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PubMed2001

Divided attention between lyrics and tunes of operatic songs: evidence for independent processing.

Excerpts from French operatic songs were used to evaluate the extent to which language and music compete for processing resources. Do these two dimensions conflict? Are they integrated into a single percept? Or are they independent? The final word of each excerpt was either semantically congruous or incongruous relative to the prior linguistic context and was sung either in or out of key. Participants were asked to detect either the semantic or the melodic incongruity (single task) or both (dual task). We predicted a dual-task deficit if these tasks conflicted and no deficit if they were either independent or integrated. In order to distinguish between these last two outcomes, trial-by-trial contingency analyses were also computed, predicting no correlation if the tasks were conflicting or independent, a positive correlation under the assumption of integration and a negative correlation if dividing attention is impossible. Our results show similar levels of performance in single and dual tasks and no correlation between dual-task judgments, thus suggesting that semantic and melodic aspects of language are processed by independent systems. In addition, a comparison between musicians and nonmusicians shows that these conclusions are independent of musical expertise.

Adolescent↗
PubMed2005

Prediction of subcellular localization using sequence-biased recurrent networks.

MOTIVATION: Targeting peptides direct nascent proteins to their specific subcellular compartment. Knowledge of targeting signals enables informed drug design and reliable annotation of gene products. However, due to the low similarity of such sequences and the dynamical nature of the sorting process, the computational prediction of subcellular localization of proteins is challenging. RESULTS: We contrast the use of feed forward models as employed by the popular TargetP/SignalP predictors with a sequence-biased recurrent network model. The models are evaluated in terms of performance at the residue level and at the sequence level, and demonstrate that recurrent networks improve the overall prediction performance. Compared to the original results reported for TargetP, an ensemble of the tested models increases the accuracy by 6 and 5% on non-plant and plant data, respectively. AVAILABILITY: The Protein Prowler incorporating the recurrent network predictor described in this paper is available online at http://pprowler.imb.uq.edu.au/

Algorithms↗
PubMed1999

Modelling of factor Xa-inhibitor complexes: a computational flexible docking approach.

In order to understand the structural basis of Factor Xa (FXa) specificity, structural complexes of FXa with its synthetic inhibitors are determined using a computational docking approach. The AutoDock suite of programs is used to determine the binding modes of the synthetic inhibitors such as 3- and 4-amidinobenzylphenyl ether (ABP), amidinophenyl pyruvic acid (APPA), diamidinobenzofuranyl ethene (DABE), and DX-9065a 2-(5'-amidino-2'-benzofuranyl)-3-(7'amidino-2'-napthyl)-propionic acid (ABAP) to FXa. The synthetic inhibitors docked in the present study are different in size, nature of linkage, and properties. Two sets of simulations were carried out for synthetic inhibitors docking to FXa. In the first set of simulations, no explicit water molecules were included. In the second set of simulations two explicit solvent molecules were considered. In all the computationally predicted synthetic inhibitor complexes of FXa, the specificity pocket residue Asp-189 is involved in hydrogen bonding with the bound inhibitor. The active site water molecule WAT522 is involved in hydrogen bonding with all the bound inhibitors. The computed energies clearly discriminate the high affinity from low affinity binders.

Amidines↗
PubMed2002

Identification of the N-terminal functional domains of Cdk5 by molecular truncation and computer modeling.

Cyclin dependent kinase (Cdk) 5, an atypical member of the Cdk family, plays a fundamental role in the development of the nervous system, and may also be involved in the pathogenesis of certain neurodegenerative diseases. Further, Cdk5 is activated by the specific regulatory proteins p39, p35, or p25 rather than cyclins, and in contrast to other members of the Cdk family is not involved in the progression of the cell cycle. A three-dimensional computer model of Cdk5-p25-ATP has been generated previously [Chou et al., Biochem Biophys Res Commun 1999;259:420-428], providing a structural basis for the study of the mechanisms of Cdk5 activation. To assess the predicted ATP and p25 binding domains at the N-terminal of Cdk5, two mutants of Cdk5 were prepared in which amino acids 9-15 (Delta9-15) or 9-47 (Delta9-47) were deleted. The results of these studies clearly demonstrate that an N-terminal loop and the PSSALRE helix are indispensable for Cdk5-p25 interactions, and amino acids 9-15 are necessary for ATP binding but are not involved in Cdk5-p25 interactions. Predicted models of Delta9-15 Cdk5 and Delta9-47 Cdk5 were generated, and were used to interpret the experimental data. The experimental and molecular modeling results confirm and extend specific aspects of the original predicted computer model, and may provide useful information for the design of highly selective inhibitors of Cdk5, which could be used in the treatment of certain neurodegenerative conditions.

Adenosine Triphosphate↗
PubMed2026

Integration of biological avatars and digital twins for "ex vivo clinical trials".

Drug development is slow, costly, and prone to late-stage failure, in part because animal models poorly predict human responses. Two human-relevant technologies are maturing in parallel: biological avatars, defined as patient- or stem-cell-derived models such as organoids and organ-on-a-chip systems, and digital twins, defined as computational models that integrate a patient's molecular and clinical data to forecast treatment responses. We propose the ex vivo clinical trial concept, in which an avatar and a digital twin are coupled in an iterative loop so that laboratory measurements refine the computational prediction and the prediction guides the next experiment, allowing candidate therapies to be tested and prioritised before a patient is exposed. We review the platforms, their predictive performance in cancer, cystic fibrosis, and liver toxicity, the conditions under which they fail, and the qualification, turnaround, and standardisation requirements that must be met before such trials can inform drug development or clinical care.

Biological avatars↗
PubMed2026

From pan-life phase insights to PhaseHub: Analyzing protein condensate complexity.

Intracellular biomolecular condensation forms multicomponent signaling hubs that regulate development, stress responses, and environmental adaptation. While the molecular grammar encoded within scaffold proteins defines the basal associative features driving condensation, heterotypic condensates are intrinsically dynamic, multicomponent, and far-from-equilibrium systems. Consequently, how condensates organize component composition, stoichiometry, and functional specificity in space and time under physiological conditions remains poorly understood. Addressing this challenge requires integrative frameworks that combine predictive biophysical features with experimental information on protein abundance, interaction networks, subcellular localization, and evolutionary conservation. In this study, we first analyzed phase separation (PS) proteins across the tree of life in 1106 species, revealing a stark contrast in computationally predicted PS propensity between eukaryotes and prokaryotes, with genome size as a key determinant. Through a broad analysis of amino acid homorepeat-containing proteins (HRPs) across all species, we uncovered how PS evolves via a balance between functional condensation and avoidance of harmful, aggregation-prone sequences. We further identified potential signaling hubs and components across kingdoms by integrating PS-positive proteins with experimentally derived abundance and interactome data from four model eukaryotic species. Using Arabidopsis as a model, we dissected the relationships among PS propensity, condensation hub prediction, HRPs, subcellular localization, and structural conservation. Finally, we developed PhaseHub, a user-friendly interface for exploring scaffold-client dynamics, PS components, sequence signatures within each PS protein, and hubs. Collectively, our work provides an evolutionary framework for understanding multicomponent PS hubs by integrating molecular grammar with physiological context, thereby facilitating hypothesis generation and rational design.

Phase Separation↗
PubMed2006

How the stabilization of INK4 tumor suppressor 3D structure evaluated by quantum chemical and molecular mechanics calculations corresponds well with experimental results: interplay of association enthalpy, entropy, and solvation effects.

The folding free energy of the INK4c tumor suppressor core, consisting of 10 helices, was determined as the sum of gas-phase interaction enthalpy, gas-phase interaction entropy, and dehydration and hydration free energy. The interaction energy and the hydration free energy were determined using the nonempirical density functional theory (DFT) method, augmented by a dispersion-energy correction term, the semiempirical density-functional tight-binding method covering the dispersion energy, and the density functional theory/conductor-like screening model (DFT/COSMO) procedure, whereas the interaction entropy was calculated with the empirical Cornell et al. force field. Alternatively, all contributions were evaluated consistently using empirical methods. All the values of the interaction energy of helix pairs are stabilizing, and the dominant stabilizing terms stem from the London dispersion energy and, in the case of charged systems, the electrostatic energy. The stabilization energy of the core, determined as the difference of the energy of the core and 10 separate helices, amounts to approximately 450 kcal/mol. Systematically, the difference in the hydration free energy of a helix pair and its separate components is smaller in magnitude than the interaction energy, and it is negative for some pairs while positive for others. The average total free energy of a core formation amounts to -29.6 kcal/mol (yielded by scaled quantum-chemical methods) and +13.9 kcal/mol (resulting from empirical methods). These values are considerably smaller than their single components, which are dominated by the interaction energy. The computationally predicted interval encloses the experimental value of the folding free energy (-2.8 kcal/mol).

Amino Acid Motifs↗
PubMed1993

Quantitative analysis of bone reactions to relative motions at implant-bone interfaces.

Connective soft tissues at the interface between implants and bone, such as in human joint replacements, can endanger the stability of the implant fixation. The potential of an implant to generate interface bone resorption and form soft tissue depends on many variables, including mechanical ones. These mechanical factors can be expressed in terms of relative motions between bone and implant at the interface or deformation of the interfacial material. The purpose of this investigation was to determine if interface debonding and subsequent relative interface motions can be responsible for interface degradation and soft tissue interposition as seen in experiments and clinical results. A finite element computer program was augmented with a mathematical description of interface debonding, dependent on interface stress criteria, and soft tissue interface interposition, dependent on relative interface motions. Three simplified models of orthopaedic implants were constructed: a cortical bone screw for fracture fixation plates, a femoral resurfacing prosthesis and a straight stem model, cemented in a bone. The predicted computer configurations were compared with clinical observations. The computer results showed how interface disruption and fibrous tissue interposition interrelate and possibly enhance each other, whereby a progressive development of the soft tissue layer can occur. Around the cortical bone screw, the predicted resorption patterns were relatively large directly under the screw head and showed a pivot point in the opposite cortex. The resurfacing cup model predicted some fibrous tissue formation under the medial and lateral cup rim, whereby the medial layer developed first because of higher initial interface stresses. The straight stem model predicted initial interface failure at the proximal parts. After proximal resorption and fibrous tissue interposition, the medial interface was completely disrupted and developed an interface layer. The distal and mid lateral side maintained within the strength criterion. Although the applied models were relatively simple, the results showed reasonable qualitative agreement with resorption patterns found in clinical studies concerning bone screws and the resurfacing cup. The hypothesis that interface debonding and subsequent relative (micro)motions could be responsible for bone resorption and fibrous tissue propagation is thereby sustained by the results.

Biomechanical Phenomena↗
PubMed2006

Double ionization of quaterrylene (C40H20) in water-ice at 20 K with Ly alpha (121.6 nm) radiation.

Polycyclic aromatic hydrocarbon (PAH) molecules undergo facile ionization in cryogenic water-ices resulting in near quantitative conversions of neutral molecules to the corresponding singly charged radical cations. Here we report, for the first time, the production and stabilization of a doubly ionized, closed shell PAH in water-ice. The large PAH quaterrylene (QTR, C40H20) is readily photoionized and stabilized as QTR 2+ in a water-ice matrix at 20 K. The kinetic analysis of photolysis shows that the QTR 2+ is formed at the expense of QTR +, not directly from QTR. The long-axis polarized S1-S0 (1(1)B(3u) <-- 1(1)Ag) transition for QTR 2+ falls at 1.59 eV (782 nm). TD-DFT calculations at the B3LYP level predict that this transition falls at 1.85 eV (670 nm) for free gas-phase QTR 2+, within the 0.3 eV uncertainty associated with these calculations. This red shift of 0.26 eV is quite similar to the 0.24 eV red shift between the TD-DFT computational prediction for the lowest energy transition for QTR + (1.68 eV) and its value in a water matrix (1.44 eV). These results suggest that multiple photoionization of such large PAHs in water-ice can be an efficient process in general.

Cations↗
PubMed2026

Screening of core targets for Di(2-ethylhexyl) Phthalate-related gastric cancer based on machine learning, molecular docking, and SHAP analysis.

PURPOSE: Given the existing uncertainties regarding the link between Di(2-ethylhexyl) phthalate (DEHP) exposure and gastric cancer (GC) progression, this study aimed to clarify their association, identify the toxic targets of DEHP, and elucidate the underlying molecular mechanisms. METHODS: Multiple integrated approaches were employed, including Gene Expression Omnibus (GEO) data analysis, network toxicology, molecular docking, and machine learning. STRING and Cytoscape tools were utilized to identify key targets, while Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the functional enrichment of intersecting targets. Machine learning and SHAP analysis were applied to screen core targets in GC. Molecular docking was performed to evaluate the binding affinity of DEHP toward core targets, and 200 ns molecular dynamics simulations were further conducted for representative complexes to validate their dynamic stability. RESULTS: A total of 18 key targets were identified using STRING and Cytoscape. GO and KEGG enrichment analyses demonstrated that these intersecting targets were primarily enriched in the extracellular region, as well as the Calcium signaling pathway and cAMP signaling pathway. Through machine learning analyses, 7 key genes (ADRB2, ESRRG, GRIA4, IL13RA2, NR3C2, PLA2G1B, and SULT2A1) were identified as core targets in GC through machine learning analyses. Molecular docking simulations revealed strong binding specificity between DEHP and the target proteins. Among them, NR3C2 and ADRB2 exhibited relatively high predictive importance in the machine learning models. DEHP showed favorable binding affinity toward these core targets, and molecular dynamics simulations further confirmed that ADRB2-DEHP and NR3C2-DEHP complexes maintained stable conformations throughout the simulation. CONCLUSIONS: Our findings identified GC associated genes that were computationally predicted as potential targets of DEHP. These results indicated structural compatibility between DEHP and its target proteins but did not prove that DEHP exposure accounts for the gene expression changes in GC.

Molecular Docking Simulation↗
PubMed1977

Prediction of abnormal growth in class III malocclusions.

Four significant factors have been identified in the lateral cephalometric head film which would indicate the likelihood of the patient growing in an abnormal Class III manner. The normal person grows approximately the same amount from nasion to nasion as he does on the corpus axis of the mandible. The abnormal Class III syndrome grows greater increments on the mandible than at the cranial base. For the purpose of determining the accuracy of computer prediction of abnormal growth, fourteen skeletal Class III cases were selected from the files of the Hokkaido University Orthodontic Department. A significant relationship was shown between abnormal growth and the sum of the standard deviation from the normal of the four cephalometric "predictor measurements." These data would give the clinician insight as to which patients might require early orthopedic treatment (chin cup), conventional orthodontic treatment, or surgical orthodontic correction after growth is complete. This is the first published demonstration of computerized cephalometric methods showing the ability to distinguish between normal and abnormal growth in a particular patient type. It is hoped that, through the comparison of thousands of predictions with actual data, more recognizable abnormal growth patterns will appear in the future.

Adolescent↗
PubMed2005

Synthesis of malarial plasmepsin inhibitors and prediction of binding modes by molecular dynamics simulations.

A series of inhibitors of the malarial aspartic proteases Plm I and II have been synthesized with L-mannitol as precursor. These inhibitors are characterized by either a diacylhydrazine or a five-membered oxadiazole ring replacing backbone amide functionalities. Molecular dynamics simulations were applied in the design process. The computationally predicted Plm II Ki values were generally in excellent agreement with the biological results. The diacylhydrazine was found to be superior over the oxadiazole as an amide bond replacement in the Plm I and II inhibitors studied. An extensive flexibility of the S2' pocket was captured by the simulations predicting the binding mode of the unsymmetrical inhibitors. Plm I and II inhibitors with single digit nanomolar Ki values devoid of inhibitory activity toward human Cat D were identified. One compound, lacking amide bonds, was found to be Plm IV selective and very potent, with a Ki value of 35 nM.

Animals↗
PubMed2000

In Vivo Analysis of Heterogeneous Brain Deformation Computations for Model-Updated Image Guidance.

Neurosurgical image-guidance has historically relied on the registration of the patient and preoperative imaging series with surgical instruments in the operating room (OR) coordinate space. Recent studies measuring intraoperative tissue motion have suggested that deformation-induced misregistration from surgical loading is a serious concern with such systems. In an effort to improve registration fidelity during surgery, we are pursuing an approach which uses a predictive computational model in conjunction with data available in the OR to update the high resolution preoperative image series. In previous work, we have developed an in vivo experimental system in the porcine brain which has been used to investigate a homogeneous finite element rendering of consolidation theory as a tissue deformation model. In this paper, our computational approach has been extended to include heterogeneous tissue property distributions determined from an image-to-grid segmentation scheme. Results produced under two different loading conditions show that heterogeneity in the stiffness properties and interstitial pressure gradients varied over a range of physiologically reasonable values account for 1-3% and 5-8% of the predicted tissue motion, respectively, while homogeneous linear elasticity is responsible for 60-70% of the surgically-induced motion that has been recoverable with our model-based approach.

Journal Article↗
PubMed2000

Conserved features of Y RNAs: a comparison of experimentally derived secondary structures.

In this study, phylogenetically conserved structural features of the Ro RNP associated Y RNAs were investigated. The human, iguana, and frog Y3 and Y4 RNA sequences have been determined previously and the respective RNAs were subjected to enzymatic and chemical probing to obtain structural information. For all of the analyzed RNAs, the probing data were used to compose secondary structures, which partly deviate from previously predicted structures. Our results confirm the existence of two stem structures, which are also found at similar positions in hY1 and hY5 RNA. For the remaining parts of hY3 and hY4 RNA the secondary structures differ from those previously proposed based upon computer predictions. What might be more important is that certain parts of the RNAs appear to be flexible, i.e., to adopt several conformations. Another striking feature is that a characteristic pyrimidine-rich region, present in every Y RNA known, is single-stranded in all secondary structures. This may suggest that this region is readily available for base pairing inter-actions with other cellular nucleic acids, which might be important for the as yet unknown function of the RNAs.

Animals↗
PubMedDate not supplied

Hyperacute extensive middle cerebral artery territory infarcts. Role of computed tomography in predicting outcome.

OBJECTIVE: To assess the prognostic value of computed tomography (CT) in hyperacute middle cerebral artery (MCA) infarcts. METHODS: The CT features, total CT score, and National Institutes of Health Stroke Scale (NIHSS) score were correlated with the 30-day mortality in 16 patients with a hyperacute MCA infarct. RESULTS: Admission NIHSS scores were significantly lower in the survival group (P = 0.016). The extent of infarct, attenuation of corticomedullary differentiation, and total CT score were associated with 30-day mortality (P < 0.05). In prediction of mortality, extent of an infarct > 67% gave sensitivity, specificity, positive predictive value, and negative predictive value rates of 86%, 100%, 100%, and 90%, respectively. Attenuation of corticomedullary differentiation gave sensitivity, specificity, positive predictive value, and negative predictive value rates of 86%, 89%, 86%, and 89%, respectively. An NIHSS score > 28 gave sensitivity, specificity, positive predictive value, and negative predictive value rates of 86%, 67%, 67%, and 86%, respectively. A CT score > 4 gave sensitivity, specificity, positive predictive value, and negative predictive value rates of 86%, 78%, 75%, and 88%, respectively. CONCLUSIONS: Computed tomography features and the admission NIHSS score are important predictors of survival in hyperacute extensive MCA infarcts.

Aged↗
PubMed2004

Automated metabolic reconstruction for Methanococcus jannaschii.

We present the computational prediction and synthesis of the metabolic pathways in Methanococcus jannaschii from its genomic sequence using the PathoLogic software. Metabolic reconstruction is based on a reference knowledge base of metabolic pathways and is performed with minimal manual intervention. We predict the existence of 609 metabolic reactions that are assembled in 113 metabolic pathways and an additional 17 super-pathways consisting of one or more component pathways. These assignments represent significantly improved enzyme and pathway predictions compared with previous metabolic reconstructions, and some key metabolic reactions, previously missing, have been identified. Our results, in the form of enzymatic assignments and metabolic pathway predictions, form a database (MJCyc) that is accessible over the World Wide Web for further dissemination among members of the scientific community.

Computational Biology↗
PubMed2002

Analysis of the sodium recirculation theory of solute-coupled water transport in small intestine.

Our previous mathematical model of solute-coupled water transport through the intestinal epithelium is extended for dealing with electrolytes rather than electroneutral solutes. A 3Na+-2K+ pump in the lateral membranes provides the energy-requiring step for driving transjunctional and translateral flows of water across the epithelium with recirculation of the diffusible ions maintained by a 1Na+-1K+-2Cl- cotransporter in the plasma membrane facing the serosal compartment. With intracellular non-diffusible anions and compliant plasma membranes, the model describes the dependence on membrane permeabilities and pump constants of fluxes of water and electrolytes, volumes and ion concentrations of cell and lateral intercellular space (lis), and membrane potentials and conductances. Simulating physiological bioelectrical features together with cellular and paracellular fluxes of the sodium ion, computations predict that the concentration differences between lis and bathing solutions are small for all three ions. Nevertheless, the diffusion fluxes of the ions out of lis significantly exceed their mass transports. It is concluded that isotonic transport requires recirculation of all three ions. The computed sodium recirculation flux that is required for isotonic transport corresponds to that estimated in experiments on toad small intestine. This result is shown to be robust and independent of whether the apical entrance mechanism for the sodium ion is a channel, a SGLT1 transporter driving inward uphill water flux, or an electroneutral Na+-K+-2Cl- cotransporter.

Algorithms↗
PubMed2004

Complete, annotated sequence of the pseudorabies virus genome.

We have obtained the complete DNA sequence of pseudorabies virus (PRV), an alphaherpesvirus also known as Aujeszky's disease virus or suid herpesvirus 1, using sequence fragments derived from six different strains (Kaplan, Becker, Rice, Indiana-Funkhauser, NIA-3, and TNL). The assembled PRV genome sequence comprises 143,461 nucleotides. As expected, it matches the predicted gene arrangement, genome size, and restriction enzyme digest patterns. More than 70 open reading frames were identified with homologs in related alphaherpesviruses; none were unique to PRV. RNA polymerase II transcriptional control elements in the PRV genome, including core promoters, splice sites, and polyadenylation sites, were identified with computer prediction programs. The correlation between predicted and experimentally determined transcription start and stop sites was excellent. The transcriptional control architecture is characterized by three key features: core transcription elements shared between genes, yielding divergent transcripts and a large number of coterminal transcripts; bifunctional transcriptional elements, yielding head-to-tail transcripts; and short repetitive sequences that could function as insulators against improperly terminated transcripts. Many of these features are conserved in the alphaherpesvirus subfamily and have important implications for gene array analyses.

Base Sequence↗