Miracle-dz/UniFAR-FTUs huggingface dataset:
Intersubject Variation in the Pharmacokinetics of Haloperidol and Reduced Haloperidol

Single oral doses (5 mg) of haloperidol were administered to 36 healthy men (26 black, 10 white) of whom 28 (22 black, 6 white) completed the study. Plasma samples harvested over 96 hours were analyzed for haloperidol and reduced haloperidol by means of a new high performance liquid chromatographic method. Reduced haloperidol was detectable in the plasma of only six of the 28 subjects (five blacks, one white). In these individuals reduced haloperidol plasma concentrations were generally much lower than those of the parent drug. This finding in the present single-dose study is in contrast to literature reports that have described levels of reduced haloperidol higher than those of the parent drug in some patients chronically medicated with haloperidol. There was wide intersubject variation in area under the plasma concentration versus time curve and apparent oral clearance values for haloperidol. The distributions of these pharmacokinetic parameters about their respective means were each leptokurtotic and skewed toward higher values. In each case the geometric mean gave a better estimate of central tendency than the arithmetic mean. Wide intersubject variation prevented the detection of significant differences in these pharmacokinetic parameters between black and white subjects or between smokers and nonsmokers.
Statistical process monitoring based on modified nonnegative matrix factorization

As an effective feature extraction and dimension reduction method, nonnegative matrix factorization NMF can yield sparse, spatially localized, part-based subspace representations by finding a low-rank matrix approximation from the original data. However, one drawback it has to suffer is its failure to retain the statistical properties of data. In this paper, NMF is modified to take the variations of data into account. This modified NMF MNMF is aimed at not only extracting the latent signals which are added together to produce the observed signals, but also capturing the main variations of data. Then MNMF can be used to extract the latent variables in a process and combine them with process monitoring techniques for fault detection. The proposed method was applied to the Tennessee Eastman Process TEP to evaluate its monitoring performance, and the experiment results demonstrated its feasibility and availability for process monitoring.
Correcting Scale Drift by Object Recognition in Single-Camera SLAM

This paper proposes a novel solution to the problem of scale drift in single-camera simultaneous localization and mapping, based on recognizing and measuring objects. When reconstructing the trajectory of a camera moving in an unknown environment, the scale of the environment, and equivalently the speed of the camera, is obtained by accumulating relative scale estimates over sequences of frames. This leads to scale drift: errors in scale accumulate over time. The proposed solution is to learn the classes of objects that appear throughout the environment and to use measurements of the size of these objects to improve the scale estimate. A bag-of-words-based scheme to learn object classes, to recognize object instances, and to use these observations to correct scale drift is described and is demonstrated reducing accumulated errors by 64% while navigating for 2.5 km through a dynamic outdoor environment.
Influence of renal dysfunction on the accuracy of procalcitonin for the diagnosis of postoperative infection after vascular surgery

Objective:Procalcitonin has been advocated as a specific biomarker for bacterial infection. We performed this study to determine whether accuracy of procalcitonin for diagnosis of postoperative bacterial infection is affected by renal function after aortic surgery. Design:Single-center prospective study. Setting:University hospital. Patients:Two hundred seventy-six patients scheduled for elective major aortic surgery. Interventions:Blood samples were taken before surgery and each day over the 5-day postoperative period, and measurement of serum procalcitonin was performed. Diagnosis of infection was performed by a blinded expert panel. Renal function was assessed using an estimate of creatinine clearance with the Cockcroft formulas. Renal dysfunction was defined as a creatinine clearance <50 mL·min−1. Measurements and Main Results:Infection was diagnosed in 67 patients. Seventy five patients (27%) had postoperative renal dysfunction. Procalcitonin was significantly higher in infected patients, with a peak reached at the fourth postoperative day, but it was significantly higher in patients with impaired renal function in both control and infected patients. The optimal threshold of procalcitonin markedly differed in patients with renal dysfunction compared with patients without renal dysfunction (2.57 vs. 0.80 ng·mL−1, p < .05). The diagnostic accuracy of procalcitonin significantly increased (0.74 vs. 0.70, p < .05) when the threshold of procalcitonin was adapted to the renal function. The elevation of procalcitonin occurred 2 days before the medical team was able to diagnose infection. Conclusions:Procalcitonin is a valuable marker of bacterial infections after major aortic surgery, but renal function is a major determinant of procalcitonin levels and thus different thresholds should be applied according to renal function impairment.
A Critical Reassessment

stages of the jazz education development using the three-tier American education system (elementary, specialized secondary and higher education) as an example have been revealed. The paper lays emphasis on the need for Ukraine to benefit from the American jazz education experience and introduce the most progressive ideas into the native education system. The higher educational establishments giving eminently qualified jazz education are represented. The peculiarities of studying at the specialised music educational establishments as Berklee College of Music and the New England Conservatory have been considered. It has been found out that jazz education in the USA can be obtained not only at the specialised music educational establishments, but also at the Department of Music in the universities. The special emphasis is laid upon the musicians-teachers, who were at the cradle of jazz education and contributed a lot to jazz education development.
Intrinsic Voltage Dependence of the Epithelial Na+ Channel Is Masked by a Conserved Transmembrane Domain Tryptophan*

Tryptophan residues critical to function are frequently located at the lipid-water interface of transmembrane domains. All members of the epithelial Na+ channel (ENaC)/Degenerin (Deg) channel superfamily contain an absolutely conserved Trp at the base of their first transmembrane domain. Here, we test the importance of this conserved Trp to ENaC/Deg function. Targeted substitution of this Trp in mouse ENaC and rat ASIC subunits decrease channel activity. Differential substitution with distinct amino acids in α-mENaC shows that it is loss of this critical Trp rather than introduction of residues having novel properties that changes channel activity. Surprisingly, Trp substitution unmasks voltage sensitivity. Mutant ENaC has increased steady-state activity at hyperpolarizing compared with depolarizing potentials associated with transient activation and deactivation times, respectively. The times of activation and deactivation change 1 ms/mV in a linear manner with rising and decreasing slopes, respectively. Increases in macroscopic currents at hyperpolarizing potentials results from a voltage-dependent increase in open probability. Voltage sensitivity is not influenced by divalent cations; however, it is Na+-dependent with a 63-mV decrease in voltage required to reach half-maximal activity per log increase in [Na+]. Mutant channels are particularly sensitive to intracellular [Na+] for removing this sodium abolishes voltage dependence. We conclude that the conserved Trp at the base of TM1 in ENaC/Deg channels protects against voltage by masking an inhibitory allosteric or pore block mechanism, which decreases activity in response to intracellular Na+.
Activation of mGlu receptors induces LTD without affecting postsynaptic sensitivity of CA1 neurons in rat hippocampal slices

Two forms of long‐term depression (LTD) of excitatory synaptic transmission have been identified in the mammalian CNS, which are induced by the synaptic activation of N‐methyl‐d‐aspartate (NMDA) and metabotropic glutamate (mGlu) receptors, respectively. The mGlu receptor‐dependent form of LTD can be activated by application of 3,5‐dihydroxyphenylglycine (DHPG), a group I selective mGlu receptor agonist. DHPG‐induced LTD is increasingly being used to investigate the mechanisms of mGlu receptor‐dependent LTD. However, recent experiments have argued for both a pre‐ and postsynaptic locus of expression of DHPG‐induced LTD. In the present study we report that DHPG‐induced LTD is not associated with changes in the sensitivity of CA1 neurons to bath applied AMPA. Furthermore, in contrast to homosynaptic LTD, DHPG‐induced LTD is also not associated with changes in sensitivity to focally uncaged l‐glutamate. These data do not support the notion that DHPG‐induced LTD requires a modification of AMPA receptors, such as their internalisation, but are compatible with a presynaptic mechanism of expression.
Protein kinase Cbeta mediates hepatic induction of sterol-regulatory element binding protein-1c by insulin

Sterol-regulatory element binding protein-1c (SREBP-1c) is a transcription factor that controls lipogenesis in the liver. Hepatic SREBP-1c is nutritionally regulated, and its sustained activation causes hepatic steatosis and insulin resistance. Although regulation of SREBP-1c is known to occur at the transcriptional level, the precise mechanism by which insulin signaling activates SREBP-1c promoter remains to be elucidated. Here we show that protein kinase C beta (PKCbeta) is a key mediator of insulin-mediated activation of hepatic SREBP-1c and its target lipogenic genes. Activation of SREBP-1c in the liver of refed mice was suppressed by either adenoviral RNAi-mediated knockdown or dietary administration of a specific inhibitor of protein kinase C beta. The effect of PKCbeta inhibition was cancelled in insulin depletion by streptozotocin (STZ) treatment of mice. Promoter analysis indicated that PKCbeta activates SREBP-1c promoter through replacement of Sp3 by Sp1 for binding to the GC box in the sterol regulatory element (SRE) complex, a key cis-element of SREBP-1c promoter. Knockdown of Sp proteins demonstrated that Sp3 and Sp1 play reciprocally negative and positive roles in nutritional regulation of SREBP-1c, respectively. This new understanding of PKCbeta involvement in nutritional regulation of SREBP-1c activation provides a new aspect of PKCbeta inhibition as a potential therapeutic target for diabetic complications.
Cloning and characterization of NM23-Bbt2 gene from amphioxus Branchiostoma belcheri tsingtauense

A full-length amphioxus (Branchiostoma belcheri tsingtauense) NM23-Bbt2, NM23-H2 homologue, cDNA was isolated from the cDNA library and sequenced. The obtained amphioxus NM23-Bbt2 cDNA contains an open reading frame coding for 171 amino acids. Sequence analysis showed that the amphioxus NM23-Bbt2 was highly conserved with that of other species, and all of them contained highly conserved motifs that play important roles in the function of NM23. RT-PCR revealed that NM23-Bbt2 is expressed in the neuronal tissues and is expressed in all stages during the embryogenesis. Nucleoside kinases are thought to have a critical role in regulatory processes such as signal transduction, proliferation, and differentiation. Taken together, these results suggest that nucleoside diphosphate kinases have an important role to play in embryogenic development in amphioxus. Phylogenetic analysis showed that the amphioxus group 1 NDPKs (Bf1-4) may be precursors of the human group 1 NDPKs, NM23-Bf5, NM23-Bf6, NM23-Bf7 and NM23-Bf8 may be precursors of NM23-H5, NM23-H6, NM23-H7 and M23-H8, respectively. Our finding of nine NM23 genes in Branchiostoma floride, the precursor of vertebrates, strongly suggests that the ancestral gene corresponding to each of vertebrates NM23 genes generated before the appearance of vertebrates. Comparison of the gene structures of NM23-H2 homologue from invertebrates to vertebrates suggests that the locations of three of the four introns are conserved in amphioxus and vertebrates.
BMPs direct sensory interneuron identity in the developing spinal cord using signal-specific not morphogenic activities

The Bone Morphogenetic Protein (BMP) family reiteratively signals to direct disparate cellular fates throughout embryogenesis. In the developing dorsal spinal cord, multiple BMPs are required to specify sensory interneurons (INs). Previous studies suggested that the BMPs act as concentration-dependent morphogens to direct IN identity, analogous to the manner in which sonic hedgehog patterns the ventral spinal cord. However, it remains unresolved how multiple BMPs would cooperate to establish a unified morphogen gradient. Our studies support an alternative model: BMPs have signal-specific activities directing particular IN fates. Using chicken and mouse models, we show that the identity, not concentration, of the BMP ligand directs distinct dorsal identities. Individual BMPs promote progenitor patterning or neuronal differentiation by their activation of different type I BMP receptors and distinct modulations of the cell cycle. Together, this study shows that a ‘mix and match’ code of BMP signaling results in distinct classes of sensory INs.
Application and Clinical Utility of the Glasgow Coma Scale Over Time: A Study Employing the NIDRR Traumatic Brain Injury Model Systems Database

Objective:To examine possible changes in Glasgow Coma Scale (GCS) scores related to changes in emergency management, such as intubation and chemical paralysis, and the potential impact on outcome prediction. Participants:10 228 patients from the Traumatic Brain Injury Model Systems national database. Design:Retrospective study examining 5-year epochs from 1987 to 2012. Main Measures:GCS score assessed in the Emergency Department (GCS scores for intubated, but not paralyzed, patients were estimated with a formula using 2 of the 3 GCS components), Outcome: Functional Independence Measure (FIM) assessed at rehabilitation admission. Results:The rate of intubation prior to GCS scoring averaged 43% and did not increase across time. However, a clear increase over time was observed in the use of paralytics or heavy sedatives, with 27% of patients receiving this intervention in the most recent epoch. Estimated GCS scores classified 69% of intubated patients as severely brain injured and 8% as mildly injured. The GCS accounted for a modest, yet consistent, amount of variability (approximately 5%-7%) in FIM scores during most epochs. Conclusions:Given the frequency of intubation and/or paralysis following brain injury in this sample, estimating GCS or exploring other means to gauge injury severity is beneficial, particularly because a portion likely did not sustain severe brain injury. There is no evidence for declining predictive utility of the GCS over time.
New iodo‐acetamido cyanines for labeling cysteine thiol residues. A strategy for evaluating plasma proteins and their oxido‐redox status

Two new iodoacetamide‐substituted cyanines, C3NIASO3 and C5NIASO3, were synthesized starting from hemicyanine and were utilized for labeling plasma proteins. Specificity, sensitivity and feasibility for SH residues was tested utilizing an equimolar mixture of standard proteins and with normal plasma. Oxidized plasma proteins following H2O2 exposure and plasma from patients with focal glomerulosclerosis were analyzed as models of altered protein oxido‐redox status. Following optimization of the assay (dye/protein ratio, pH), C3NIASO3 and C5NIASO3 gave a sensitivity slightly better than N‐hydroxysuccinimidyl dyes for plasma proteins and were successfully employed for differential display electrophoresis (DIGE). Twenty‐nine proteins were detected in normal plasma after 2‐DE while less proteins were detected in plasma of patients with glomerulosclerosis. Following massive ‘in vitro' oxidation with H2O2, C3NIASO3 and C5NIASO3 failed to detect any residual SH, implicating massive oxidation. In conclusion, this study describes the synthesis of two new iodoacetamide cyanines that can be utilized for the analysis of plasma proteins with 2‐DE and DIGE. They are also indicated for the definition of the oxido‐redox status of proteins and were successfully utilized to extend the analysis of oxidation damage in patients with glomerulosclerosis.
A Review of TeV Scale Lepton-Hadron and Photon-Hadron Colliders

The investigation of lepton-hadron and photon-hadron collisions at TeV scale is crucial both to clarify the strong interaction dynamics from nuclei to quark-parton level and for adequate interpretation of experimental data from future hadron colliders (LHC and VLHC). In this presentation different TeV scale lepton-hadron and photon-hadron collider proposals (such as THERA, “LEP”-LHC, QCD Explorer etc) are discussed. The advantages of linac-ring type colliders has been shown comparatively.
Influence of Age on the Selenium Status in Belgium and The Netherlands

ABSTRACT. Plasma selenium concentration and glutathione peroxidase activity in red blood cells were determined in subjects from different age groups. The selenium level (mean ± SD) found in infancy (0 to 6 months) was 2 ± 0.6 /μg/dl, with the lowest value of 1 /μg/dl observed in a 4- month-old infant. These levels were significantly lower (p<0.001) than the value of 9.5 ± 1.1 /μg/dl found in the adult group and 7.7 ± 1.3 μg/dl found in the group of older children (2 to 15 yr). Younger children (6 to 24 months of age) had intermediate levels of 5 ± 1.2 /μg/dl. When the data were plotted on a logarithmic scale as a function of age, the figure shows clearly that the plasma selenium levels increase steadily with age throughout life after an initial drop at 60 to 90 days. There was a satisfactory correlation between the plasma selenium concentration and the enzyme glutathione peroxidase activity in the red blood cells (Spearman's ρ=0.45, p<0.005). Although very low selenium values were observed, the enzyme glutathione peroxidase activity remained above 10 U/g hemoglobin (with only one exception) in all patients.
Chronic sequelae of E. coli O157: systematic review and meta-analysis of the proportion of E. coli O157 cases that develop chronic sequelae.

OBJECTIVE This was a systematic review and meta-analysis to determine the proportion of Escherichia coli O157 cases that develop chronic sequelae. DATA SOURCES We conducted a systematic review of articles published prior to July 2011 in Pubmed, Agricola, CabDirect, or Food Safety and Technology Abstracts. STUDY SELECTION Studies were selected that reported the number of E. coli O157 cases that developed reactive arthritis (ReA), hemolytic uremic syndrome (HUS), irritable bowel syndrome, inflammatory bowel disease, or Guillain Barré syndrome. METHODS Three levels of screening and data extraction of articles were conducted using predefined data fields. Meta-analysis was performed on unique outcome measures using a random-effects model, and heterogeneity was assessed using the I² value. Meta-regression was used to explore the influence of nine study-level variables on heterogeneity. RESULTS A total of 82 studies were identified reporting 141 different outcome measures; 81 reported on HUS and one reported on ReA. Depending on the number of cases of E. coli O157, the estimate for the proportion of E. coli O157 cases that develop HUS ranged from 17.2% in extra-small studies (<50 cases) to 4.2% in extra-large studies (>1000 cases). Heterogeneity was significantly associated with group size (p<0.0001); however, the majority of the heterogeneity was unexplained. CONCLUSIONS High unexplained heterogeneity indicated that the study-level factors examined had a minimal influence on the variation of estimates reported.
Identification of a Palmitic Acid-modified Form of Human Sonic hedgehog*

During hedgehog biosynthesis, autocatalytic processing produces a lipid-modified amino-terminal fragment (residues 24–197 in the human Sonic hedgehog sequence) that is responsible for all known hedgehog signaling activity and that is highly conserved evolutionarily. Published in vitro biochemical studies using Drosophila hedgehog identified the membrane anchor as a cholesterol, and localized the site of attachment to the COOH terminus of the fragment. We have expressed full-length human Sonic hedgehog in insect and in mammalian cells and determined by mass spectrometry that, in addition to cholesterol, the human hedgehog protein is palmitoylated. Peptide mapping and sequencing data indicate that the palmitoyl group is attached to the NH2 terminus of the protein on the α-amino group of Cys-24. Cell-free palmitoylation studies demonstrate that radioactive palmitic acid is readily incorporated into wild type Sonic hedgehog, but not into variant forms lacking the Cys-24 attachment site. The lipid-tethered forms of hedgehog showed about a 30-fold increase in potency over unmodified soluble hedgehog in a cell- based (C3H10T1/2 alkaline phosphatase induction) assay, suggesting that the lipid tether plays an important role in hedgehog function. The observation that an extracellular protein such as Shh is palmitoylated is highly unusual and further adds to the complex nature of this protein.
Cell sources for in vitro human liver cell culture models

In vitro liver cell culture models are gaining increasing importance in pharmacological and toxicological research. The source of cells used is critical for the relevance and the predictive value of such models. Primary human hepatocytes (PHH) are currently considered to be the gold standard for hepatic in vitro culture models, since they directly reflect the specific metabolism and functionality of the human liver; however, the scarcity and difficult logistics of PHH have driven researchers to explore alternative cell sources, including liver cell lines and pluripotent stem cells. Liver cell lines generated from hepatomas or by genetic manipulation are widely used due to their good availability, but they are generally altered in certain metabolic functions. For the past few years, adult and pluripotent stem cells have been attracting increasing attention, due their ability to proliferate and to differentiate into hepatocyte-like cells in vitro. However, controlling the differentiation of these cells is still a challenge. This review gives an overview of the major human cell sources under investigation for in vitro liver cell culture models, including primary human liver cells, liver cell lines, and stem cells. The promises and challenges of different cell types are discussed with a focus on the complex 2D and 3D culture approaches under investigation for improving liver cell functionality in vitro. Finally, the specific application options of individual cell sources in pharmacological research or disease modeling are described.