-synchronized beams) are used. An alternative to the use of margins is to do the planning based on blurred dose distributions.

Humans↗
PubMed2003

The neurotoxicity induced by ethanol withdrawal in mature organotypic hippocampal slices might involve cross-talk between metabotropic glutamate type 5 receptors and N-methyl-D-aspartate receptors.

BACKGROUND: We recently reported that the sodium salt of acamprosate (Na-acamprosate) demonstrates the characteristics of an antagonist at metabotropic glutamate type 5 receptors (mGluR5s) rather than at N-methyl-d-aspartate receptors (NMDARs). Because mGluR5s are able to enhance the function of NMDARs, this interplay may be involved in the dysregulation of glutamatergic transmission during ethanol withdrawal. The following studies use organotypic hippocampal slice cultures at a mature age to investigate the potential for this interplay in the neurotoxicity associated with withdrawal from long-term ethanol exposure. METHODS: At 25 days in vitro, organotypic hippocampal slice cultures prepared from male and female 8-day-old rats were exposed to an initial concentration of 100 mM ethanol for 10 days before undergoing a 24-hr period of withdrawal. The effects of Na-acamprosate; 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893), a noncompetitive antagonist at mGluR5s; 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester, a noncompetitive antagonist at mGluR1s; dizocilpine (MK-801), a noncompetitive NMDAR antagonist; and staurosporine on the neurotoxicity induced by ethanol withdrawal were assessed by determining differences in propidium iodide uptake. Polypeptide levels of mGluR5s and the NR1 and NR2B subunits of NMDARs were also determined via Western blot analyses after 10 days of ethanol exposure. RESULTS: Significant neurotoxicity was always evident in the CA1 hippocampal region after a 24-hr withdrawal period. This spontaneous neurotoxicity resulted from intrinsic changes induced by the long-term presence of ethanol. Na-acamprosate (200-1000 microM), SIB-1893 (200-500 microM), MK-801 (20 microM), and staurosporine (200 nM) were all neuroprotective. The polypeptide levels of mGluR5s and NR1 and NR2B subunits of NMDARs were all increased after ethanol exposure; however, the increase in mGluR5s did not achieve statistical significance. CONCLUSIONS: From this model of long-term ethanol exposure and withdrawal, the functional interplay between mGluR5s and NMDARs might represent a novel target for the prevention of neurotoxicity associated with ethanol withdrawal.

Animals↗
PubMed1996

How child health care nurses view a mother-infant relationship. A qualitative study.

Too many children in Sweden grow up under difficult circumstances. Every child should have the opportunity to grow up to be a confident person. We know today that the new-born child is able to influence its surroundings. The main purpose of child health care in Sweden is to reduce mortality, morbidity and disability in children, and also to reduce any detrimental effects on the family. Child Health Care (CHC)-nurses provide community and security for parents and children in developing relationships. The aims of this study were to identify how CHC-nurses view a mother-infant relationship, and how they can improved this relationship. Ten CHC-nurses were interviewed about mother-infant relationships. Verbatim transcripts were analysed using constant comparative analysis. The emerging core category was interplay. Under this construct there were two categories; maternal ability and signals from the infant. Different substantive codes were given under these categories, viz. body language, vocal language, poor health, expectations and life situation. In describing how to improve the mother-infant relationship, promoting an understanding of interplay was the core category. Three categories/strategies were perceived; visualize, respect and demonstrate. The results were then compared with the literature. This study indicates that interplay is of greatest importance in a mother-infant relationship.

Attitude of Health Personnel↗
PubMed2003

Quantifying the effect of intrafraction motion during breast IMRT planning and dose delivery.

Respiratory motion during intensity modulated radiation therapy (IMRT) causes two types of problems. First, the clinical target volume (CTV) to planning target volume (PTV) margin needed to account for respiratory motion means that the lung and heart dose is higher than would occur in the absence of such motion. Second, because respiratory motion is not synchronized with multileaf collimator (MLC) motion, the delivered dose is not the same as the planned dose. The aims of this work were to evaluate these problems to determine (a) the effects of respiratory motion and setup error during breast IMRT treatment planning, (b) the effects of the interplay between respiratory motion and multileaf collimator (MLC) motion during breast IMRT delivery, and (c) the potential benefits of breast IMRT using breath-hold, respiratory gated, and 4D techniques. Seven early stage breast cancer patient data sets were planned for IMRT delivered with a dynamic MLC (DMLC). For each patient case, eight IMRT plans with varying respiratory motion magnitudes and setup errors (and hence CTV to PTV margins) were created. The effects of respiratory motion and setup error on the treatment plan were determined by comparing the eight dose distributions. For each fraction of these plans, the effect of the interplay between respiratory motion and MLC motion during IMRT delivery was simulated by superimposing the respiratory trace on the planned DMLC leaf motion, facilitating comparisons between the planned and expected dose distributions. When considering respiratory motion in the CTV-PTV expansion during breast IMRT planning, our results show that PTV dose heterogeneity increases with respiratory motion. Lung and heart doses also increase with respiratory motion. Due to the interplay between respiratory motion and MLC motion during IMRT delivery, the planned and expected dose distributions differ. This difference increases with respiratory motion. The expected dose varies from fraction to fraction. However, for the seven patients studied and respiratory trace used, for no breathing, shallow breathing, and normal breathing, there were no statistically significant differences between the planned and expected dose distributions. Thus, for breast IMRT, intrafraction motion degrades treatment plans predominantly by the necessary addition of a larger CTV to PTV margin than would be required in the absence of such motion. This motion can be limited by breath-hold, respiratory gated, or 4D techniques.

Algorithms↗
PubMed1999

Adsorption from solutions on synthetic hydroxyapatite: nonaqueous vs. aqueous solvents.

It is useful in restorative dentistry and etiology of bone diseases to know that certain general rules may be derived from a priori considerations of the adsorption of chemicals to synthetic hydroxyapatite (which is the structural prototype of tooth and bone mineral). This article systematically synthesizes the extensive studies on the subject by the author, and rationalizes and extends these rules. Though not a review article, the work of some researchers may not have found an adequate representation here, because they did not determine, in the case of nonaqueous solvents, the reversibility of adsorption; or, in the case of aqueous solvents, the concentration of all constituent ions of the system, thus missing the occurrence of processes other than adsorption. The adsorption of solutes from nonaqueous solvents on hydroxyapatite is mainly regulated by the interplay of hydrogen bonding between adsorbate, adsorbent, and solvent. It does not involve any significant role of ionic nature of the apatite surface, because it is masked by the chemisorbed and physisorbed water. This interplay of hydrogen bonding in conjunction with chemical and structural characteristics of the adsorbed molecules controls their reversibility and the orientation of the adsorbates on the surface. In general, the process may be considered as true adsorption, because no other material exchange process is involved. The "adsorption" of solutes from aqueous solutions generally involves ion-exchange with the apatite surface, and may be affected by the concentrations of potential determining ions (Ca(2+), phosphates, H(+), etc.) in the solution. The solute in aqueous solution may be removed by two other mechanisms, either by formation of a surface complex or by chemically reacting with calcium or phosphate ions to form a new phase that precipitates out of solution. Therefore, the concentration of calcium and phosphate ions in solution should also be monitored to elucidate the mechanism of the process. Adsorption of polymers seems to be determined primarily by their multiple hydrogen bonding, their relative molar mass, and their ability to self-associate. The hydrogen ion concentration plays a decisive role in each one of the above mechanisms.

Adsorption↗
PubMed2001

Factors Controlling the Addition of Carbon-Centered Radicals to Alkenes-An Experimental and Theoretical Perspective.

The successful exploitation of syntheses involving the generation of new carbon-carbon bonds by radical reactions rests on some prior knowledge of the rate constants for the addition of carbon-centered radicals to alkenes and other unsaturated molecules, and of the factors controlling them. Two former classical reviews in Angewandte Chemie by Tedder (1982) and by Giese (1983) provided mechanistic insight and led to various qualitative rules on the complex interplay of enthalpic, polar, and steric effects. In the meantime, the field has experienced very rapid progress: many more experimental absolute rate constants have become available, and there have been major advances in the efficiency and reliability of quantum-chemical methods for the accurate calculation of transition structures, reaction barriers, and reaction enthalpies. Herein we review this progress, recommend suitable experimental and theoretical procedures, and display representative data series for radical additions to alkenes. On this basis, and guided by the pictorial tool of the state-correlation diagram for radical additions, we then offer a new and more stringent quantification of the controlling factors. Our analysis leads to a partial revision of the previous qualitative rules, and it more clearly exhibits the interplay of the reaction enthalpy effects, polar charge-transfer contributions, and steric substituent effects on the reaction energy barrier. The various contributions are cast into the form of new, simple, and physically meaningful but non-linear, predictive equations for the preestimation of rate constants. These equations prove successful in several tests but call for additional theoretical and experimental foundation. The kinetics of related reactions such as polymer propagation, copolymerization, and the addition of radicals to alkynes and aromatic compounds is shown to follow the same principles.

Journal Article↗
PubMed1994

Protein tracking-induced supercoiling of DNA: a tool to regulate DNA transactions in vivo?

An interplay between DNA-dependent biological processes appears to be crucial for cell viability. At the molecular level, this interplay relies heavily on the communication between DNA-bound proteins, which can be facilitated and controlled by the dynamic structure of double-stranded DNA. Hence, DNA structural alterations are recognized as potential tools to transfer biological information over some distance within a genome. Until recently, however, direct evidence for DNA structural information as a mediator between cellular processes was lacking. This changed when the concept of transient waves of DNA supercoiling, induced by proteins tracking along the right-handed DNA double helix, came into the limelight. Indeed, a number of observations now suggest that helix tracking-induced DNA structural information might be exploited to participate in the regulation of a variety of DNA transactions in vivo.

Animals↗
PubMed2003

On the nature of the forces controlling selectivity in the high performance capillary electrochromatographic separation of peptides.

In this minireview, the nature of the forces controlling selectivity in the high performance capillary electrochromatographic (HP-CEC) separation of peptides has been examined. For uncharged and charged peptides, a synergistic interplay occurs in HP-CEC systems between adsorptive/partitioning events and electrokinetically driven motion. Moreover, at high field strengths, both bulk electrophoretic migration and surface electrodiffusion occur. Thus, the migration behavior of peptides in different HP-CEC systems can be rationalized in terms of the combined consequences of these various processes. Moreover, in HP-CEC, the buffer electrolyte interacts with both the peptide analytes and the sorbent as bulk phenomena. These buffer-mediated processes control the solvational characteristics, ionization status and conformational behavior of the peptides as well as regulate the double-layer properties of the sorbent, and the ion flux and electro-osmotic flow characteristics of the HP-CEC system per se. These buffer electrolyte effects mediate mutual interactions between the peptide and the sorbent, irrespective of whether the interaction occurs at the surface of microparticles packed into a capillary, at the surface of a contiguous monolithic structure formed or inserted within the capillary or at the walls of the capillary as is the case with open tubular HP-CEC. Diverse molecular and submolecular forces thus coalesce to provide the basis for the different experimental modes under which HP-CEC can be carried out. As a consequence of this interplay, experimental parameters governing the separation of peptides in HP-CEC can be varied over a wide range of conditions, ensuring numerous options for enhanced selectivity, speed, and resolution of peptides. The focus of the peptide separation examples presented in this minireview has been deliberately restricted to the use of HP-CEC capillaries packed with n-alkyl-bonded silicas or mixed-mode strong ion exchange sorbents, although other types of sorbent chemistries can be employed. From these examples, several conclusions have been drawn related to the use of HP-CEC in the peptide sciences. These observations confirm that variation of a specific parameter, such as the pH or the content of the organic solvent modifier in the buffer electrolyte, simultaneously influences all other physicochemical aspects of the specific HP-CEC separation. Peptide selectivity in HP-CEC thus cannot be fine-tuned solely through the use of single parameter optimization methods. In this context, HP-CEC differs significantly from the analogous reverse phase high performance liquid chromatography (RP-HPLC) procedures with peptides. Rather, more sophisticated multiparameter optimization procedures, involving knowledge of (a) the field strength polarity, (b) its contour and flux characteristics, (c) effects of buffer electrolyte composition and pH, (e) the influence of the temperature, and (f) the impact of the sorbent characteristics, are required if the full capabilities offered by HP-CEC procedures are to be exploited. In this minireview, the HP-CEC migration behavior of several different sets of synthetic peptides has been examined, and general guidelines elaborated from these fundamental considerations to facilitate the interpretation and modulation of peptide selectivity in HP-CEC.

Chromatography, Micellar Electrokinetic Capillary↗
PubMed2005

A kinetic model of quantitative real-time polymerase chain reaction.

Real-time polymerase chain reaction (PCR) is one of the most sensitive and accurate methods for quantifying transcript levels especially for those expressed at low abundance. The selective amplification of target DNA over multiple cycles allows its initial concentration to be determined. The amplification rate is a complex interplay of the operating conditions, initial reactant concentrations, and reaction rate constants. Experimentally, the compounded effect of all factors is quantified in terms of an effective efficiency, which is estimated by curve fitting to the amplification data. We present a comprehensive model of PCR to study the effect of various reactant concentrations on the amplification efficiency. The model is used to calculate the kinetic progression of the target DNA concentration with cycle number under conditions when different species are stoichiometrically or kinetically limiting. The reaction efficiency remains constant for the initial cycles. As the primer concentration becomes limiting, the efficiency is marked by a gradual decrease. This is in contrast to a steep decline under nucleotide limiting conditions. Under some conditions, commonly used experimentally, increasing primer concentration has the adverse effect of reducing the final amplified template concentration. This phenomenon seen at times experimentally is explained by the simulation results under rate limiting enzyme concentrations. Primer dimer formation is shown to significantly affect the reaction rates, effective efficiency, and the estimated initial concentrations. This model, by describing the interplay of the many operating variables, will be a useful tool in designing PCR conditions and evaluating its results.

Computer Simulation↗
PubMed1994

Congenital heart disease and pregnancy.

In Europe and North America, a dramatic fall in the incidence of rheumatic fever and rheumatic heart disease has coincided with advances in medical and surgical management of congenital heart disease and has resulted in a shift in the relative incidence of these two categories of cardiac disorders in women of child-bearing age. This review deals with pregnancy and congenital heart disease--unoperated and operated. Central to this topic is the intricate interplay between maternal circulatory and respiratory physiology and maternal congenital heart disease, and the effects of this interplay upon the fetus which is exposed to risks that threaten its intrauterine viability and to risks that subsequently express themselves as developmental defects or transmitted congenital malformations of the heart or circulation.

Delivery, Obstetric↗
PubMed2026

Multi-Omics Integration Identifies a Five-Gene Metabolic Signature With Experimental Validation in Clear Cell Renal Cell Carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is hallmarked by profound metabolic reprogramming; however, its intricate crosstalk with the tumor immune microenvironment (TIME) and its clinical ramifications remain inadequately elucidated. This study aims to systematically decipher the metabolic-immune interplay in ccRCC through multi-omics integration, with the goal of identifying robust prognostic biomarkers and actionable therapeutic vulnerabilities. AIMS: This study aims to systematically decipher the metabolic-immune interplay in clear cell renal cell carcinoma (ccRCC) through multi‑omics integration, and to identify robust prognostic biomarkers and actionable therapeutic vulnerabilities that can inform precision risk stratification and individualized treatment strategies. METHODS: We integrated bulk transcriptomic, genomic, and clinical data from multiple ccRCC cohorts. Differential expression and functional enrichment analyses were performed to characterize metabolic pathway alterations. Mendelian randomization (MR) was employed to infer causal relationships between metabolic disorders and ccRCC risk. A machine learning-based prognostic framework, incorporating SHAP (SHapley Additive exPlanations) for feature interpretability, was constructed and rigorously validated. TIME heterogeneity was dissected using deconvolution algorithms, while drug sensitivity, tumor mutation burden (TMB), and TIDE scores were utilized to assess therapeutic responses and immune evasion. Candidate gene function was evaluated through in vitro gain- and loss-of-function assays, with expression validated via TCGA, HPA, western blot, and qRT-PCR. RESULTS: Enrichment analysis identified coordinated dysregulation in lipid metabolism, energy homeostasis, and hypoxia response pathways. MR analysis confirmed lipid metabolism disorders as a causal risk factor for ccRCC. Our machine-learning model, centered on five core SHAP-identified features (SUCLA2, ACAT1, PC, SUCLG1, and HMGCS2), demonstrated superior predictive accuracy over conventional clinical staging. Immune profiling unveiled dichotomous TIME states: the low-risk group retained active immune surveillance, whereas the high-risk group was enriched with immunosuppressive subsets. Drug sensitivity screening pinpointed LY2109761 and carmustine as high-risk-specific candidate agents. Furthermore, TMB and TIDE analyses stratified high-risk patients displaying genomic instability and immune evasion phenotypes. Functionally, SUCLA2 knockdown significantly enhanced ccRCC cell proliferation and invasion, while its overexpression suppressed these malignant phenotypes, corroborating its tumor-suppressive role. Expression patterns of the hub genes were consistently validated across multi-level datasets and experimental assays. CONCLUSION: This study establishes a precision oncology framework for ccRCC by functionally linking metabolic biomarkers, immunophenotypes, and stratified therapeutic strategies. Importantly, we identify SUCLA2 as a potential functional tumor suppressor and a promising target for further mechanistic and translational investigation.

Humans↗