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PubMed2005

Prospects of second generation artificial intelligence tools in calibration of chemical sensors.

Multivariate data driven calibration models with neural networks (NNs) are developed for binary (Cu++ and Ca++) and quaternary (K+, Ca++, NO3- and Cl-) ion-selective electrode (ISE) data. The response profiles of ISEs with concentrations are non-linear and sub-Nernstian. This task represents function approximation of multi-variate, multi-response, correlated, non-linear data with unknown noise structure i.e. multi-component calibration/prediction in chemometric parlance. Radial distribution function (RBF) and Fuzzy-ARTMAP-NN models implemented in the software packages, TRAJAN and Professional II, are employed for the calibration. The optimum NN models reported are based on residuals in concentration space. Being a data driven information technology, NN does not require a model, prior- or posterior- distribution of data or noise structure. Missing information, spikes or newer trends in different concentration ranges can be modeled through novelty detection. Two simulated data sets generated from mathematical functions are modeled as a function of number of data points and network parameters like number of neurons and nearest neighbors. The success of RBF and Fuzzy-ARTMAP-NNs to develop adequate calibration models for experimental data and function approximation models for more complex simulated data sets ensures AI2 (artificial intelligence, 2nd generation) as a promising technology in quantitation.

Artificial Intelligence↗
PubMed1976

Model consideration for the origin of life. Environmental structure as stimulus for the evolution of chemical systems.

In an attempt to understand the origin of living systems we encounter the following problems: How can we conceive the origin of the first self-reproducing forms, and by means of what stimuli could a constant increase in the complexity of such forms commence? How can a translation apparatus for genetic information develop? One cannot imagine that such an apparatus for the synthesis of enzymes can function alone without the interference of enzymes themselves, which, however, could only become available after the construction of the apparatus itself. What stimulus mechanism is conceivable that leads to the division of the genetic apparatus into a replication system, and an enzyme-synthesis system? The main problem therefore, is not the search for basic theoretical concepts. It is not a question which can be answered by means of specific experiments. One should rather explore the principal possibilities of how molecules combine to produce more and more complicated functional units. We look for the fundamental structural changes in the organizational systems and the driving forces initiating these developments. Questions concerning the detailed chemical realization are of secondary importance. In trying to solve the puzzle of how the genetic apparatus is gradually built up as complex aggregates of molecules, we consider a consistent causal chain of simple and transparent physiochemical model steps. The driving force for the self-organization of matter is seen in a specific environmental structure to be found on the surface of the earth. By this structure, which is periodic in time and heterogeneous in space, evolution is initiated and driven towards a continuously increasing degree of complexity correlated with a continuous expansion of the accessible living space. This process is a necessity under proper environmental conditions. Accidental events initiate each step but do not determine the general course of evolution which is determined by the selection mechanism.

Adenosine Monophosphate↗
PubMed1997

Biochemical and morphological correlations in human gallbladder with reference to membrane permeability.

There is good evidence that gallbladder epithelium is permeable to a diverse range of molecules which move into the epithelial cell from the lumen or the basement membrane. Morphological investigations have shown both secretory mucous droplets, components of the endocytosis pathway together with evidence of a system allowing passage of molecules across the basement membrane. This indicates that the gallbladder epithelium may be influenced by molecules presented via the apical and basal membranes, complicating our understanding of gallbladder function, particularly in disease. Gallbladder disease increases the proteoglycan content of the basement membrane, but the implication of this in terms of permeability remains to be defined. Indeed, it remains unknown whether this precedes disease or is a manifestation of the disease process. The removal of water from hepatic bile by gallbladder involves two counter ion transport systems. Autoradiography shows that ion transport occurs into the lateral intracellular spaces but it remains unclear whether this leads to a hypertonic solution in these spaces causing an osmotically driven water absorption or if the process involves an osmotically linked isotonic secretion. These ion pumps are reversible, for water is absorbed during the interdigestive phase but fluid is secreted into the lumen during digestion or in the presence of disease. Appropriate neural stimulation can increase or decrease fluid absorption from the lumen while vasoactive intestinal peptide or secretin promote fluid secretion, probably mediated by prostaglandins leading to raised cyclic AMP acting at the cellular level. Immediate control may depend on intracellular Ca2+ which activates a calmodulin-protein kinase, phosphorylating the counter ion transporters to downregulate their activity. Failure of this regulatory process may explain the initial increase in bile concentrating potential seen in the development of gallstones although the mechanism of such failure remains unknown. More concentrated bile increases movement of biliary compounds into gallbladder epithelial cells which alter gallbladder function in a complex manner. Secondary bile acids are raised in gallstone disease and increase permeability of the gallbladder epithelium to molecules including cholesterol. This cholesterol absorbed from the lumen may have paramount importance to gallbladder function. Raised biliary cholesterol reduces gallbladder motility, possibly by increasing the amount of cholesterol in gallbladder muscle membranes and reducing contraction in response to cholecystokinin. However, increased secondary bile acids are also associated with an alteration in phospholipid acyl groups which may alter ion transport activity and/or cholesterol solubility within the micelle/vesicle. As the acyl groups show increased arachidonate levels the production of prostaglandins could be raised, although currently it is not known if this phospholipid arachidonate enters the epithelial cells. In addition, gallbladder inflammation is associated with raised phospholipase A2 activity, leading to formation of fatty acids and lysophospholipid which causes membrane damage. The fatty acids are likely to displace cholesterol from the micelle but may also act directly on the epithelium, possibly increasing prostaglandin production and thus stimulating mucin secretion. Increased mucin secretion is seen early in gallstone disease but the evidence presently available cannot determine if this is a causative factor.

Absorption↗
PubMed1996

Exploration of the conformational space of oxytocin and arginine-vasopressin using the electrostatically driven Monte Carlo and molecular dynamics methods.

Conformational analysis of the neurohypophyseal hormones oxytocin (OT) and arginine-vasopressin (AVP) has been carried out using two different computational approaches and three force fields, namely by the Electrostatically Driven Monte Carlo (EDMC) method, with the Empirical Conformational Energy Program for Peptides (ECEPP/3) force field or with the ECEPP/3 force field plus a hydration-shell model, and by simulated-annealing molecular dynamics with the Consistent Valence Force Field (CVFF). The low-energy conformations obtained for both hormones were classified using the minimal-tree clustering algorithm and characterized according to the locations of beta-turns in the cyclic moieties. Calculations with the CVFF force field located conformations with a beta-turn at residues 3 and 4 as the lowest energy ones both for OT and for AVP. In the ECEPP/3 force field the lowest energy conformation of OT contained a beta-turn at residues 2 and 3, conformations with this location of the turn being higher in energy for AVP. The latter difference can be attributed to the difference in the size of the side chain in position 3 of the sequences: the bulkier phenylalanine residue of AVP in combination with the bulky Tyr2 residue hinders the formation of a turn at residues 2 and 3. Conformations of OT and AVP with a turn at residues 3,4 were in the best agreement with the x-ray structures of deaminooxytocin and pressinoic acid (the cyclic moiety of vasopressin), respectively, and with the nmr-derived distance constraints. Generally, the low-energy conformations obtained with the hydration-shell model were in a better agreement with the experimental data than the conformations calculated in vacuo. It was found, however, that the obtained low-energy conformations do not satisfy all of the nmr-derived distance constraints and the nuclear Overhauser effect pattern observed in nmr studies can be fully explained only by assuming a dynamic equilibrium between conformations with beta-turns at residues 2,3, 3,4, and 4,5. The low-energy structures of OT with a beta-turn at residues 2,3 have the disulfide ring conformations close to the model proposed recently for a potent bicyclic antagonist of OT [M. D. Shenderovich et al. (1994) Polish Journal of Chemistry, Vol. 25, pp. 921-927], although the native hormone differs from the bicyclic analogue by the conformation of the C-terminal tripeptide. This finding confirms the hypothesis of different receptor-bound conformations of agonists and antagonists of OT.

Amino Acid Sequence↗
PubMed1997

Sequencing in nanofabricated arrays: a feasibility study.

The feasibility of using nanofabricated arrays as electrophoretic chambers for DNA sequencing is investigated. A specific array design, consisting of rows of closely spaced posts, separated by longer open spaces, is proposed. Molecules driven through the array by an electric field get hooked over obstacles at successive rows and their progress through the device is delayed as a consequences. The dependence of the delay time on molecular size is derived. Numerical evaluation indicates that a device of modest dimensions, operating at high fields, can rapidly resolve oligonucleotides containing several hundred bases.

DNA↗
PubMed1993

Characterization and expression of a novel Na(+)-inorganic phosphate transporter at the liver plasma membrane of the rat.

BACKGROUND: Phosphate transport across the plasma membrane of the intestine and kidney occur by an Na(+)-dependent process. The mechanism by which phosphate enters the hepatocytes across the basolateral membrane is not known. Therefore, our study was designed to investigate whether the plasma membranes of the liver possess a specialized transport system for translocation of phosphate into the hepatocyte. METHODS: Liver plasma membrane vesicles and expression of liver poly(A)+ RNA into Xenopus laevis oocytes was used. RESULTS: Phosphate was driven into the intravesicular space as depicted by the equation y = 493.96x + 0.001, r2 = 0.96. Inwardly directed Na+ and pH gradients stimulated phosphate uptake, with a Vmax of 0.58 +/- 0.03 and 0.22 +/- 0.03 nmol/mg protein/10 s, at pH 6.1 and 7.4, respectively (P < 0.05). Km values were 0.39 +/- 0.07 and 0.25 +/- 0.1 mmol/L, respectively. To confirm the presence of a phosphate carrier, the liver Na+ phosphate transporter was expressed in X. laevis oocytes. The size-selected messenger RNA encoding for the phosphate transporter was 1.6 kilobases (kb) with kinetic parameters of Vmax 6.75 +/- 0.9 pmol/mg protein/5 min and Km of 0.29 +/- 0.1 mmol/L, compared with a Vmax of 0.41 +/- 0.03 pmol/mg protein/5 min and a Km of 0.085 +/- 0.022 mmol/L for water injection. Colonic poly(A)+ RNA did not stimulate phosphate uptake in the oocytes. CONCLUSION: The combined studies of plasma membrane vesicles and the expression system into X. laevis oocytes confirm the presence of an Na(+)-phosphate transporter at the liver plasma membranes.

Animals↗
PubMed2006

Scanning for the scanner: FMRI of audition by read-out omissions from echo-planar imaging.

Echo-planar imaging (EPI) generates considerable acoustic noise by rapidly oscillating gradients. In functional magnetic resonance imaging (FMRI), unshielded EPI sounds activate the auditory system inasmuch as it is responsive. Instead of attenuating EPI noise, our goal was to utilize it for auditory FMRI by omitting read-outs from the pulse sequence's gradient train. Read-out gradient pulses are the primary noise determinant of EPI introducing its peak sound level and fundamental frequency peak which inversely relates to twice the echo spacing. Using model-driven analyses, we demonstrate that withholding read-outs from EPI is suited to reliably evoke hemodynamic blood oxygenation level-dependent (BOLD) signal modulations bilaterally in the auditory cortex of normal hearing subjects (n=60). To investigate the utility of EPI read-out omissions for auditory FMRI at an individual subject's level, we compare traditional Family-Wise-Error-Rate (FWER)-corrected maximum height thresholding to spatial mixture modeling (SMM). With the latter, appropriate bilateral auditory activations were confirmed in 95% of the individuals, whereas FWER-based voxel thresholding detected such activations in up to 72%. We illustrate the applicability of this novel EPI modification for clinical diagnostic purposes and report on a patient with bilateral large vestibular aqueducts (LVAs) and severe binaural sensorineural hearing loss (SNHL). In this particular case, read-out omissions from EPI were used to assert residual audition prior to cochlear implantation (CI). Requiring no specific task compliance or sophisticated stimulation equipment other than the scanner on its own, FMRI by read-out omissions lends itself to auditory investigations and to quickly probe audition.

Acoustic Stimulation↗
PubMed1997

Thermographic assessment of heat generated on the root surface during post space preparation.

The mechanical preparation of a post space in a root filled tooth is commonly carried out using rotating instruments in a slow handpiece. This procedure creates frictional heat which may be transferred to the root surface. In this investigation, the temperature changes on the root surface of 12 root filled, extracted human premolar teeth during preparation of post spaces were analysed using an infrared thermal imaging camera. A rotational speed of 8000 r.p.m. was used and the teeth were prepared with size 2 and 3 Peeso reamers and a red Parapost drill to the optimal length. The results indicate that very large temperatures are generated on the root surface and that this is greatest during the Parapost preparation stage. The long-term clinical effects of post space preparation by engine driven drills would warrant further investigation.

Bicuspid↗
PubMed2006

Surgical treatment of neck hyperextension in duchenne muscular dystrophy by posterior interspinous fusion.

STUDY DESIGN: Seven patients affected by Duchenne muscular dystrophy with neck hyperextension or poor head control in extension have undergone surgery consisting of posterior cervical interspinous fusion. OBJECTIVE: To report the results of surgical treatment of neck hyperextension executed simultaneously with the correction of the thoracolumbar scoliosis. SUMMARY OF BACKGROUND DATA: A severely progressive deformity of the spine in patients affected by DMD can involve also the cervical spine presenting a rigid neck hyperextension or poor head control in extension, forcing the patients to assume awkward compensating postures in order to look straight ahead, worsening significantly their quality of life. METHODS: The procedure consisted of a posterior approach to the cervical spine, correction of the hyperextension by releasing the fibrotic muscles and ligaments, and stabilization with bone grafts driven into the interspinous spaces, to achieve solid fusion. RESULTS: No surgical complications were observed, and fusion was achieved in all patients. The mean angle between C2-C7 decreased from an average of 29.8 degrees (7 degrees -56 degrees) before surgery, to an average of 18.5 degrees (6 degrees-30 degrees) at 1 year of follow-up. Range of motion between C1-C2 was preserved. CONCLUSIONS: Surgical treatment of neck hyperextension in these patients contributes to a better sitting position, to an easier nursing, to a better appearance.

Adolescent↗
PubMed2004

Citrate transport in the human prostate epithelial PNT2-C2 cell line: electrophysiological analyses.

Although prostate synthesizes and releases large amounts of citrate, the mechanism of the release is not well understood. Most known citrate transporters mediate uptake of citrate from extracellular space and, consequently, are driven by the transmembrane Na+ gradient, which would not be appropriate for prostatic function. In the present study, we investigated citrate transport in a normal human prostate cell line, PNT2-C2, using mainly electrophysiological methods. Intracellular application of citrate through the patch pipette in the whole-cell recording mode induced an outward current whilst in response to extracellular citrate an inward current was recorded. Membrane currents induced by citrate were bigger than those elicited by other (equimolar) Krebs cycle intermediates. Both inward and outward citrate-induced currents had the same ionic dependence, inhibitor profile and reversal potential. In particular, the currents were strongly dependent on the transmembrane K+ gradient. Uptake and release of citrate and their K+ dependence were confirmed by spectrophotometric enzyme analyses. Citrate-induced membrane currents were also sensitive to pH, consistent with the transporter preferring the trivalent form. Application of intracellular Zn2+ generated an outward current which had the same quantitative K+ dependence as the citrate-induced currents. Extracellular application of a membrane-permeant Zn2+ chelator generated an inward current. These experiments suggested that m-aconitase was tonically active in PNT2-C2 cells. Determination of 'forward' and 'reverse' K+ stoichiometry both suggested a citrate: K+ ratio of 1: 4. We conclude that normal prostatic epithelial cells possess an electrogenic citrate transporter which mediates the cotransfer of 1 trivalent citrate anion alongside 4 K+ out of cells and thus generates a net outward current.

Carrier Proteins↗
PubMed2003

PG-mediated closure of paracellular pathway and not restitution is the primary determinant of barrier recovery in acutely injured porcine ileum.

Small bowel epithelium is at the frontline of intestinal barrier function. Restitution is considered to be the major determinant of epithelial repair, because function recovers in parallel with restitution after acute injury. As such, studies of intact mucosa have largely been replaced by migration assays of cultured epithelia. These latter studies fail to account for the simultaneous roles played by villous contraction and paracellular permeability in recovery of barrier function. NSAIDs result in increased intestinal permeability and disease exacerbation in patients with inflammatory bowel disease (IBD). Thus we examined the reparative attributes of endogenous PGs after injury of ileal mucosa by deoxycholate (6 mM) in Ussing chambers. Recovery of transepithelial electrical resistance (TER) from 20-40 Omega.cm2 was abolished by indomethacin (Indo), whereas restitution of 40-100% of the villous surface was unaffected despite concurrent arrest of villous contraction. In the presence of PG, resident crypt and migrating epithelial cells were tightly apposed. In tissues treated with Indo, crypt epithelial cells had dilated intercellular spaces that were accentuated in the migrating epithelium. TER was fully rescued from the effects of Indo by osmotic-driven collapse of the paracellular space, and PG-mediated recovery was significantly impaired by blockade of Cl- secretion. These studies are the first to clearly distinguish the relative contribution of paracellular resistance vs. restitution to acute recovery of epithelial barrier function. Restitution was ineffective in the absence of PG-mediated paracellular space closure. Failure of PG-mediated repair mechanisms may underlie barrier failure resulting from NSAID use in patients with underlying enteropathy.

Animals↗
PubMed1992

Stabilization of gaze during circular locomotion in darkness. II. Contribution of velocity storage to compensatory eye and head nystagmus in the running monkey.

1. Yaw eye in head (Eh) and head on body velocities (Hb) were measured in two monkeys that ran around the perimeter of a circular platform in darkness. The platform was stationary or could be counterrotated to reduce body velocity in space (Bs) while increasing gait velocity on the platform (Bp). The animals were also rotated while seated in a primate chair at eccentric locations to provide linear and angular accelerations similar to those experienced while running. 2. Both animals had head and eye nystagmus while running in darkness during which slow phase gaze velocity on the body (Gb) partially compensated for body velocity in space (Bs). The eyes, driven by the vestibuloocular reflex (VOR), supplied high-frequency characteristics, bringing Gb up to compensatory levels at the beginning and end of the slow phases. The head provided substantial gaze compensation during the slow phases, probably through the vestibulocollic reflex (VCR). Synchronous eye and head quick phases moved gaze in the direction of running. Head movements occurred consistently only when animals were running. This indicates that active body and limb motion may be essential for inducing the head-eye gaze synergy. 3. Gaze compensation was good when running in both directions in one animal and in one direction in the other animal. The animals had long VOR time constants in these directions. The VOR time constant was short to one side in one animal, and it had poor gaze compensation in this direction. Postlocomotory nystagmus was weaker after running in directions with a long VOR time constant than when the animals were passively rotated in darkness. We infer that velocity storage in the vestibular system had been activated to produce continuous Eh and Hb during running and to counteract postrotatory afterresponses. 4. Continuous compensatory gaze nystagmus was not produced by passive eccentric rotation with the head stabilized or free. This indicates that an aspect of active locomotion, most likely somatosensory feedback, was responsible for activating velocity storage. 5. Nystagmus was compared when an animal ran in darkness and in light. the beat frequency of eye and head nystagmus was lower, and the quick phases were larger in darkness. The duration of head and eye quick phases covaried. Eye quick phases were larger when animals ran in darkness than when they were passively rotated. The maximum velocity and duration of eye quick phases were the same in both conditions. 6. The platform was counterrotated under one monkey in darkness while it ran in the direction of its long vestibular time constant.(ABSTRACT TRUNCATED AT 400 WORDS)

Adaptation, Physiological↗
PubMed1992

Pathways for fluid loss from the peritoneal cavity.

During peritoneal dialysis, fluid is transported out of the peritoneal cavity by lymphatic and nonlymphatic pathways, thereby decreasing net ultrafiltration by 40-50% and reducing small solute clearance by 15-20%. The direct lymphatic pathway consists of the diaphragmatic lymphatics, which directly connect the peritoneal cavity to the bloodstream. The interstitial lymphatic and direct blood entry pathways convey fluid that has been driven into the interstitial space of the tissue surrounding the peritoneal cavity by the increased intraperitoneal pressure, and return it to the bloodstream. Since flow through lymphatic pathways is only a portion of the flow through all pathways, total fluid loss is greater than lymph flow. The best technique for estimating lymph flow is direct measurement by cannulation of lymphatic vessels, a technique that is not clinically feasible. The tracer disappearance technique, which measures the rate at which macromolecules leave the peritoneal cavity, is an indirect measure of fluid loss. The tracer appearance technique, which measures the rate at which macromolecules reach the blood from the peritoneal cavity, slightly overestimates lymph flow because some tracer may enter the bloodstream directly from the tissues. Much of the previous controversy over the contribution of the lymphatic pathways to total fluid loss can be resolved by understanding the differences in what these techniques measure.

Ascitic Fluid↗
PubMed2025

What is on the Horizon Beyond Platinum and Immunotherapy for Patients With Advanced Non-Small Cell Lung Cancer Without Actionable Genomic Aberrations?

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide. While targeted therapy and immunotherapy have transformed first-line management, most patients without actionable genomic alterations (AGAs) will experience disease progression within the first year of their initial treatment. Here, we review pivotal trials, emerging strategies, challenges, and unmet needs for patients with advanced NSCLC without AGAs. Docetaxel with or without ramucirumab is the standard second-line therapy for patients who have progressed after platinum-based chemotherapy and immunotherapy. Targeted therapy is only suitable for patients with specific AGAs. Understanding the hallmarks of cancer immune evasion is key to developing new strategies beyond chemoimmunotherapy. The combination of antiangiogenic agents with immune checkpoint inhibitors (ICIs) has shown mixed results after progression on platinum and ICI. Bispecific antibodies, particularly ivonescimab, have shown encouraging early efficacy in this space. Artificial intelligence-driven pathomics and radiomics tools may help to refine treatment selection in the future. Chimeric antigen receptor T-cell therapy remains investigational. Patients with advanced NSCLC without AGAs who progressed after chemoimmunotherapy have limited treatment options. Novel therapies such as specific antibodies have shown promising results. Future progress will depend on the development of predictive biomarkers and understanding the mechanisms of resistance to ICIs to guide drug development.

Humans↗
PubMed2001

Coupling biology and oceanography in models.

The dynamics of marine ecosystems, i.e. the changes of observable chemical-biological quantities in space and time, are driven by biological and physical processes. Predictions of future developments of marine systems need a theoretical framework, i.e. models, solidly based on research and understanding of the different processes involved. The natural way to describe marine systems theoretically seems to be the embedding of chemical-biological models into circulation models. However, while circulation models are relatively advanced the quantitative theoretical description of chemical-biological processes lags behind. This paper discusses some of the approaches and problems in the development of consistent theories and indicates the beneficial potential of the coupling of marine biology and oceanography in models.

Animals↗
PubMed2006

MRI image overlay: applications to arthrography needle insertion.

Magnetic Resonance Imaging (MRI) has unmatched potential for planning, guiding, monitoring and controlling interventions. MR arthrography (MRA) is the imaging gold standard to assess small ligament and fibrocartilage injury in joints. In contemporary practice, MRA consists of two consecutive sessions: 1) an interventional session where a needle is driven to the joint space and gadolinium contrast is injected under fluoroscopy or CT guidance. 2) A diagnostic MRI imaging session to visualize the distribution of contrast inside the joint space and evaluate the condition of the joint. Our approach to MRA is to eliminate the separate radiologically guided needle insertion and contrast injection procedure by performing those tasks on conventional high-field closed MRI scanners. We propose a 2D augmented reality image overlay device to guide needle insertion procedures. This approach makes diagnostic high-field magnets available for interventions without a complex and expensive engineering entourage.

Arthrography↗