[Design of "inverse substrates": a new approach for the chemical studies of hydrolytic enzymes (author's transl)].
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Animals↗
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Results for “Inverse design”
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Predicting food taste with bound-driven optimization.
The prediction of sensory attributes from ingredient-level formulations is an emerging challenge at the intersection of food science and artificial intelligence. We address the fundamental question of whether the taste of a food can be predicted from its ingredients by treating recipes as composite materials. We apply Hashin-Shtrikman (HS) and Reuss-Voigt (RV) bounds, techniques originally developed for elastic moduli, as a null-hypothesis additive baseline for five taste dimensions (sweetness, sourness, bitterness, umami, saltiness) on a curated dataset of 70 recipes decomposed into 115 distinct ingredients scored against a library of 209 ingredient-level taste references with trained-panel ground truth. This baseline systematically under-predicts perceived taste: 77% of actual taste values exceeded the HS upper bound, with the exceedance rate ranging from 26% (bitterness) to 97% (saltiness). We traced this gap to specific processing chemistry (Maillard reactions, caramelization, evaporative concentration, protein hydrolysis, and nucleotide synergy) and introduced a hybrid model that augments the HS baseline with eight chemistry-proxy features encoding these mechanisms. Our results show that our interpretable hybrid model eliminates the systematic bias and reduces mean absolute error by 27%-62% for sweetness, sourness, umami, and saltiness while using only 10 interpretable features, achieving performance comparable to a black-box Lasso regression on 115 per-ingredient features. We further demonstrate constrained inverse design via Differential Evolution, recovering ingredient formulations that match target taste profiles subject to compositional bounds. Our work demonstrates how key chemical processes during food preparation can inform and augment physics-based and machine learning models, providing a quantitative fingerprint of processing chemistry's contribution to taste perception and paving the way for model-driven food formulation with targeted sensory characteristics.
Composite material bounds↗
Intracellular H+ buffering power and its dependency on intracellular pH.
Intracellular hydrogen ion (H+) buffering power, conventionally defined as the amount of acid or base that would have to be introduced into the cell cytosol to decrease or increase ipH by one pH unit, is generally said to increase as intracellular pH (ipH) decreases. This implies that the cell has a lesser capability to resist acute acid or base perturbations at its steady state ipH than at any lower ipH. We re-examined this notion, reasoning that the logarithmic nature of the pH unit could limit the validity of the conventional expression of buffering power in imparting physiologic insight into the mechanisms of cellular H+ homeostasis. The mathematical derivation of the formula, delta i[NH4+]/delta ipH, conventionally used to estimate buffering power using the NH4Cl technique, revealed that this parameter is, by design, inversely proportional to the exponential of ipH. This a priori dependence on pH dictates an increase in buffering power with decreasing ipH, and thereby interferes with the assessment of the physiologic capability of the intracellular milieu to buffer protons at different ipH levels. To circumvent this problem, buffering power was defined as the amount of hydrogen ions that would have to be added to or removed from the cell to effect a change in the concentration of H+ in the cell cytosol of 1 mM (a term heretofore referred to as the cell H+ buffering coefficient). The mathematical derivation of the formula used to calculate the cell H+ buffering coefficient, delta i[NH4+]/delta[H+]i, does not suffer from an a priori dependence on ipH.(ABSTRACT TRUNCATED AT 250 WORDS)
Acid-Base Equilibrium↗
Design and implementation of magnetization transfer pulse sequences for clinical use.
The transfer of magnetization between a free and a bound pool of spins is described in terms of the respective longitudinal relaxation times and the life times of spins in each pool. The effect of an off resonance radiofrequency (RF) pulse in producing saturation in the bound pool and a consequent decrease in both the available longitudinal magnetization and the T1 of spins in the free pool is described. The effects of increasing duration of the saturating RF pulse on image pixel signal intensity were used to determine values for the decrease in both T1 and the available magnetization in gray and white matter of the brain as well as in muscle, fat, and CSF. At 0.15 T the available magnetization of muscle was reduced by approximately 60% and its T1 was decreased from 350 to 150 ms. The available magnetization of white and gray matter was reduced by 40% and their values of T1 were reduced by 80-110 ms. The reduction in available magnetization was used to increase contrast on proton density weighted or T2-weighted SE pulse sequences. These changes were also used to design inversion recovery (IR) pulse sequences with particular contrast properties. A short inversion time (TI) magnetization transfer (MT) IR (MT-STIR) pulse sequence was used to reduce the signal from normal muscle to zero to produce an angiographic effect in the leg. Increased tissue contrast was observed with a T2-weighted (MT-SE) sequence in a patient with bilateral cerebral infarction and with an MT-IR pulse sequence in a patient who had an intracranial hematoma. Three patients with cerebral tumors showed high lesion contrast with MT-STIR sequences. Components within two tumors were changed to different degrees by MT and in one case change in the brain attributable to recent radiotherapy treatment was only identified with an MT-STIR sequence. Magnetization transfer can be used to manipulate both the available longitudinal magnetization and the T1 of normal and abnormal tissues. The changes in tissue contrast produced by this can be very substantial and are likely to be of importance in clinical imaging.
Adult↗
Geometric mechanogenomics: engineering boundary conditions for deterministic cell fate control.
In tissue development and regeneration, cellular behavior has traditionally been interpreted through biochemical signaling frameworks. However, cells exist within physically defined environments, where geometric boundary conditions - including confinement, curvature, anisotropy, and multicellular architecture - define the mechanical state space in which mechanical forces are generated, transmitted, and interpreted. Here, we introduce geometric mechanogenomics, a conceptual framework that positions geometry as an upstream spatial regulator linking tissue-scale boundary conditions to nuclear mechanics, chromatin organization, and genome regulation. We propose a boundary-to-nucleus axis through which geometric information is decoded by adhesion-mediated mechanotransduction, cytoskeletal force transmission, and nuclear mechanoregulation to regulate chromatin accessibility, epigenetic remodeling, and transcriptional programs. Rather than introducing new mechanotransduction pathways, this framework emphasizes that geometry spatially organizes conserved mechanotransductive machinery to generate context-dependent mechanogenomic outcomes. We further discuss how engineered geometries reduce morphogenetic stochasticity, coordinate multicellular organization, and establish mechanical memory that influences long-term cell fate. Finally, we highlight current challenges in establishing predictive geometry-to-genome relationships and discuss emerging opportunities enabled by spatial omics, artificial intelligence-assisted inverse design, and dynamic biomaterials for programmable mechanobiology, regenerative medicine, developmental biology, and disease modeling.
genome organization↗
Inverse protein folding problem: designing polymer sequences.
We consider the question of how to design proteins. How can we find "good" amino acid sequences (i) that fold to a desired "target" structure as a native conformation of lowest accessible free energy and (ii) that will not simultaneously fold to many other conformations of the same free energy? Current protein designs often focus on helix propensities and turns. We focus here on designing the hydrophobicity. For a model of self-avoiding hydrophobic/polar chains on two-dimensional square lattices, geometric proofs and exhaustive enumerations show the following results. (i) The strategy hydrophobic residues inside/polar residues outside is not optimal. Placement of additional hydrophobic residues on the surface is often necessary. (ii) To avoid unwanted conformations, the designed sequence must have neither too many nor too few hydrophobic residues. (iii) The computational complexity of inverse folding appears to be in a different class than folding: unlike the folding problem, the design problem does not scale exponentially with chain length. Some design strategies, described here for the lattice model, produce good sequences and scale only linearly with chain length.
Drug Design↗
[Lefort 1 osteotomy. The proposal of an outline modification].
A modified outline of Lefort 1 osteotomy using an "inverse step" design is proposed which ensures simple and effective down-fracture and pterygo-maxillary separation. Osteosynthesis of the mobilized fragment is facilitated due to the improved contact of bone surfaces, particularly laterally. Combined rigid and supple osteosyntheses allow some degree of post-operative adjustment.
Bone Transplantation↗
High signal regions in normal white matter shown by heavily T2-weighted CSF nulled IR sequences.
Inversion recovery (IR) sequences with an inversion time (TI) designed to markedly reduce or null the signal from CSF (TI of approximately 2,100 ms at 1.0 T) and a very long echo time (TE) of 240 ms were used to image the brain of two normal adult volunteers, one 34-year-old man with an intrinsic tumor, and one 3-month-old infant with an infarct. Using these very heavily T2-weighted pulse sequences, adult gray and white matter showed similar signal intensity in many areas of the brain, but normal white matter in regions of the centrum semiovale, posterior internal capsule, parietopontile tract, occipitothalamic radiation, and brain stem showed a much higher signal intensity than surrounding gray or white matter. The infant displayed a low signal intensity in myelinated regions in the internal capsule and occipitothalamic radiation and a high signal in unmyelinated white matter. In many of the images there were strong similarities to the distribution of high signal within white matter seen with pulsed gradient spin echo sequences (TE 130 ms) designed to demonstrate effects due to anisotropic diffusion. Arguments are advanced to support the view that the high signal intensity in white matter tracts is due to one or more long T2 components that may be associated with unmyelinated or sparsely myelinated fibres within white matter. The resemblance to diffusion weighted images may reflect the fact that both employ long TEs and both produce a low signal from CSF. If myelin possessed a different susceptibility from axoplasm so that magnetic field gradients were generated around nerve fibres when their orientation was not parallel to B0, diffusion of water might then produce the observed dependence on fibre direction. The high signal regions in white matter are a potential source of confusion in image interpretation, and measurements of T2 in white matter need to be made with these regional variations in mind. The concept of normal appearing white matter also needs to be applied with a knowledge of these differences. The IR sequences used in this study provide a very high T2 dependence with a low signal from CSF and may be useful for detecting disease in the CNS of adults and children.
Adult↗
Electrocardiographic changes resembling myocardial ischaemia in asymptomatic men with normal coronary arteriograms.
T wave and ST segment abnormalities in 20 asymptomatic men aged 18 to 55 were investigated because they were identical with myocardial ischaemic changes, and the professional livelihood of the subjects was jeopardised. Coronary arteriograms showed unobstructed arteries in all except one in whom a 50 per cent lesion of the left anterior descending artery was present. Left ventricular angiograms showed a normal contraction pattern, Ejection fractions were normal in 12 and increased in 8. Three characteristic electrocardiographic patterns were observed: flat or inverted T waves in leads II, III, aVF, and V4 to 6 designated type 1; deep T inversion particularly evident in leads V2 to 5 designated type 2, and minor ST segment depression in the inferior and lateral leads without T changes designated type 3. Characteristically, type 1 changes were temporarily suppressed by either beta-blockade or an overnight rest and were more abnormal in the standing position. Type 2 and 3 changes were relatively uninfluenced by these manoeuvres. Maximal treadmill exercise tests were positive in 6 and borderline or negative in 14. When repeated after oxprenolol all tests were negative. Echocardiograms showed asymmetric septal hypertrophy in 3 subjects (ratio of greater than 1.5 between ventricular septum and posterior left ventricular wall). After normalisation by an overnight rest, type 1 T wave abnormalities were reproduced by intravenous adrenaline infusion (0.024 to 0.18 microgram/kg/min) but not by noradrenaline or by adrenaline after prior administration of oxprenolol. When the T waves had remained deeply inverted before infusion despite rest (type 2) adrenaline infusion normalised them and again noradrenaline was without effect. This effect was also prevented by oxprenolol. Type 3 changes were uninfluenced by catecholamine infusion. Plasma catecholamine estimations suggest that catecholamine hypersecretion and hypersensitivity may both be relevant, particularly the latter. The apparent bimodal response of the ventricular myocardium to adrenaline infusion is not surprising since in vitro experiments suggest that reversal of T wave polarity in either direction may result from summation of changes in action potential duration in different parts of the heart. Such changes may be unimodal, that is both areas involved show lengthening or shortening of action potential duration, but by occurring at different rates may lead to a bimodal change in the differences in duration which generate the T wave.
Adolescent↗
Sequence-structure matching in globular proteins: application to supersecondary and tertiary structure determination.
A methodology designed to address the inverse globular protein-folding problem (the identification of which sequences are compatible with a given three-dimensional structure) is described. By using a library of protein finger-prints, defined by the side chain interaction pattern, it is possible to match each structure to its own sequence in an exhaustive data base search. It is shown that this is a permissive requirement for the validation of the methodology. To pass the more rigorous test of identifying proteins that are not close sequence homologs, but that have similar structure, the method has been extended to include insertions and deletions in the sequence, which is compared to the fingerprint. This allows for the identification of sequences having little or no sequence homology to the fingerprint. Examples include plastocyanin/azurin/pseudoazurin, the globin family, different families of proteases and cytochromes, including cytochromes c' and b-562, actinidin/papain, and lysozyme/alpha-lactalbumin. Turning to supersecondary structure prediction, we find that alpha/beta/alpha fragments possess sufficient specificity to identify their own and related sequences. By threading a beta-hairpin through a sequence, it is possible to predict the location of such hairpins and turns with remarkable fidelity. Thus, the method greatly extends existing techniques for the prediction of both global structural homology and local supersecondary structure.
Amino Acid Sequence↗
Alzheimer disease: measuring loss of cerebral gray matter with MR imaging.
The distributions of the cerebral gray matter, the white matter, and the intracranial cerebrospinal fluid (CSF) were measured in 14 patients with Alzheimer disease (AD) and in 14 healthy control subjects. The measurements, derived from two specifically designed magnetic resonance inversion-recovery sequences, compensate for partial signal averaging. The percentage of the gray matter in the brains of AD patients (44.9% +/- 4.4) was significantly lower than in control subjects (50.2% +/- 3.2). The most significant reduction (P less than .001) occurred in the temporal lobes (13.8%) and a central region (12.8); the reduction in frontal lobe (11.2%) and occipital lobe (9.2%) was also statistically significant (P less than .01). There was an increase in the CSF volume in the temporal, occipital, and frontal regions; no region showed a significant difference in the white matter content. The findings of diffuse changes and temporal lobe involvement in AD are consistent with pathologic observations of cortical cell loss.
Aged↗
Calcium and blood pressure. An epidemiologic perspective.
We reviewed the research literature on the epidemiologic relationship between blood pressure levels and calcium, with an emphasis on dietary intake. A conceptual framework for causal inference is summarized; then the designs and results of observational and intervention studies are presented. Of 25 reports of observational studies relating intake of calcium or calcium-rich foods to blood pressure, the majority found some evidence of an inverse association. However, many analyses did not support this relationship, and only two studies have confirmed the inverse association with a prospective design. Nineteen randomized controlled clinical trials of calcium supplementation have been reported, excluding those exclusively in pregnant women. Eleven of these showed no significant effects on blood pressure; in two trials, both systolic and diastolic pressure were significantly reduced; and in the remainder results were equivocal. Pooled analyses yielded estimates of a small (1.8 mm Hg), significant reduction in systolic blood pressure, but no effect on diastolic pressure. Epidemiologic relationships with serum and urinary calcium, and the possible mechanisms of these effects, are also discussed. We conclude that the evidence from studies in humans is suggestive, but not conclusive, regarding a role for calcium in hypertension. Recommendations for further epidemiologic studies are presented.
Blood Pressure↗
Relation of physical activity and cardiovascular fitness to coronary heart disease, Part I: A meta-analysis of the independent relation of physical activity and coronary heart disease.
BACKGROUND: This paper is the first of two reports that together review the scientific evidence regarding the inverse relation between physical activity and cardiovascular fitness and coronary heart disease (CHD). METHODS: In Part I, the evidence suggesting a causal link between physical activity and CHD protection independent of other CHD risk factors is reviewed, accounting for bias, confounding, and different study designs. RESULTS: A strong, consistent inverse relation is found. Using meta-analytic techniques, the relative risk of the independent relation of physical inactivity to CHD is 1.37, with a 95 percent confidence interval (1.27-1.48). CONCLUSIONS: A graded biologic response of CHD protection to physical activity is shown, but the intensity, duration, and frequency of activity necessary for CHD benefit remain unclear. Plausible biologic mechanisms for the inverse relation of physical activity to CHD are the risk factor modifications that accrue with physical activity.
Causality↗
Stimulus intensity and experimental design effects on motor response processing.
Experimental design effects and range effects may have influenced previous studies on motor response processing (Grice & Hunter, 1964; Grice, Nullmeyer, & Schnizlein, 1979; Poulton, 1973). This investigation was conducted concurrently with two experiments. First, Erlebacher's (1977) more powerful analysis of variance (ANOVA) model, which allows for the testing of the independent variable (stimulus intensity effect), the experimental design effect (between-subjects [BS] vs. within-subjects [WS]), and the important interaction between independent variable and experimental design was utilized to clarify if the nature of the experimental design (BS, WS) biases motor response processing. Second, Erlebacher's (1977) ANOVA model was used to determine if motor response processing was affected by stimulus intensity and experimental design when different ranges of auditory stimuli were compared. Results indicate motor response processing was inversely affected by increasing stimulus intensity. Experimental design effects and range effects did not appear to bias motor response processing. We conclude stimulus intensity effects on motor response processing appear to be the result of true neuromotor functioning and not artifacts of experimental design or of range effects.
Acoustic Stimulation↗
The effects of symmetrical recombination site hixC on Hin recombinase function.
An artificial recombination site hixC composed of two identical half-sites that bind the Hin recombinase served as a better operator in vivo than the wild type site hixL (Hughes, K. T., Youderian, P., and Simon, M. I (1988) Genes & Dev. 2, 937-948). In vitro binding assays such as gel retardation assay and methylation protection assay demonstrated that Hin binds to hixC as tightly as it binds to hixL, even when the sites are located in negatively supercoiled plasmids. However, hixC served as a poor recombination site when it was subjected to the standard inversion assay in vitro. hixC showed a 16-fold slower inversion rate than the wild type. A series of biochemical assays designed to probe different stages of the Hin-mediated inversion reaction, demonstrated that Hin dimers bound to hixC have difficulty in forming paired hix site intermediates. KMnO4 and S1 nuclease assays detected an anomalous structure of the center of hixC only when the site was in negatively supercoiled plasmids. Mutational analysis in the central region of hixC and assays of paired hix site formation with topoisomers of the hixC substrate plasmid suggested that Hin is not able to pair hixC sites because of the presence of the anomalous structure in the center of the site. The structure does not behave like a DNA "cruciform" since Hin dimers still bind efficiently to the site. It is thought to consist of a short denatured "bubble" encompassing 2 base pairs. During the study of mutations in the center of hixC, it was found that Hin is not able to cleave DNA if a guanine residue is one of the two central nucleotides close to the cleavage site. Furthermore, Hin acts in a concerted fashion and cannot cleave any DNA strand if one of the four strands in the inversion intermediate is not cleavable.
Base Sequence↗
[Appearance on effort of an image of a sub-epicardial lesion in the absence of signs of myocardial necrosis. Clinical, electrocardiographic and coronographic studies of 10 cases].
A clinical, electrocardiographic and coronarographic study of ten cases shows that surelevation of ST-segment during exercise (without any signs of infarction) correspond to very different clinical situations of anatomical state of coronary vessels, occurrence of coronary spasm and evolution of the ischemic disease. "Inversed coronary Insufficiency" is proposed to design this syndrome. Practical recommandations are formulated.
Adult↗
Elucidation of a pericentric inversion of a D-group chromosome in the mother of a child with Patau's syndrome.
The mother of a child with Patau's syndrome has an inversion of chromosome 13. The karyotype is designated 46, XX, inv (13) (p13q21). It is deduced that the deceased child had the karyotpye 46, XY, rec(13), dup q, inv(13) (p13q21).
Abnormalities, Multiple↗
Production of nitric oxide by murine bone marrow cells. Inverse correlation with cellular proliferation.
The present studies were designed to assess the ability of primary cultures of bone marrow cells to produce nitric oxide. We found that two inflammatory stimuli, IFN-gamma and LPS, were potent inducers of nitric oxide production by bone marrow cells. In addition, the CSF granulocyte-macrophage (GM)-CSF and IL-3 as well as TNF-alpha, while inactive by themselves, were synergistic with LPS and IFN-gamma in inducing nitric oxide production. Maximal effects were observed with combinations of GM-CSF and LPS. Nitric oxide production by bone marrow cells was found to be dependent on the presence of L-arginine in the culture medium and inhibitable by NG-monomethyl-L-arginine and L-canavanine, two nitric oxide synthase inhibitors. Nitric oxide produced by the cells was also suppressed by TGF-beta 1 and the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate. Separation of bone marrow cells by density gradient centrifugation and flow cytometry revealed that the granulocyte-containing fraction was largely responsible for nitric oxide production. In additional experiments we found that treatment of bone marrow cells with GM-CSF significantly stimulated bone marrow cell growth. In contrast, the combination of GM-CSF and LPS or IFN-gamma markedly suppressed cellular proliferation. This suppression was completely reversed by treatment of the cells with NG-monomethyl-L-arginine. Taken together, these data demonstrate that various inflammatory stimuli and cytokines induce nitric oxide production by primary cultures of bone marrow cells and that this mediator may play a role in the regulation of bone marrow cell growth and development.
Animals↗