Understanding the decision process underlying gaze control is an important question in cognitive neuroscience with applications in diverse fields ranging from psychology to computer vision. The ...decision for choosing an upcoming saccade target can be framed as a selection process between two states: Should the observer further inspect the information near the current gaze position (local attention) or continue with exploration of other patches of the given scene (global attention)? Here we propose and investigate a mathematical model motivated by switching between these two attentional states during scene viewing. The model is derived from a minimal set of assumptions that generates realistic eye movement behavior. We implemented a Bayesian approach for model parameter inference based on the model's likelihood function. In order to simplify the inference, we applied data augmentation methods that allowed the use of conjugate priors and the construction of an efficient Gibbs sampler. This approach turned out to be numerically efficient and permitted fitting interindividual differences in saccade statistics. Thus, the main contribution of our modeling approach is two-fold; first, we propose a new model for saccade generation in scene viewing. Second, we demonstrate the use of novel methods from Bayesian inference in the field of scan path modeling.
53 compounds with clinically established ability to cross or not to cross the blood-brain barrier by passive diffusion were characterized by means of surface activity measurements in terms of three ...parameters, i.e., the air-water partition coefficient, Kaw, the critical micelle concentration, CMCD, and the cross-sectional area, AD. A three-dimensional plot in which the surface area, AD, is plotted as a function of K-1aw and CMCD shows essentially three groups of compounds: (i) very hydrophobic compounds with large air-water partition coefficients and large cross-sectional areas, AD > 80 A2 which do not cross the blood-brain barrier, (ii) compounds with lower air-water partition coefficients and an average cross-sectional area, AD congruent with 50 A2 which easily cross the blood-brain barrier, and (iii) hydrophilic compounds with low air-water partition coefficients (AD < 50 A2) which cross the blood-brain barrier only if applied at high concentrations. It was shown that the lipid membrane-water partition coefficient, Klw, measured previously, can be correlated with the air-water partition coefficient if the additional work against the internal lateral bilayer pressure, pibi = 34 +/- 4 mN/m is taken into account. The partitioning into anisotropic lipid membranes decreases exponentially with increasing cross-sectional areas, AD, according to Klw = const. Kaw exp(-ADpibi/kT) where kT is the thermal energy. The cross-sectional area of the molecule oriented at a hydrophilic-hydrophobic interface is thus the main determinant for membrane permeation provided the molecule is surface active and has a pKa > 4 for acids and a pKa < 10 for bases.
To date, over 20 peptides or proteins have been identified that can form amyloid fibrils in the body and are thought to cause disease. The mechanism by which amyloid peptides cause the cytotoxicity ...observed and disease is not understood. However, one of the major hypotheses is that amyloid peptides cause membrane perturbation. Hence, we have studied the interaction between lipid bilayers and the 37 amino acid residue polypeptide amylin, which is the primary constituent of the pancreatic amyloid associated with type 2 diabetes. Using a dye release assay we confirmed that the amyloidogenic human amylin peptide causes membrane disruption; however, time-lapse atomic force microscopy revealed that this did not occur by the formation of defined pores. On the contrary, the peptide induced the formation of small defects spreading over the lipid surface. We also found that rat amylin, which has 84% identity with human amylin but cannot form amyloid fibrils, could also induce similar lesions to supported lipid bilayers. The effect, however, for rat amylin but not human amylin, was inhibited under high ionic conditions. These data provide an alternative theory to pore formation, and how amyloid peptides may cause membrane disruption and possibly cytotoxicity.
Verapamil and amlodipine are calcium ion influx inhibitors of wide clinical use. They are partially charged at neutral pH and exhibit amphiphilic properties. The noncharged species can easily cross ...the lipid membrane. We have measured with solid-state NMR the structural changes induced by verapamil upon incorporation into phospholipid bilayers and have compared them with earlier data on amlodipine and nimodipine. Verapamil and amlodipine produce a rotation of the phosphocholine headgroup away from the membrane surface and a disordering of the fatty acid chains. We have determined the thermodynamics of verapamil partitioning into neutral and negatively charged membranes with isothermal titration calorimetry. Verapamil undergoes a pK-shift of ΔpKa=1.2 units in neutral lipid membranes and the percentage of the noncharged species increases from 5% to 45%. Verapamil partitioning is increased for negatively charged membranes and the binding isotherms are strongly affected by the salt concentration. The electrostatic screening can be explained with the Gouy-Chapman theory. Using a functional phosphate assay we have measured the affinity of verapamil, amlodipine, and nimodipine for P-glycoprotein, and have calculated the free energy of drug binding from the aqueous phase to the active center of P-glycoprotein in the lipid phase. By combining the latter results with the lipid partitioning data it was possible, for the first time, to determine the true affinity of the three drugs for the P-glycoprotein active center if the reaction takes place exclusively in the lipid matrix.
The purpose of this study was to develop a multitarget, multicolor fluorescence
in situ hybridization (FISH) assay for the detection of urothelial carcinoma (UC) in urine specimens. Urinary cells ...obtained from voided urine specimens of 21 patients with UC and 9 normal donors were analyzed with nine different centromere enumeration probes and a single locus-specific indicator probe to determine an optimal set of FISH probes for UC detection. The four probes with the greatest sensitivity for UC detection were then labeled with a unique fluorophore and combined into a single probe set. The probes with the greatest combined sensitivity for UC detection were CEP3, CEP7, CEP17, and the 9p21 (
P16) LSI. This probe set was used to evaluate urine specimens acquired from 179 patients for prospective testing (46 with biopsy-proven UC). FISH slides were evaluated by scanning the slide for cells with nuclear features suggestive of malignancy and assessing the FISH signal pattern of these cells for polysomy (ie, gains of two or more different chromosomes). A receiver operator characteristic curve revealed that a cutoff of 5 cells with polysomy as the positive criterion for cancer resulted in an overall sensitivity of 84.2% for patients with biopsy-proven UC and a specificity of 91.8% among patients with genitourinary disorders but no evidence of UC. This study demonstrates that a multitarget, multicolor FISH assay containing centromeric probes to chromosomes 3, 7, and 17 and a locus-specific probe to band 9p21 has high sensitivity and specificity for the detection of UC in voided urine specimens.
Modulators and inhibitors of multidrug efflux transporters, like P-glycoprotein, are used to reduce or inhibit multidrug resistance, MDR, which leads to a failure of the chemotherapy of e.g. cancers, ...epilepsy, bacterial, parasitic, and fungal diseases. Binding and transport of first-, second-, and third-generation modulators and inhibitors of P-glycoprotein are discussed, taking into account the properties of the drug (H-bonding potential, dimensions, and pK(a) values) as well as the properties of the membrane.
Data assimilation in dynamical cognitive science Engbert, Ralf; Rabe, Maximilian M.; Schwetlick, Lisa ...
Trends in cognitive sciences,
February 2022, 2022-02-00, 20220201, Letnik:
26, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Dynamical models make specific assumptions about cognitive processes that generate human behavior. In data assimilation, these models are tested against time-ordered data. Recent progress on Bayesian ...data assimilation demonstrates that this approach combines the strengths of statistical modeling of individual differences with the those of dynamical cognitive models.
We determine the relative sensitivities of cytology and fluorescence in situ hybridization (FISH) for the detection of urothelial carcinoma.
A mixture of fluorescent labeled probes to the centromeres ...of chromosomes 3, 7 and 17, and band 9p21 (P16/CDKN2A gene) was used to assess urinary cells for chromosomal abnormalities indicative of malignancy. A total of 280 urine specimens from 265 patients, including 150 with a history of urothelial carcinoma and 115 without a history of urothelial carcinoma, were analyzed. FISH analysis was performed without prior knowledge of clinical findings, that is biopsy, cystoscopy and cytology results. A positive result was defined as 5 or more urinary cells with gains of 2 or more chromosomes.
A total of 75 biopsies showed urothelial carcinoma at FISH analysis among the 265 patients. The sensitivity of urine cytology for pTa (36 cases), pTis (18) and pT1-pT4 (15) tumors was 47%, 78% and 60%, respectively, for an overall sensitivity of 58%. The sensitivity of FISH for pTa (37 cases), pTis (17) and pT1-pT4 (19) tumors was 65%, 100% and 95%, respectively, for an overall sensitivity of 81%. FISH was significantly more sensitive than cytology for pTis (p = 0.046), pT1-pT4 (p = 0.025), grade 3 (p = 0.003) and all tumors (p = 0.001). The specificity of cytology and FISH among patients without cystoscopic evidence of urothelial carcinoma and no history of urothelial carcinoma was 98% and 96%, respectively (p = 0.564).
The sensitivity of FISH for the detection of urothelial carcinoma is superior to that of cytology, and the specificity of FISH and cytology for urothelial carcinoma are not significantly different. Further prospective studies are required but FISH has the potential to improve significantly the management of urothelial carcinoma.
Antinuclear antibodies (ANA) are considered as a key serological feature of systemic autoimmune rheumatic diseases (SARD) which include syndromes like systemic lupus erythematodes (SLE), systemic ...sclerosis (SSc), mixed connective tissue disease (MCTD), Sjögren's syndrome (SS) or dermatomyositis/polymyositis (DM/PM). ANA, commonly detected by indirect immunofluorescence assays on HEp-2 cells (IF-ANA), recommended as the screening test of choice (ACR), comprise a plethora of antibody specificities, a part of which are important serological markers of the diagnostic armamentarium in SARD. However, the applicability of IF-ANA as global screening test is hampered by its limited diagnostic specificity for resulting positive in up to 20% of apparently healthy individuals. About half of IF-ANA in healthy individuals target the chromosome associated protein DFS70/LEDGF, which tethers transcriptional coactivators or lentiviral integrases to transcriptionally active chromatin moieties and induces pro-survival stress factor transcriptions. Because of their rare prevalence in SARD patients, isolated anti-DFS70 antibodies are being increasingly considered as important biomarker to exclude the diagnosis of SARD.
Scrutinizing the relevant articles cited in NCBI concerning the DFS70/LEDGF protein, the diverse methods of anti-DFS70 determination in human sera supplemented by own experiences and critical review of the complete literature relevant to anti-DFS70 and SARD.
Antibodies to DFS70/LEDGF (anti-DFS70), disclosed by IF-ANA, are characterized by a dense fine speckled (DFS) nucleoplasmic fluorescence pattern (DFS-ANA) accompanied by a striking staining of the condensed chromosomes in mitotic cells. By means of various methods anti-DFS70 may be found in 7.8 ± 6.2% (MD 7.6%) of apparently healthy individuals, may sometimes display rather high antibody titers and antibody carriers do not seem to manifest SARD symptoms within a five year interval. Their prevalence in non-selected cohorts originating from routine IF-ANA screenings (38643 tested individuals) fluctuates between 0.8 and 8.4% (MD 1.7%), depending on patient selection criteria and test performance. The proper appreciation of these data is hampered partially because of missing verification of antibody specificities partially by lack of specifications of associated disease or accompanying SARD specific marker antibodies. A metaanalysis of five studies including 1243 SARD patients confirms the rare mean prevalence of solitary anti-DFS70 (0.7 ± 0.9%, MD 0.45%) in SARD patients. The mean prevalence of anti-DFS70 accompanied by SARD specific markers is 3.8 ± 2.9% (MD 2.9%). In patients exclusively harbouring anti-DFS70 the likelihood ratio (LR+) for the absence of SARD approaches a significant value of 10.9.
Since anti-DFS70 according to the available data may being regarded as a possible biomarker for ruling out the diagnosis of a systemic autoimmune rheumatic disease, it seems to be indispensable to identify properly DFS-ANA patterns in the routine IF-ANA screening, to confirm the anti-DFS70 specificity by appropriate confirmation assays and to communicate the results with annotating comments to the clinician, in order to ameliorate the proper assessment of the pathological significance of serological results and the selection of adequate follow-up investigations.
Abstract Objective Excess lipid intake has been implicated in the pathophysiology of hepatosteatosis and hepatic insulin resistance. Lipids constitute approximately 50% of the cell membrane mass, ...define membrane properties, and create microenvironments for membrane-proteins. In this study we aimed to resolve temporal alterations in membrane metabolite and protein signatures during high-fat diet (HF)-mediated development of hepatic insulin resistance. Methods We induced hepatosteatosis by feeding C3HeB/FeJ male mice an HF enriched with long-chain polyunsaturated C18:2n6 fatty acids for 7, 14, or 21 days. Longitudinal changes in hepatic insulin sensitivity were assessed via the euglycemic-hyperinsulinemic clamp, in membrane lipids via t-metabolomics- and membrane proteins via quantitative proteomics-analyses, and in hepatocyte morphology via electron microscopy. Data were compared to those of age- and litter-matched controls maintained on a low-fat diet. Results Excess long-chain polyunsaturated C18:2n6 intake for 7 days did not compromise hepatic insulin sensitivity, however, induced hepatosteatosis and modified major membrane lipid constituent signatures in liver, e.g. increased total unsaturated, long-chain fatty acid-containing acyl-carnitine or membrane-associated diacylglycerol moieties and decreased total short-chain acyl-carnitines, glycerophosphocholines, lysophosphatidylcholines, or sphingolipids. Hepatic insulin sensitivity tended to decrease within 14 days HF-exposure. Overt hepatic insulin resistance developed until day 21 of HF-intervention and was accompanied by morphological mitochondrial abnormalities and indications for oxidative stress in liver. HF-feeding progressively decreased the abundance of protein-components of all mitochondrial respiratory chain complexes, inner and outer mitochondrial membrane substrate transporters independent from the hepatocellular mitochondrial volume in liver. Conclusions We assume HF-induced modifications in membrane lipid- and protein-signatures prior to and during changes in hepatic insulin action in liver alter membrane properties – in particular those of mitochondria which are highly abundant in hepatocytes. In turn, a progressive decrease in the abundance of mitochondrial membrane proteins throughout HF-exposure likely impacts on mitochondrial energy metabolism, substrate exchange across mitochondrial membranes, contributes to oxidative stress, mitochondrial damage, and the development of insulin resistance in liver.
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