bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inborn errors of coenzyme A metabolism and neurodegeneration
Authors: Di Meo Ivano , Carecchio Miryam , Tiranti Valeria 
Published: February 2019

AbstractTwo inborn errors of coenzyme A (CoA) metabolism are responsible for distinct forms of neurodegeneration with brain iron accumulation (NBIA), a heterogeneous group of neurodegenerative diseases having as a common denominator iron accumulation mainly in the inner portion of globus pallidus. Pantothenate kinase‐associated neurodegeneration (PKAN), an autosomal recessive disorder with progressive impairment of movement, vision and cognition, is the most common form of NBIA and is caused by mutations in the pantothenate kinase 2 gene (PANK2), coding for a mitochondrial enzyme, which phosphorylates vitamin B5 in the first reaction of the CoA biosynthetic pathway. Another very rare but similar disorder, denominated CoPAN, is caused by mutations in coenzyme A synthase gene (COASY) coding for a bi‐functional mitochondrial enzyme, which catalyzes the final steps of CoA biosynthesis. It still remains a mystery why dysfunctions in CoA synthesis lead to neurodegeneration and iron accumulation in specific brain regions, but it is now evident that CoA metabolism plays a crucial role in the normal functioning and metabolism of the nervous system.
The decision to discontinue screening for carnitine uptake disorder in New Zealand
Authors: Wilson Callum , Knoll Detlef , de Hora Mark , Kyle Campbell , Glamuzina Emma , Webster Dianne 
Published: February 2019

AbstractWhen screening for carnitine uptake disorder (CUD), the New Zealand (NZ) newborn screening (NBS) service identified infants as screen‐positive if they had initial and repeat free carnitine (C0) levels of less than 5.0 μmol/L. Since 2006, the NBS service has identified two infants with biochemical and genetic features consistent with neonatal CUD and nine mothers with features consistent with maternal CUD. A review of the literature suggests that these nine women reflect less than half the true prevalence and that CUD is relatively common. However, the NZ results (two infants) suggest a very low sensitivity and positive predictive value of NBS. While patients presenting with significant disease due to CUD are well described, the majority of adults with CUD are asymptomatic. Nonetheless, treatment with high‐dose oral L‐carnitine is recommended. Compliance with oral L‐carnitine is likely to be poor long term. This may represent a specific risk as treatment could repress the usual compensatory mechanisms seen in CUD, such that a sudden discontinuation of treatment may be dangerous. L‐carnitine is metabolized to trimethylamine‐N‐oxide (TMAO) and treated patients have extremely high plasma TMAO levels. TMAO is an independent risk factor for atherosclerosis and, thus, caution should be exercised regarding long‐term treatment with high‐dose carnitine of asymptomatic patients who may have a biochemical profile without disease. Due to these concerns, the NZ Newborn Metabolic Screening Programme (NMSP) initiated a review via a series of advisory and governance committees and decided to discontinue screening for CUD.
Patterns, evolution, and severity of striatal injury in insidious‐ vs acute‐onset glutaric aciduria type 1
Authors: Boy Nikolas , Garbade Sven F. , Heringer Jana , Seitz Angelika , Kölker Stefan , Harting Inga 
Published: February 2019

AbstractBackgroundStriatal injury in patients with glutaric aciduria type 1 (GA1) results in a complex, predominantly dystonic, movement disorder. Onset may be acute following acute encephalopathic crisis (AEC) or insidious without apparent acute event.MethodsWe analyzed clinical and striatal magnetic resonance imaging (MRI) findings in 21 symptomatic GA1 patients to investigate if insidious‐ and acute‐onset patients differed in timing, pattern of striatal injury, and outcome.ResultsEleven patients had acute and ten had insidious onset, two with later AEC (acute‐on‐insidious). The median onset of dystonia was 10 months in both groups, and severity was greater in patients after AEC (n = 8 severe, n = 5 moderate) than in insidious onset (n = 4 mild, n = 3 moderate, n = 1 severe). Deviations from guideline‐recommended basic metabolic treatment were identified in six insidious‐onset patients. Striatal lesions were extensive in all acute‐onset patients and restricted to the dorsolateral putamen in eight of ten insidious‐onset patients. After AEC, the two acute‐on‐insidious patients had extensive striatal changes superimposed on pre‐existing dorsolateral putaminal lesions. Two insidious‐onset patients with progressive dystonia without overt AEC also had extensive striatal changes, one with sequential striatal injury revealed by diffusion‐weighted imaging. Insidious‐onset patients had a latency phase of 3.5 months to 6.5 years between detection and clinical manifestation of dorsolateral putaminal lesions.ConclusionsInsidious‐onset type GA1 is characterized by dorsolateral putaminal lesions, less severe dystonia, and an asymptomatic latency phase, despite already existing lesions. Initially normal MRI during the first months and deviations from guideline‐recommended treatment in a large proportion of insidious‐onset patients substantiate the protective effect of neonatally initiated treatment.
Proposal for an individualized dietary strategy in patients with very long‐chain acyl‐CoA dehydrogenase deficiency
Authors: Bleeker Jeannette C. , Kok Irene L. , Ferdinandusse Sacha , de Vries Maaike , Derks Terry G.J. , Mulder Margot F. , Williams Monique , Gozalbo Estela Rubio , Bosch Annet M. , van den Hurk Dorine T. , de Sain‐van der Velden Monique G.M. , Waterham Hans R. , Wijburg Frits A. , Visser Gepke 
Published: February 2019

AbstractBackgroundPatients with very long chain acyl‐CoA dehydrogenase deficiency (VLCADD), a long chain fatty acid oxidation disorder, are traditionally treated with a long chain triglyceride (LCT) restricted and medium chain triglyceride (MCT) supplemented diet. Introduction of VLCADD in newborn screening (NBS) programs has led to the identification of asymptomatic newborns with VLCADD, who may have a more attenuated phenotype and may not need dietary adjustments.ObjectiveTo define dietary strategies for individuals with VLCADD based on the predicted phenotype.MethodWe evaluated long‐term dietary histories of a cohort of individuals diagnosed with VLCADD identified before the introduction of VLCADD in NBS and their beta‐oxidation (LC‐FAO) flux score (rate of oleate oxidation) in cultured skin fibroblasts in relation to the clinical outcome. Based on these results a dietary strategy is proposed.ResultsSixteen individuals with VLCADD were included. One had an LC‐FAO flux score >90%, was not on a restricted diet and is asymptomatic to date. Four patients had an LC‐FAO flux score <10%, and significant VLCADD related symptoms despite the use of strict diets including LCT restriction, MCT supplementation and nocturnal gastric drip feeding. Patients with an LC‐FAO flux score between 10 and 90% (n = 11) showed a more heterogeneous phenotype.ConclusionsThis study shows that a strict diet cannot prevent poor clinical outcome in severely affected patients and that the LC‐FAO flux is a good predictor of clinical outcome in individuals with VLCADD identified before its introduction in NBS. Hereby, we propose an individualized dietary strategy based on the LC‐FAO flux score.
Inhibiting PNP for the therapy of hyperuricemia in Lesch–Nyhan disease: Preliminary in vitro studies with analogues of immucillin‐G
Authors: Jacomelli Gabriella , Baldini Eva , Mugnaini Claudia , Micheli Vanna , Bernardini Giulia , Santucci Annalisa 
Published: February 2019

AbstractLesch‐Nyhan disease (LND) is a rare X‐linked genetic disorder, with complete hypoxanthine‐guanine phosphoribosyltransferase (HGPRT) deficiency, uric acid (UA), hypoxanthine and xanthine accumulation, and a devastating neurologic syndrome. UA excess, causing renal failure, is commonly decreased by xanthine oxidoreductase (XOR) inhibitors, such as allopurinol, yielding a xanthine and hypoxanthine increase. Xanthine accumulation may result in renal stones, while hypoxanthine excess seems involved in the neurological disorder. Inhibition of purine nucleoside phosphorylase (PNP) represents a different strategy for lowering urate. PNP catalyzes the cleavage of purine ribo‐ and d‐ribo‐nucleosides into ribose/deoxyribose phosphate and free bases, starting catabolism to uric acid. Clinical trials demonstrated that PNP inhibitors, initially developed as anticancer drugs, lowered UA in some gouty patients, in association or not with allopurinol. The present study tested the reliability of an analogue of immucillin‐G (C1a), a PNP inhibitor, as a therapy for urate, hypoxanthine, and xanthine excess in LND patients by blocking hypoxanthine production upstream. The therapeutic aim is to limit the administration of XOR inhibitors to LND patients by supplying the PNP inhibitor in low doses, avoiding d‐nucleoside toxicity. We report studies conducted in primary cultures of skin fibroblasts from controls and LND patients grown in the presence of the PNP inhibitor. Cell viability, oxypurine release in culture medium, and endocellular nucleotide pattern have been monitored in different growth conditions (inhibitor concentration, time, added inosine). Our results demonstrate effective PNP inhibition by low inhibitor concentration, with reduced hypoxanthine release, and no appreciable toxicity in control or patient cells, suggesting a new therapeutic strategy for LND hyperuricemia.
Mapping mononuclear phagocytes in blood, lungs, and lymph nodes of sarcoidosis patients
Authors: Lepzien Rico , Rankin Gregory , Pourazar Jamshid , Muala Ala , Eklund Anders , Grunewald Johan , Blomberg Anders , Smed-Sörensen Anna 
Published: February 2019

Abstract
Sarcoidosis is a T-cell driven inflammatory disease characterized by granuloma formation. Mononuclear phagocytes (MNPs)—macrophages, monocytes, and dendritic cells (DCs)—are likely critical in sarcoidosis as they initiate and maintain T cell activation and contribute to granuloma formation by cytokine production. Granulomas manifest primarily in lungs and lung-draining lymph nodes (LLNs) but these compartments are less studied compared to blood and bronchoalveolar lavage (BAL). Sarcoidosis can present with an acute onset (usually Löfgren’s syndrome (LS)) or a gradual onset (non-LS). LS patients typically recover within 2 years while 60% of non-LS patients maintain granulomas for up to 5 years. Here, four LS and seven non-LS patients underwent bronchoscopy with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). From each patient, blood, BAL, endobronchial biopsies (EBBs), and LLN samples obtained by EBUS-TBNA were collected and MNPs characterized using multicolor flow cytometry. Six MNP subsets were identified at varying frequencies in the anatomical compartments investigated. Importantly, monocytes and DCs were most mature with migratory potential in BAL and EBBs but not in the LLNs suggesting heterogeneity in MNPs in the compartments typically affected in sarcoidosis. Additionally, in LS patients, frequencies of DC subsets were lower or lacking in LLNs and EBBs, respectively, compared to non-LS patients that may be related to the disease outcome. Our work provides a foundation for future investigations of MNPs in sarcoidosis to identify immune profiles of patients at risk of developing severe disease with the aim to provide early treatment to slow down disease progression.
Fabrication of homogenous three‐dimensional biomimetic tissue for mass spectrometry imaging
Authors: Song Xiaowei , He Jiuming , Li Chao , Sun Chenglong , Pang Xuechao , Zhang Jin , Zang Qingce , Luo Zhigang , Li Xin , Zhang Ruiping , Abliz Zeper 
Published: February 2019

AbstractReference samples are essential for mass spectrometric method optimization, data quality control, and target analyte quantitation. However, it is highly challenging to prepare an ideal homogeneous, standard‐spiked tissue sample for mass spectrometry imaging (MSI) research. Herein, we present a standard‐spiked 3D biomimetic tissue model fabricated with native cells, homogenate matrix, and biocompatible polymer. Unlike traditional homogenized tissue surrogates or those constructed with “on‐tissue” or “under‐tissue” micropipetting strategies, this simulated tissue shares both structural integrity of cells and homogeneous properties of matrix. As a result, analyte standards could undergo more in‐depth incorporation and has a more comparable native status with a real tissue. Series of tissue sections made from the 3D tissue model were proven to be feasible and useful for the parameter optimization, analyte quantitation, and calibration curve fitting for the air‐flow assisted desorption electrospray ionization MSI. Additionally, by analyzing the quality control model sections, we proposed a median principal component score calibration and demonstrated that this method can normalize instrumental fluctuations to stable levels in a large‐scale untargeted MSI experiments for the reliable metabolomic biomarker discovery. Thus, these results indicated that the standard‐spiked 3D biomimetic tissue has convincing significance in MSI analysis
Evolutionary concept of inflammatory response and stroke
Authors: Duris K. , Jurajda M. 
Published: February 2019

AbstractThe immune system plays an important role under both physiological and pathological conditions. Immune surveillance as well as defense and healing processes are crucial for the organism, but the immune system has a natural tendency to act aggressively when excessively stimulated. We may assume that the immune system is not designed to deal with severe conditions, such as polytrauma or severe stroke, because these are not compatible with life in the wilderness and evolution has no chance to act in such cases. These conditions are associated with exaggerated/deregulated inflammatory response, which may cause more damage than initial pathology. In this article, we would like to sketch a basic concept of the immune system–brain interactions from the evolutionary point of view and to discuss some implications related to stroke.
GABA‐containing compound gammapyrone protects against brain impairments in Alzheimer’s disease model male rats and prevents mitochondrial dysfunction in cell culture
Authors: Pilipenko Vladimirs , Narbute Karina , Amara Ines , Trovato Angela , Scuto Maria , Pupure Jolanta , Jansone Baiba , Poikans Janis , Bisenieks Egils , Klusa Vija , Calabrese Vittorio 
Published: February 2019

AbstractNeuroinflammation, oxidative stress, decreased glucose/energy metabolism, and disrupted neurotransmission are changes that occur early in sporadic Alzheimer’s disease (AD), manifesting as mild cognitive impairment. Recently, the imbalanced function of the gamma‐aminobutyric acid (GABA) system was identified as a critical factor in AD progression. Thus, maintaining balance among neurotransmitter systems, particularly the GABA system, can be considered a beneficial strategy to slow AD progression. The present study investigated the effects of the compound gammapyrone, a molecule containing three GABA moieties: “free” moiety attached to the position 4 of the 1,4‐dihydropyridine (DHP) ring, and two “crypto” moieties as part of the DHP scaffold. The “free” and “crypto” GABA moieties are linked by a peptide bond (–CONH–), resulting in a peptide‐mimicking structure. In a nontransgenic male rat AD model generated by intracerebroventricular (icv) streptozocin (STZ) administration, gammapyrone (0.1 and 0.5 mg/kg ip) mitigated the impairment of spatial learning and memory, prevented astroglial and microglial neuroinflammation, and normalized acetylcholine breakdown and GABA biosynthesis. In PC12 cells, gammapyrone protected against oxidative stress, mitochondrial dysfunction and apoptosis caused by the mitochondrial toxin di‐2‐ethylhexyl phthalate (DEHP). Gammapyrone did not bind to GABA‐A and GABA‐B receptors in vitro; therefore, we cannot attribute its neuroprotective action to a specific interaction with GABA receptors. Nevertheless, we suggest that the peptide‐like regulatory mechanisms of gammapyrone or its allosteric modulatory properties are essential for the observed effects. Since, the icv STZ model resembles the early stages of AD, gammapyrone, and/or its congeners could be useful in the design of anti‐dementia drugs.
Hardworking coworkers: A multilevel cross‐national look at group work hours and work–family conflict
Authors: Vaziri Hoda , Benson George S. , Salazar Campo Maritza 
Published: February 2019

SummaryThis study investigates the relationship between coworker work hours and perceived work‐to‐family conflict (WFC) in a multinational sample of professional service employees. Building on recent research on the ways in which workgroups influence individual WFC, we demonstrate that the average hours worked by coworkers has a significant relationship to reported WFC independent of an employee's own work hours. Although this finding is universal across the multinational sample, national cultural differences were found to moderate the relationship, such that employees in more collectivist countries are more strongly influenced by average coworker hours than their counterparts in less collectivist countries. The multilevel analysis was conducted using a sample of 7,600 professional service employees in 497 different workgroups across 20 countries. The results provide support for the effect of culture on the relationship between group average hours and perceptions of WFC. We conclude with a discussion of how national culture affects WFC.
Study of a terrestrial Martian analogue: Geochemical characterization of the Meñakoz outcrops (Biscay, Spain)
Authors: Ruiz‐Galende Patricia , Torre‐Fdez Imanol , Aramendia Julene , Gómez‐Nubla Leticia , Castro Kepa , Arana Gorka , Madariaga Juan Manuel 
Published: February 2019

AbstractThe necessity to create databases for the proper interpretation of the results obtained by the rovers that will be sent by ESA to Mars implies the study of terrestrial Martian analogues. In this work, the Meñakoz outcrops, which are basaltic volcanic rocks interbedded with Turonian sediments coming from a Cretaceous submarine volcano outcrop located in Biscay (northern Spain), have been studied and proposed as a Martian analogue. Considering that Raman and near infrared spectroscopies are two of the techniques that will go on‐board the rovers in the next planetary missions, they were used to characterize the samples collected in Meñakoz. As was expected, silicates (phyllosilicates) were the major minerals detected by those techniques in the Meñakoz samples, but also, compounds such as sulfates and oxides could be detected. Phyllosilicates are very important because they are some of the compounds that have been reported to be present on the Mars surface in previous missions and specifically in Oxia Planum, the landing site for the ExoMars 2020 rover of the ESA missions to Mars. This fact provides reasons to propose the emplacement of Meñakoz as Martian analogue.
Estrogen receptor beta expression correlates with proliferation in desmoid tumors
Authors: Santti Kirsi , Ihalainen Hanna , Rönty Mikko , Karlsson Christina , Haglund Caj , Sampo Mika , Tarkkanen Maija , Blomqvist Carl 
Published: February 2019

AbstractBackground and objectivesEstrogen receptor signaling and cyclin D1 have a major role in tumor cell proliferation in breast cancer. Desmoid tumors are rare neoplasms that may respond to endocrine treatment. The present study aimed to investigate the expression levels and the clinical relevance of estrogen receptor beta (ERβ) and cyclin D1 in desmoid tumors.MethodsThis study consists of 83 patients with a surgically treated desmoid tumor. ERβ and cyclin D1 expression was examined by immunohistochemistry in tissue microarrays. Cyclin A and Ki67 were studied in our previous work.ResultsMedian ERβ expression was 10.8%. ERβ expression correlated with expression of the proliferation antigens Ki67 (rp = 0.35, P = 0.003), cyclin D1 (rp = 0.34, P = 0.004), and cyclin A (rp = 0.34, P = 0.004). ERβ immunoexpression showed a trend towards predictive impact for recurrence as a continuous variable. Further explorative analysis indicated that very high ERβ expression was related to high risk of relapse (hazard ratio [HR] 2.6; P = 0.02).Median cyclin D1 expression was 15.6%. High cyclin D1 expression was associated with high Ki67 and cyclin A expression. Cyclin D1 was not associated with time to recurrence.ConclusionsERβ and cyclin D1 immunopositivity correlated with high proliferation in desmoid tumors. High ERβ expression might be predictive for postoperative recurrence.
Enhanced striatopallidal gamma‐aminobutyric acid (GABA)A receptor transmission in mouse models of huntington's disease
Authors: Perez‐Rosello Tamara , Gelman Simon , Tombaugh Geoffrey , Cachope Roger , Beaumont Vahri , Surmeier D. James 
Published: February 2019

ABSTRACTBackgroundHuntington's disease (HD) is caused by a CAG repeat expansion in the huntingtin gene. This mutation leads to progressive dysfunction that is largely attributable to dysfunction of the striatum. The earliest signs of striatal pathology in HD are found in indirect pathway gamma‐Aminobutyric acid (GABA)‐ergic spiny projection neurons that innervate the external segment of the globus pallidus (GPe). What is less clear is whether the synaptic coupling of spiny projection neurons with GPe neurons changes in HD.ObjectivesThe principal goal of this study was to determine whether striatopallidal synaptic transmission was altered in 2 mouse models of HD.MethodsStriatopallidal synaptic transmission was studied using electrophysiological and optogenetic approaches in ex vivo brain slices from 2 HD models: Q175 heterozygous (het) and R6/2 mice.ResultsStriatopallidal synaptic transmission increased in strength with the progression of behavioral deficits in Q175 and R6/2 mice. The alteration in synaptic transmission was evident in both prototypical and arkypallidal GPe neurons. This change did not appear attributable to an increase in the probability of GABA release but, rather, to an enhancement in the postsynaptic response to GABA released at synaptic sites. This alteration significantly increased the ability of striatopallidal axon terminals to pause ongoing GPe activity.ConclusionsIn 2 mouse models of HD, striatopallidal synaptic transmission increased in parallel with the progression of behavioral deficits. This adaptation could compensate in part for the concomitant deficit in the ability of corticostriatal signals to activate spiny projection neurons and pause GPe activity. © 2019 International Parkinson and Movement Disorder Society
Does the Index of Ideality of Correlation Detect the Better Model Correctly?
Authors: Toropova Alla P. , Toropov Andrey A. 
Published: February 2019

AbstractThe CORAL software is a tool to build up predictive models for various endpoints by means of Quantitative Structure‐Property/Activity Relationships (QSPRs/QSARs). A new criterion for assessment of the predictive potential of QSPR/QSAR models, so‐called Index of Ideality of Correlation (IIC) is applied to improve the software. The ability of the IIC to detect models with better predictive potential is checked up with groups of random splits of data into the structured training set and extrenal validation set. To this end, two endpoints are examined (i) Toxicity towards Fathead minnow (Pimephales promelas); and (ii) drug load capasity of samples “micelle‐polymer”. Applications of the IIC for endpoint represented by traditional Simplified Molecular Input‐Line Entry System (SMILES) together with so‐called quasi‐SMILES has shown the suitability of the IIC be a tool to detect better model.