bluuebunny/crossref_metadata_2025_split huggingface dataset:
Supported liquid extraction and LC–MS-MS determination of iloperidone and olanzapine in rat plasma: Application to a pharmacokinetic study
Authors: Gangu Naidu Ch , Nageswara Rao R , Prasada Rao A V , Nagesh Kumar K , Padiya Raju , Madhusudhan Rao V 
Published: June 2018

AbstractA sensitive, selective rapid bioanalytical assay method was developed and quantification of iloperidone (ILP) and olanzapine (OLZ) in rat plasma was done by mass spectrometry. Systematic sample preparation and extraction procedure were carried out by supported liquid extraction using dichloromethane to extract both the eluents (ILP and OLZ) from rat plasma samples. The extorted samples were injected on a selective Waters XTerra® C18 reverse-phase bonded column (250 × 4.6 mm i.d., 5 μm) using acetonitrile and 15 mM ammonium formate containing 0.05% trifluoroacetic acid (60:40 v/v) for isocratic elution mode and detected by mass spectrometry. Calibration curves were drawn with the respective assay statistical data and showed linear regression coefficients greater than 0.9996 over the concentration ranges 2–5,000 ng/mL for ILP and OLZ, respectively. The absolute mean recoveries were found to be in the replicate range of 87.12–94.47%, respectively. The obtained results by the method revealed good intra and interday assay performance in terms of 1.70–5.90% precision and 0–5% accuracy. The validated bioassay method has been successfully applied to the pharmacokinetics in rats.
Multiplicity-freeness of Unitary Representations in Sections of Holomorphic Hilbert Bundles
Authors: Miglioli Martín , Neeb Karl-Hermann 
Published: June 2018

Abstract
We prove several results asserting that the action of a Banach–Lie group on Hilbert spaces of holomorphic sections of a holomorphic Hilbert space bundle over a complex Banach manifold is multiplicity-free. These results require the existence of compatible anti-holomorphic bundle maps and certain multiplicity-freeness assumptions for stabilizer groups. For the group action on the base, the notion of an $(S,\sigma )$-weakly visible action (generalizing T. Koboyashi’s visible actions) provides an effective way to express the assumptions in an economical fashion. In particular, we derive a version for group actions on homogeneous bundles for larger groups. We illustrate these general results by several examples related to operator groups and von Neumann algebras.
Quantifying Codon Usage in Signal Peptides: Gene Expression and Amino Acid Usage Explain Apparent Selection for Inefficient Codons
Authors: Cope Alexander L. , Hettich Robert L. , Gilchrist Michael A. 
Published: June 2018

AbstractThe Sec secretion pathway is found across all domains of life. A critical feature of Sec secreted proteins is the signal peptide, a short peptide with distinct physicochemical properties located at the N-terminus of the protein. Previous work indicates signal peptides are biased towards translationally inefficient codons, which is hypothesized to be an adaptation driven by selection to improve the efficacy and efficiency of the protein secretion mechanisms. We investigate codon usage in the signal peptides ofE. coliusing the Codon Adaptation Index (CAI), the tRNA Adaptation Index (tAI), and the ribosomal overhead cost formulation of the stochastic evolutionary model of protein production rates (ROC-SEMPPR). Comparisons between signal peptides and 5’-end of cytoplasmic proteins using CAI and tAI are consistent with a preference for inefficient codons in signal peptides. Simulations reveal these differences are due to amino acid usage and gene expression - we find these differences disappear when accounting for both factors. In contrast, ROC-SEMPPR, a mechanistic population genetics model capable of separating the effects of selection and mutation bias, shows codon usage bias (CUB) of the signal peptides is indistinguishable from the 5’-ends of cytoplasmic proteins. Additionally, we find CUB at the 5’-ends is weaker than later segments of the gene. Results illustrate the value in using models grounded in population genetics to interpret genetic data. We show failure to account for mutation bias and the effects of gene expression on the efficacy of selection against translation inefficiency can lead to a misinterpretation of codon usage patterns.
Cell Cycle, Energy Metabolism and DNA Repair Pathways in Cancer Cells are Suppressed by Compound Kushen Injection
Authors: Cui Jian , Qu Zhipeng , Harata-Lee Yuka , Nwe Aung Thazin , Shen Hanyuan , Wang Wei , L Adelson David 
Published: June 2018

AbstractIn this report we examine candidate pathways perturbed by Compound Kushen Injection (CKI) a Traditional Chinese Medicine (TCM) that we have previously shown to alter the gene expression patterns of multiple pathways and induce apoptosis in cancer cells. We have measured protein levels in HEPG2 and MDA-MB-231 cells for genes in the cell cycle pathway, DNA repair pathway and DNA double strand breaks (DSBs) previously shown to have altered expression by CKI. We have also examined energy metabolism by measuring [ADT]/[ATP] ratio (cell energy charge), lactate production and glucose consumption. Our results demonstrate that CKI can suppress protein levels for cell cycle regulatory proteins and DNA repair while increasing the level of DSBs. We also show that energy metabolism is reduced based on reduced glucose consumption and reduced cellular energy charge. Our results validate these pathways as important targets for CKI. We also examined the effect of the major alkaloid component of CKI, oxymatrine and determined that it had no effect on DSBs, a small effect on the cell cycle and increased the cell energy charge. Our results indicate that CKI likely acts through the effect of multiple compounds on multiple targets where the observed phenotype is the integration of these effects and synergistic interactions.
A fat-tissue sensor couples growth to oxygen availability by remotely controlling insulin secretion
Authors: Texada Michael J. , Joergensen Anne F. , Christensen Christian F. , Smith Daniel K. , Marple Dylan F.M. , Thomas Danielsen E. , Petersen Sine K. , Hansen Jakob L. , Halberg Kenneth A. , Rewitz Kim F. 
Published: June 2018

AbstractOrganisms adapt their metabolism and growth to the availability of nutrients and oxygen, which are essential for normal development. This requires the ability to sense these environmental factors and respond by regulation of growth-controlling signals, yet the mechanisms by which this adaptation occurs are not fully understood. To identify novel growth-regulatory mechanisms, we conducted a global RNAi-based screen in Drosophila for size differences and identified 89 positive and negative regulators of growth. Among the strongest hits was the FGFR homologue breathless necessary for proper development of the tracheal airway system. Breathless deficiency results in tissue hypoxia (low oxygen), sensed primarily in this context by the fat tissue. The fat, in response, relays this information through release of one or more humoral factors that remotely inhibit insulin secretion from the brain, thereby restricting systemic growth. Thus our findings show that the fat tissue acts as an oxygen sensor that allows the organism to reduce its growth in adaptation to limited oxygen conditions.
Altering the temporal regulation of one transcription factor drives sensory trade-offs
Authors: Ramaekers Ariane , Weinberger Simon , Claeys Annelies , Kapun Martin , Yan Jiekun , Wolf Reinhard , Flatt Thomas , Buchner Erich , Hassan Bassem A. 
Published: June 2018

SUMMARYSize trade-offs of visual versus olfactory organs is a pervasive feature of animal evolution. ComparingDrosophilaspecies, we find that larger eyes correlate with smaller antennae, where olfactory organs reside, and narrower faces. We demonstrate that this tradeoff arises through differential subdivision of the head primordium into visual versus non-visual fields. Specification of the visual field requires a highly-conserved eye development gene calledeyelessin flies and Pax6 in humans. We discover that changes in the temporal regulation ofeyelessexpression during development is a conserved mechanism for sensory trade-offs within and betweenDrosophilaspecies. We identify a natural single nucleotide polymorphism in the cis-regulatory region ofeyelessthat is sufficient to alter its temporal regulation and eye size. Because Pax6 is a conserved regulator of sensory placode subdivision, we propose that alterations in the mutual repression between sensory territories is a conserved mechanism for sensory trade-offs in animals.
C. elegansgenetic background modifies the core transcriptional response in an α-synuclein model of Parkinson’s disease
Authors: Wang Yiru A. , Snoek Basten L. , Sterken Mark G. , Riksen Joost A.G. , Stastna Jana J. , Kammenga Jan E. , Harvey Simon C. 
Published: June 2018

AbstractAccumulation of protein aggregates is a major cause of Parkinson’s disease (PD), a progressive neurodegenerative condition that is one of the most common causes of dementia. TransgenicCaenorhabditis elegansworms expressing the human synaptic protein α-synuclein show inclusions of aggregated protein and replicate the defining pathological hallmarks of PD. It is however not known how PD progression and pathology differs among individual genetic backgrounds. Here, we compared gene expression patterns, and investigated the phenotypic consequences of transgenic α-synuclein expression in five differentC. elegansgenetic backgrounds. Transcriptome analysis indicates that the effects of -synuclein expression on pathways associated with nutrient storage, lipid transportation and ion exchange depend on the genetic background. The gene expression changes we observe suggest that a range of phenotypes will be affected by α-synuclein expression. We experimentally confirm this, showing that the transgenic lines generally show delayed development, reduced lifespan, and an increased rate of matricidal hatching. These phenotypic effects coincide with the core changes in gene expression, linking developmental arrest, mobility, metabolic and cellular repair mechanisms to α-synuclein expression. Together, our results show both genotype-specific effects and core alterations in global gene expression and in phenotype in response to -synuclein. We conclude that the PD effects are substantially modified by the genetic background, illustrating that genetic background mechanisms should be elucidated to understand individual variation in PD.
Neural gain control measured through cortical gamma oscillations is associated with individual variations in sensory sensitivity
Authors: Orekhova EV , Stroganova TA , Schneiderman JF , Lundström S , Riaz B , Sarovic D , Sysoeva OV , Gillberg C , Hadjikhani N 
Published: June 2018

AbstractGamma oscillations facilitate information processing by shaping the excitatory input/output of neuronal populations, and their suppression by strong excitatory drive may stem from inhibitory-based gain control of network excitation. Individual variations in the gamma suppression may therefore reflect efficiency of gain control and subjective sensitivity to everyday sensory events. To test this prediction, we assessed the link between self-reported sensory sensitivity and changes in magneto-encephalographic gamma oscillations as a function of motion velocity of high-contrast visual gratings. The induced gamma oscillations increased in frequency and decreased in power with increasing stimulation intensity. As expected, weaker suppression of the gamma response correlated with sensory hypersensitivity. Robustness of this result was confirmed by its replication in the two samples: neurotypical subjects and people with autism, who had generally higher sensory sensitivity. We conclude that intensity-related suppression of gamma response is a promising biomarker of homeostatic control of the excitation-inhibition balance in the visual cortex.
Palbociclib and fulvestrant act in synergy to modulate central carbon metabolism in breast cancer cells
Authors: Warth Benedikt , Palermo Amelia , Rattray Nicholas J.W. , Lee Nathan V , Zhu Zhou , Hoang Linh T. , Mazurek Anthony , Dann Stephen , VanArsdale Todd , Fantin Valeria , Shields David , Siuzdak Gary , Johnson Caroline H. 
Published: June 2018

SummaryPalbociclib, is a selective inhibitor of cyclin-dependent kinases 4 and 6 and used as a first-line treatment for patients with estrogen receptor positive breast cancer. It has been shown that patients have improved progression-free survival when treated in combination with fulvestrant, an estrogen receptor antagonist. However, the mechanisms for this survival advantage are not known. We sought to analyze metabolic and transcriptomic changes in MCF-7 adenocarcinoma breast cancer cells following single and combined treatments to determine if selective metabolic pathways are targeted during combination therapy. Our results showed that individually, the drugs caused metabolic disruption to the same metabolic pathways, however fulvestrant additionally attenuated the pentose phosphate pathway and the production of important coenzymes. A comprehensive effect was observed when the drugs were applied together, confirming the combinatory therapy′s synergism in the cell model. This study highlights the power of merging high-dimensional datasets to unravel mechanisms involved in cancer metabolism and therapy.Highlights○First study employing multi-omics to investigate combined therapy on breast cancer cells○Fulvestrant attenuates the pentose phosphate pathway and coenzyme production○Synergism of palbociclib and fulvestrant was confirmed in vitro○Altered key pathways have been identifiedeTOC BlurbJohnson et al. applied an innovative multi-omics approach to decipher metabolic pathways affected by single versus combination dosing of palbociclib and fulvestrant in estrogen receptor positive breast cancer. Key metabolites and genes were correlated within metabolic pathways and shown to be involved in the drugs′ synergism.
Nitrative signaling into cardiac lactate dehydrogenase Trp324 modulates active site loop mobility and activity under metabolic stress
Authors: Nogales Cristian , Frijhoff Jeroen , Thoenges Detlef , Sessions Richard B. , Sickmann Albert , Nedvetskaya Tatiana , Ibarra-Alvarado Cesar , Schmitz Vera , Rösen Peter , Goedecke Axel , Jovanović Aleksandar , Perlman David H. , Klinke Anna , Baldus Stephan , Casas Ana I. , Bai Péter , Szabo Csaba , Feelisch Martin , Schmidt Harald H.H.W. 
Published: June 2018

AbstractProtein tyrosine nitration is a hallmark of oxidative stress related disease states, commonly detected as anti-nitrotyrosine immunoreactivity. The precise reactive oxygen sources, mechanisms of nitration as well as the modified target proteins and functional consequences, however, remain often unclear. Here we explore protein tyrosine nitration under basal conditions and find surprisingly physiologically nitrated proteins. Upon purifying a prominent physiologically nitrotyrosine immunopositive in hearts from mouse, rat and pig, we identify it as lactate dehydrogenase (LDH). Mechanistically, LDH’s degree of basal nitration depended on two canonical sources, NO synthase (NOS) and myeloperoxidase (MPO), respectively. When validating the nitrated amino acid by MALDI-TOF mass spectrometry, we, surprisingly, located LDH nitration not to a tyrosine but the C-terminal tryptophan, Trp324. Molecular dynamics simulations suggested that Trp324 nitration restricts the interaction of the active site loop with the C-terminal α-helix essential for activity. This prediction was confirmed by enzyme kinetics revealing an apparent lower Vmax of nitrated LDH, although yet unidentified concurrent oxidative modifications may contribute. Protein nitration is, thus, not a by definition disease marker but reflects also physiological signaling by eNOS/NO, MPO/nitrite and possibly other pathways. The commonly used assay of anti-nitrotyrosine immunoreactivity is apparently cross-reactive to nitrotryptophan requiring a reevaluation of the protein nitration literature. In the case of LDH, nitration of Trp324 is aggravated under cardiac metabolic stress conditions and functionally limits maximal enzyme activity. Trp324-nitrated LDH may serve both as a previously not recognized disease biomarker and possibly mechanistic lead to understand the metabolic changes under these conditions.
Notch3 Promotes Prostate Cancer-Induced Bone Lesion Development via MMP-3
Authors: Ganguly Sourik S. , Hostetter Galen , Tang Lin , Frank Sander B. , Saboda Kathylynn , Mehra Rohit , Wang Lisha , Li Xiaohong , Keller Evan T. , Miranti Cindy K. 
Published: June 2018

ABSTRACTProstate cancer metastases primarily localize in the bone where they induce a unique osteoblastic response. Elevated Notch activity is associated with high-grade disease and metastasis. To address how Notch affects prostate cancer bone lesions, we manipulated Notch expression in mouse tibia xenografts and monitored tumor growth, lesion phenotype, and the bone microenvironment. Prostate cancer cell lines that induce mixed osteoblastic lesions in bone expressed 5-6 times more Notch3, than tumor cells that produce osteolytic lesions. Expression of active Notch3 (NICD3) in osteolytic tumors reduced osteolytic lesion area and enhanced osteoblastogenesis, while loss of Notch3 in osteoblastic tumors enhanced osteolytic lesion area and decreased osteoblastogensis. This was accompanied by a respective decrease and increase in the number of active osteoclasts and osteoblasts at the tumor-bone interface, without any effect on tumor proliferation. Conditioned medium from NICD3-expressing cells enhanced osteoblast differentiation and proliferation in vitro, while simultaneously inhibiting osteoclastogenesis. MMP-3 was specifically elevated and secreted by NICD3-expressing tumors, and inhibition of MMP-3 rescued the NICD3-induced osteoblastic phenotypes. Clinical osteoblastic bone metastasis samples had higher levels of Notch3 and MMP-3 compared to patient matched visceral metastases or osteolytic metastasis samples. We identified a Notch3-MMP-3 axis in human prostate cancer bone metastases that contributes to osteoblastic lesion formation by blocking osteoclast differentiation, while also contributing to osteoblastogenesis. These studies define a new role for Notch3 in manipulating the tumor microenvironment in bone metastases.
Losing maternal care: Neotenic gene expression in the preoptic area of avian brood parasites
Authors: Lynch Kathleen S. , O’Connell Lauren A. , Louder Matthew I. M. , Pellicano Anthony , Gaglio Annmarie , Xiang Angell , Balakrishnan Christopher N. , Fischer Eva K. 
Published: June 2018

AbstractParental care for is critical for offspring survival in many species. However, parental behaviors have been lost in roughly 1% of avian species known as the obligate brood parasites. To shed light on molecular and neurobiological mechanisms mediating brood parasitic behavior, brain gene expression patterns between two brood parasitic species and one closely related non-parasitic Icterid (blackbird) species were compared. Our analyses focused on gene expression changes specifically in the preoptic area (POA), a brain region known to play a critical role in maternal behavior across vertebrates. Using comparative transcriptomic approaches, we identified gene expression patterns associated with brood parasitism and evaluated two alternative explanations for the evolution of brood parasitism: reduced expression of parental-related genes in the POA versus retention of juvenile (neotenic) gene expression. While we did not find evidence for large scale gene downregulation, expression patterns did reflect substantial evidence for neotenic POA gene expression in parasitic birds. Differentially expressed genes with previously established roles in parental care were identified. Targeted examination of these selected candidate genes in additional hypothalamic regions revealed species differences in gene expression patterns is not POA-specific. Together, these results provide new insights into neurogenomics underlying maternal behavior loss in avian brood parasites.
Relationships between meconium concentrations of acute phase proteins
Authors: Lisowska‐Myjak Barbara , Skarżyńska Ewa , Płazińska Maria , Jakimiuk Artur 
Published: June 2018

SummaryMeconium concentrations of naturally accumulated ceruloplasmin (CER), lactoferrin (LF), and neutrophil gelatinase‐associated lipocalin (NGAL) and their relationships considered as a panel of acute phase proteins could be used for the assessment of fetal homeostasis. CER, LF and NGAL concentrations were measured using enzyme‐linked immunosorbent assay kits in meconium portions (n = 80) collected from 19 healthy neonates. The coefficients of variation (CV) of the meconium LF (1.77) and NGAL (1.26) were about two‐fold higher than that of CER (0.73) with significant (P < 0.05) correlations between all three parameters. The LF to NGAL ratio (CV = 0.67) correlated strongly with the CER concentrations (r = 0.39, P < 0.01). These correlations between CER, LF and NGAL concentrations suggest their combined involvement in the metabolic processes in the developing fetus.
Total flucloxacillin plasma concentrations poorly reflect unbound concentrations in hospitalized patients with Staphylococcus aureus bacteraemia
Authors: Chin Paul Ken Leong , Drennan Philip George , Gardiner Sharon Jane , Zhang Mei , Dalton Simon Charles , Chambers Stephen Thomas , Begg Evan James 
Published: June 2018

AimsFlucloxacillin dosing may be guided by measurement of its total plasma concentrations. Flucloxacillin is highly protein bound with fraction unbound in plasma (fu) of around 0.04 in healthy individuals. The utility of measuring unbound flucloxacillin concentrations for patients outside the intensive care unit (ICU) is not established. We aimed to compare flucloxacillin fu in non‐ICU hospitalised patients against healthy volunteers, and to examine the performance of a published model for predicting unbound concentrations, using total flucloxacillin and plasma albumin concentrations.MethodsData from 12 healthy volunteers (248 samples) and 47 hospitalized patients (61 samples) were examined. Plasma flucloxacillin concentrations were measured using a validated liquid chromatography–tandem mass spectrometry method. Flucloxacillin fu for the two groups was compared using a generalized estimating equation model to account for clustered observations. The performance of the single protein binding site prediction model in hospitalized patients was compared with measured unbound concentrations using Bland–Altman plots.ResultsThe median (range) flucloxacillin fu for healthy (median albumin 45 g l–1) and hospitalized individuals (median albumin 30 g l–1) were 0.04 (0.02–0.07) and 0.10 (0.05–0.37), respectively (P < 0.0001). The prediction model underpredicted unbound flucloxacillin concentrations with a mean bias (95% limits of agreement) of –54% (–137%, +30%).ConclusionsThe flucloxacillin fu values observed in our cohort of hospitalized patients had a wide range and were greater than those of healthy individuals. Unbound flucloxacillin plasma concentrations were predicted poorly by the model. Instead, unbound concentrations should be measured to guide dosing.