The intersection of law and medicine: the case for providing federal funding for embryonic stem cell research.
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Embryo Research↗
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A computational model of a class of gene networks with positive and negative controls.
This article proposes a computational framework for modelling the logical behavior of a class of gene networks. We characterize the basic behavior of genes in terms of a state-and-transition structure, and model the individual genes as language-generating automata. We consider positive and negative controls as the interaction mechanisms among the genes, and treat such controls as constraints (also expressed in automata) imposed on the behavior of the gene network. By computing the intersection of the languages generated by the gene models and the constraints, we obtain the complete set of pathways in a gene network. Implications and possible improvement of this work are discussed.
Computational Biology↗
Molecular characterization of the genomic region linked with apomixis in Pennisetum/Cenchrus.
Apomixis is defined as asexual reproduction through seeds, although this outcome can be achieved by multiple pathways. Since little is known about the molecular control of these pathways, how they might intersect is also a mystery. Two of these pathways in the grass family, diplospory and apospory, are receiving attention from molecular biologists. Apospory in Pennisetum/Cenchrus, two genera of panicoid grasses, results in the formation of four-nucleate embryo sacs that lack antipodals. Sexual reproduction frequently aborts so that the resulting seed is composed of (1) a parthenogenetically derived embryo that is genetically identical to the mother and (2) endosperm formed through pseudogamy. The transmission of apomixis is associated with the transfer of a linkage block on a single chromosome. This linkage block contains repetitive sequences as well as hemizygous, low-copy DNA sequences. Fluorescence in situ hybridization has demonstrated that these DNA regions occur on only a single chromosome, but not its homologs, in the polyploid apomicts studied. Features of the apomixis-associated region resemble those of other chromosomal segments isolated from recombination and replete with "selfish" DNAs.
Cenchrus↗
Climate and the weight/height relationship in sub-Saharan Africa.
25 populations of the rain forest and 44 of the open country, all descended from the West-Central African stock which lived in the latter biome, are compared for body weight and height. On a log weight/height diagram, the 69 populations cluster along a straight line which intersects the lines of equal body weight/surface ratio: the shorter the body size, the lower the ratio tends to be. The rain forest populations are concentrated in the lower part of the bivariate distribution. The shortest one, the Mbuti Pygmies, has a very low ratio despite a relatively heavy weight. The shorter stature of the rain forest populations seems to be largely genetic in origin; it probably results from selective pressure exerted by the thermal stres in this hot and wet biome where sweating is of low thermolytic efficiency. The amount of reduction of adult stature depends for a large part on the number of generations spent in the forest by the population. Line A (in figure 1) is similar to a growth trend. The 69 populations differ genetically by the target that growth has to reach on a common log weight/height trend line. They achieve this differentiation through different speeds of growth.
Adaptation, Physiological↗
Use of a synthetic lethal screen to identify yeast mutants impaired in endocytosis, vacuolar protein sorting and the organization of the cytoskeleton.
To identify new genes whose products act on the endocytic and vacuolar protein sorting pathways, we screened for mutants that display synthetic growth defects with delta ypt51, a mutant impaired in membrane traffic at a point where these pathways intersect. Seven mutants that fell into six different complementation groups were found to fit this criterium. Two of the mutants (ysl1 and ysl2) are new, two others are defective in the VAN1 gene. Mutants in VAN1 were previously identified by their resistance to the drug orthovanadate. The others represent known endocytosis (rvs167 and sac6) and vacuolar protein sorting (vps41) mutants. As suggested by their genetic interactions with delta ypt51, the newly identified mutants are impaired in endocytosis, vacuolar protein sorting and vacuole biogenesis. In addition, van1 and ysl2 display actin cytoskeletal defects.
Actins↗
Moving towards individualized medicine with pharmacogenomics.
Individuals respond differently to drugs and sometimes the effects are unpredictable. Differences in DNA that alter the expression or function of proteins that are targeted by drugs can contribute significantly to variation in the responses of individuals. Many of the genes examined in early studies were linked to highly penetrant, single-gene traits, but future advances hinge on the more difficult challenge of elucidating multi-gene determinants of drug response. This intersection of genomics and medicine has the potential to yield a new set of molecular diagnostic tools that can be used to individualize and optimize drug therapy.
Drug Design↗
Soft tissue sarcoma as a model disease to examine cancer immunotherapy.
Immunotherapy is in its infancy for many diseases, whether they are neoplastic or autoimmune. The major issues for cancer immunotherapy today involve the definition of molecular targets and the generation of effector mechanisms to attack the targets of interest. Soft tissue sarcomas provide a unique opportunity to examine the immune response against defined antigens. Many types of sarcomas contain tumor-specific chromosomal translocations encoding fusion proteins, which are attractive targets for immunotherapy. Our understanding of the immune system is also coming into clearer focus with the discovery of dendritic cells as powerful natural adjuvants and the teasing out of mechanisms leading to immunity versus tolerance as examples. It is hoped that the intersection of cellular immunology and sarcoma molecular biology will lead to new modalities of therapy for this group of patients with this heterogeneous group of diseases.
Antigens, Neoplasm↗
The chapel and the operating room: the struggle of Roman Catholic clergy, physicians, and believers with the dilemmas of obstetric surgery, 1800-1900.
By 1800, the Roman Catholic Church and organized medicine faced the dilemma of how to resolve cases of obstructed births. American physicians usually practiced destructive operations, like craniotomy, in an attempt to save the lives of mothers. The church allowed such operations after the death of the infant. A new technique of surgery, the cesarean operation, offered hope that both patients would survive childbirth. Medical progress, and an emerging Catholic belief that the fetus was human, prompted Catholic physicians to advocate the new operation, and stirred a renewed debate among European theologians on the propriety of craniotomy. In America, the broad Christian tradition promoted by the Catholic Church began to inform medicine on the moral and ethical parameters of surgery. American physicians, for their part, engaged in their own debate on the propriety of the cesarean operation. This article, focusing on the cesarean debate, reveals the intersections of Catholicism and medical progress amid the growth of obstetric surgery from 1800 to 1900.
Abortion, Therapeutic↗
Nonlinearity and thresholds in dose-response relationships for carcinogenicity due to sampling variation, logarithmic dose scaling, or small differences in individual susceptibility.
Nonlinear and threshold-like shapes of dose-response curves are often observed in tests for carcinogenicity. Here, we present three examples where an apparent threshold is spurious and can be misleading for low dose extrapolation and human cancer risk assessment. Case #1: For experiments that are not replicated, such as rodent bioassays for carcinogenicity, random variation can lead to misinterpretation of the result. This situation was simulated by 20 random binomial samplings of 50 animals per group, assuming a true linear dose response from 5% to 25% tumor incidence at arbitrary dose levels 0, 0.5, 1, 2, and 4. Linearity was suggested only by 8 of the 20 simulations. Four simulations did not reveal the carcinogenicity at all. Three exhibited thresholds, two showed a nonmonotonic behavior with a decrease at low dose, followed by a significant increase at high dose ("hormesis"). Case #2: Logarithmic representation of the dose axis transforms a straight line into a sublinear (up-bent) curve, which can be misinterpreted to indicate a threshold. This is most pronounced if the dose scale includes a wide low dose range. Linear regression of net tumor incidences and intersection with the dose axis results in an apparent threshold, even with an underlying true linear dose-incidence relationship. Case #3: Nonlinear shapes of dose-cancer incidence curves are rarely seen with epidemiological data in humans. The discrepancy to data in rodents may in part be explained by a wider span of individual susceptibilities for tumor induction in humans due to more diverse genetic background and modulation by co-carcinogenic lifestyle factors. Linear extrapolation of a human cancer risk could therefore be appropriate even if animal bioassays show nonlinearity.
Animals↗
Innate and acquired immunity intersect in a global view of the acute-phase response.
Recognition of stereotypic chemical patterns by sentinel cells of the innate immune system provokes a transient deviation from homeostasis, the acute-phase response (APR). Although APR effectors have been identified individually, the complexity of the response suggested that emergent properties would be uncovered by a more comprehensive examination. Our global assessment revealed that approximately 7% of genes in the mouse are mobilized in the hepatic APR to endotoxin. Extensive metabolic adjustments include suppression of pathways for cholesterol, fatty acid, and phospholipid synthesis. Increased expression of genes for innate defense was accompanied by coordinate induction of the MHC class I antigen presentation machinery, illustrating an intersection between innate and adaptive immunity.
Acute-Phase Reaction↗
[Gompertzian analysis of ischemic cardiopathy mortality in Spain, 1951-1992].
INTRODUCTION AND OBJECTIVES: In Spain ischemic heart disease mortality was increasing prior to 1975 and has decreased since 1975. This trend is common to both genders. The goal of this paper is to separate the genetic, environmental and competitive risk factors influencing this evolution. METHODS: The Gompertz function was adjusted cross-sectionally to age-specific mortality due to ischemic heart disease for each year from 1951 to 1992. The Gompertzian longitudinal analysis was applied to the coefficients obtained to estimate the effect due to environmental and competitive factors. RESULTS: Ischemic heart disease in Spain is a Gompertzian disease with an intersection point at 67 years for men and 40 years for women. Environmental factors were increasing before 1975 and have decreased since then. However, the competitive factors decreased in men since 1980 and in women since 1951 on. CONCLUSION: The evolution of risk factors (smoking, hypercholesterolemia and hypertension) is responsible for the major proportion of ischemic disease mortality changes. Treatment of instaured ischemic disease has a low influence.
Adult↗
The Dorsocross T-box genes are key components of the regulatory network controlling early cardiogenesis in Drosophila.
Cardiac induction in Drosophila relies on combinatorial Dpp and Wg signaling activities that are derived from the ectoderm. Although some of the actions of Dpp during this process have been clarified, the exact roles of Wg, particularly with respect to myocardial cell specification, have not been well defined. Our present study identifies the Dorsocross T-box genes as key mediators of combined Dpp and Wg signals during this process. The Dorsocross genes are induced within the segmental areas of the dorsal mesoderm that receive intersecting Dpp and Wg inputs. Dorsocross activity is required for the formation of all myocardial and pericardial cell types, with the exception of the Eve-positive pericardial cells. In an early step, the Dorsocross genes act in parallel with tinman to activate the expression of pannier, a cardiogenic gene encoding a Gata factor. Our loss- and gain-of-function studies, as well as the observed genetic interactions among Dorsocross, tinman and pannier, suggest that co-expression of these three genes in the cardiac mesoderm, which also involves cross-regulation, plays a major role in the specification of cardiac progenitors. After cardioblast specification, the Dorsocross genes are re-expressed in a segmental subset of cardioblasts, which in the heart region develop into inflow valves (ostia). The integration of this new information with previous findings has allowed us to draw a more complete pathway of regulatory events during cardiac induction and differentiation in Drosophila.
Animals↗
Intersection between the regulators of sister chromatid cohesion establishment and maintenance in budding yeast indicates a multi-step mechanism.
Sister chromatid cohesion is established during S phase and maintained until anaphase. The cohesin complex (Mcd1p/Scc1p, Smc1p, Smc3p Irr1p/Scc3p in budding yeast) serves a structural role as it is required at all times when cohesion exists. Pds5p colocalizes temporally and spatially with cohesin on chromosomes but is thought to serve as a regulator of cohesion maintenance during mitosis. In contrast, Ctf7p/Eco1p is required during S phase for establishment but is not required during mitosis. Here we provide genetic and biochemical evidence that the pathways of cohesion establishment and maintenance are intimately linked. Our results show that mutants in ctf7 and pds5 are synthetically lethal. Moreover, over-expression of either CTF7 or PDS5 exhibits reciprocal suppression of the other mutant's temperature sensitivity. The suppression by CTF7 is specific for pds5 mutants as CTF7 over-expression increases the temperature sensitivity of an mcd1 mutant but has no effect on smc1 or smc3 mutants. Three additional findings provide new insights into the process of cohesion establishment. First, over-expression of ctf7 alleles deficient in acetylase activity exhibit significantly reduced suppression of the pds5 mutant but exacerbated toxicity to the mcd1 mutant. Second, using chromosome spreads and chromatin immuno-precipitation, we find either cohesin complex or Pds5p chromosomal localization is altered in ctf7 mutants. Finally, biochemical analysis reveals that Ctf7p and Pds5p coimmunoprecipitate, which physically links these regulators of cohesion establishment and maintenance. We propose a model whereby Ctf7p and Pds5p cooperate to facilitate efficient establishment by mediating changes in cohesin complex on chromosomes after its deposition.
Alleles↗
Role of electron-driven proton-transfer processes in the excited-state deactivation of the adenine-thymine base pair.
Exploratory electronic structure calculations have been performed with the CC2 (simplified singles and doubles coupled-cluster) method for two conformers of the adenine (A)-thymine (T) base pair, with emphasis on excited-state proton-transfer reactions. The Watson-Crick conformer and the most stable (in the gas-phase) conformer of the A-T base pair have been considered. The equilibrium geometries of the ground state and of the lowest excited electronic states have been determined with the MP2 (second-order Møller-Plesset) and CC2 methods, respectively. Vertical and adiabatic excitation energies, oscillator strengths, and dipole moments of the excited states are reported. Of particular relevance for the photochemistry of the A-T base pair are optically dark (1)pipi* states of charge-transfer character. Although rather high in energy at the ground-state equilibrium geometry, these states are substantially lowered in energy by the transfer of a proton, which thus neutralizes the charge separation. A remarkable difference of the energetics of the proton-transfer reaction is predicted for the two tautomers of A-T: in the Watson-Crick conformer, but not in the most stable conformer, a sequence of conical intersections connects the UV-absorbing (1)pipi* state in a barrierless manner with the electronic ground state. These conical intersections allow a very fast deactivation of the potentially reactive excited states in the Watson-Crick conformer. The results provide evidence that the specific hydrogen-bonding pattern of the Watson-Crick conformer endows this structure with a greatly enhanced photostability. This property of the Watson-Crick conformer of A-T may have been essential for the selection of this species as carrier of genetic information in early stages of the biological evolution.
Adenine↗
Comparison of the ability of freeze etch and freeze substitution to preserve actin filament structure.
In order to test the ability of freeze substitution to accurately preserve the ultrastructure of the actin component of the cytoskeleton, the structure of rotary shadowed actin filaments was compared following preparation by glutaraldehyde fixation and freeze etch or freeze substitution. Freeze substituted actin filaments were further processed by either etching away frozen organic solvent or critical-point-drying before rotary shadowing. Comparison of filament diameters showed no significant difference between actin filaments that were directly etched and those that were freeze substituted and then etched. However, freeze substituted and then critical-point-dried filaments were significantly larger in diameter than filaments that were directly etched in water. The long pitch (right-handed) two start helix was not affected by the different methods of preparation. However, the left-handed "genetic" helical repeat that was prominent in actin filaments prepared by freeze etch was more difficult to detect in freeze substituted specimen, especially following critical-point-drying. Although the organization and distribution of actin filaments in extracted cells was similar in both freeze substituted and freeze etched specimens, there were some detectable differences. In cells that were freeze substituted and then critical-point-dried, filaments appeared to intersect at greater angles and seemed more "taut." These results suggest that freeze substitution can preserve the overall morphology of actin filaments, but some chemical or physical modification of macromolecular surface structure may occur during the substitution process and these changes may be further exaggerated by subsequent processing steps.
Actins↗
[Hyperhomocysteinemia: an independent risk factor or a simple marker of vascular disease?. 1. Basic data].
Recent epidemiological studies have suggested that hyperhomocysteinemia is associated with increased risk of vascular disease. Homocysteine is a sulphur-containing amino acid whose metabolism stands at the intersection of two pathways: remethylation to methionine, which requires folate and vitamin B12 (or betaine in an alternative reaction); and transsulfuration to cystathionine which requires vitamin B6. The two pathways are coordinated by S-adenosylmethionine which acts as an allosteric inhibitor of the methylenetetrahydrofolate reductase (MTHFR) and as an activator of cystathionine beta-synthase (CBS). Hyperhomocysteinemia arises from disrupted homocysteine metabolism. Severe hyperhomocysteinemia is due to rare genetic defects resulting in deficiencies in CBS, MTHFR, or in enzymes involved in methyl cobalamine synthesis and homocysteine methylation. Mild hyperhomocysteinemia seen in fasting condition is due to mild impairment in the methylation pathway (i.e. folate or B12 deficiencies or MTHFR thermolability). Post-methionine-load hyperhomocysteinaemia may be due to heterozygous cystathionine-beta-synthase defect or B6 deficiency. Patients with homocystinuria and severe hyperhomocysteinemia develop arterial thrombotic events, venous thromboembolism, and more seldom premature arteriosclerosis. Experimental evidence suggests that an increased concentration of homocysteine may result in vascular changes through several mechanisms. High levels of homocysteine induce sustained injury of arterial endothelial cells, proliferation of arterial smooth muscle cells and enhance expression/activity of key participants in vascular inflammation, atherogenesis, and vulnerability of the established atherosclerotic plaque. These effects are supposed to be mediated through its oxidation and the concomitant production of reactive oxygen species. Other effects of homocysteine include: impaired generation and decreased bioavailability of endothelium-derived relaxing factor/nitric oxide; interference with many transcription factors and signal transduction; oxidation of low-density lipoproteins; lowering of endothelium-dependent vasodilatation. In fact, the effect of elevated homocysteine appears multifactorial affecting both the vascular wall structure and the blood coagulation system.
Animals↗
Identification of Cis-regulatory elements in the mouse Pax9/Nkx2-9 genomic region: implication for evolutionary conserved synteny.
We previously reported close physical linkage between Pax9 and Nkx2-9 in the human, mouse, and pufferfish (Fugu rubripes) genomes. In this study, we analyzed cis-regulatory elements of the two genes by comparative sequencing in the three species and by transgenesis in the mouse. We identified two regions including conserved noncoding sequences that possessed specific enhancer activities for expression of Pax9 in the medial nasal process and of Nkx2-9 in the ventral neural tube. Remarkably, the latter contained the consensus Gli-binding motif. Interestingly, the identified Pax9 cis-regulatory sequences were located in an intron of the neighboring gene Slc25a21. Close examination of an extended genomic interval around Pax9 revealed the presence of strong synteny conservation in the human, mouse, and Fugu genomes. We propose such an intersecting organization of cis-regulatory sequences in multigenic regions as a possible mechanism that maintains evolutionary conserved synteny.
Animals↗
Integrated single-cell transcriptomics, Mendelian randomization, and machine learning identify CEBPZ as an immune-related biomarker in oral lichen planus.
BACKGROUND: Oral lichen planus (OLP) is a chronic, immune-mediated oral mucosal disease with complex pathophysiology and potential for malignant transformation. Understanding its molecular basis is critical for the development of precise diagnostic and therapeutic strategies. OBJECTIVES: We aimed to identify key immune-related biomarkers and characterize cellular dynamics in OLP, with a particular focus on the role of CEBPZ in disease pathogenesis. MATERIAL AND METHODS: We analyzed single-cell RNA sequencing (scRNA-seq) data from OLP lamina propria samples (GSE211630) to identify disease-specific T-cell subpopulations using high-dimensional weighted gene co-expression network analysis (hdWGCNA) for oxidative stress-related gene modules.-data-based Mendelian randomization (SMR) integrated FinnGen genome-wide association study (GWAS; 342,499 Europeans) data with Genotype-Tissue Expression (GTEx) expression quantitative trait loci (eQTL) data to identify causal genes. Machine learning (ML) models (least absolute shrinkage and selection operator (LASSO) and convolutional neural network (CNN)) were developed using bulk RNA-seq datasets (GSE52130 and GSE38616) for diagnostic purposes. RESULTS: We identified OLP-specific T-cell populations (clusters 0, 3, 5, 7, 13, and 15) with enhanced migration inhibition factor (MIF) pathway signaling toward B cells and monocytes. Two oxidative stress-associated modules contained hub genes, including CEBPZ. Summary-data-based Mendelian randomization analysis identified 231 OLP-associated genes, with CEBPZ uniquely intersecting LASSO-selected markers (odds ratio (OR) = 1.057, 95% confidence interval (95% CI) = 1.013-1.102, p = 0.010). Machine learning models achieved area under the curve (AUC) values ranging from 0.653 to 0.745, with the CNN model reaching a validation accuracy of 0.735. CEBPZ showed elevated expression in OLP T cells and correlated with enhanced MIF-(CD74+CXCR4) signaling. CONCLUSIONS: This integrative approach identifies CEBPZ as a pivotal biomarker linking genetic susceptibility, oxidative stress, and immune dysregulation in OLP. Our diagnostic models offer promising tools for OLP management.
CEBPZ↗