bluuebunny/crossref_metadata_2025_split huggingface dataset:
TLR3 agonists induce fibronectin aggregation by activated astrocytes: a role of pro-inflammatory cytokines and fibronectin splice variants
Authors: Werkman Inge , Sikkema Arend H. , Versluijs Joris B. , Qin Jing , de Boer Pascal , Baron Wia 
Published: January 2020

AbstractMultiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system which eventually results in axonal loss mainly due to failure of remyelination. Previously we have shown that the persistent presence of stable astrocyte-derived fibronectin aggregates in MS lesions impairs OPC differentiation, and thereby remyelination. Here we set out to discern whether and, if so, how inflammatory mediators as present in MS lesions trigger astrocytes to form fibronectin aggregates. Our findings revealed that in slice cultures only upon demyelination, the TLR3 agonist Poly(I:C) evoked astrocytes to form fibronectin aggregates. Consistently, pro-inflammatory cytokine-pretreated astrocytes were more susceptible to Poly(I:C)-induced fibronectin aggregation, indicating that astrocytes form fibronectin aggregates upon a double hit by inflammatory mediators. The underlying mechanism involves disrupted fibronectin fibrillogenesis at the cell surface as a result of a cytokine-induced increase in relative mRNA levels of EIIIApos-Fn over EIIIBpos-Fn and a Poly(I:C)-mediated decrease in integrin affinity. Remarkably, fibronectin aggregation is exacerbated by white matter astrocytes compared to grey matter astrocytes, which may be a reflection of higher expression levels of EIIIApos-fibronectin in white matter astrocytes. Hence, interfering with alternative fibronectin splicing and/or TLR3-mediated signaling may prevent fibronectin aggregation and overcome remyelination failure in MS lesions.
Genome- and transcriptome-derived microsatellite loci in lumpfish Cyclopterus lumpus: molecular tools for aquaculture, conservation and fisheries management
Authors: Maduna Simo N. , Vivian-Smith Adam , Jónsdóttir Ólöf Dóra Bartels , Imsland Albert K. D. , Klütsch Cornelya F. C. , Nyman Tommi , Eiken Hans Geir , Hagen Snorre B. 
Published: January 2020

AbstractThe lumpfishCyclopterus lumpusis commercially exploited in numerous areas of its range in the North Atlantic Ocean, and is important in salmonid aquaculture as a biological agent for controlling sea lice. Despite the economic importance, few genetic resources for downstream applications, such as linkage mapping, parentage analysis, marker-assisted selection (MAS), quantitative trait loci (QTL) analysis, and assessing adaptive genetic diversity are currently available for the species. Here, we identify both genome- and transcriptome-derived microsatellites loci fromC. lumpusto facilitate such applications. Across 2,346 genomic contigs, we detected a total of 3,067 microsatellite loci, of which 723 were the most suitable ones for primer design. From 116,555 transcriptomic unigenes, we identified a total of 231,556 microsatellite loci, which may indicate a high coverage of the available STRs. Out of these, primer pairs could only be designed for 6,203 loci. Dinucleotide repeats accounted for 89 percent and 52 percent of the genome- and transcriptome-derived microsatellites, respectively. The genetic composition of the dominant repeat motif types showed differences from other investigated fish species. In the genome-derived microsatellites AC/GT (67.8 percent), followed by AG/CT (15.1 percent) and AT/AT (5.6 percent) were the major motifs. Transcriptome-derived microsatellites showed also most dominantly the AC/GT repeat motif (33 percent), followed by A/T (26.6 percent) and AG/CT (11 percent). Functional annotation of microsatellite-containing transcriptomic sequences showed that the majority of the expressed sequence tags encode proteins involved in cellular and metabolic processes, binding activity and catalytic reactions. Importantly, STRs linked to genes involved in immune system process, growth, locomotion and reproduction were discovered in the present study. The extensive genomic marker information reported here will facilitate molecular ecology studies, conservation initiatives and will benefit many aspects of the breeding programmes ofC. lumpus.
Human antibodies neutralizing diphtheria toxin in vitro and in vivo
Authors: Wenzel Esther Veronika , Bosnak Margarita , Tierney Robert , Schubert Maren , Brown Jeffrey , Dübel Stefan , Efstratiou Androulla , Sesardic Dorothea , Stickings Paul , Hust Michael 
Published: January 2020

AbstractDiphtheria is an infectious disease caused by Corynebacterium diphtheriae. The bacterium primarily infects the throat and upper airways and the produced diphtheria toxin (DT), which binds to the elongation factor 2 and blocks protein synthesis, can spread through the bloodstream and affect organs, such as the heart and kidneys. For more than 125 years, the therapy against diphtheria has been based on polyclonal horse sera directed against DT (diphtheria antitoxin; DAT). Animal sera have many disadvantages including serum sickness, batch-to-batch variation in quality and the use of animals for production. In this work, 400 human recombinant antibodies were generated against DT from two different phage display panning strategies using a human immune library. A panning in microtiter plates resulted in 22 unique in vitro neutralizing antibodies and a panning in solution combined with a functional neutralization screening resulted in 268 in vitro neutralizing antibodies. 61 unique antibodies were further characterized as scFv-Fc with 35 produced as fully human IgG1. The best in vitro neutralizing antibody showed an estimated relative potency of 454 IU/mg and minimal effective dose 50% (MED50%) of 3.0 pM at a constant amount of DT (4x minimal cytopathic dose) in the IgG format. The targeted domains of the 35 antibodies were analyzed by immunoblot and by epitope mapping using phage display. All three DT domains (enzymatic domain, translocation domain and receptor binding domain) are targets for neutralizing antibodies. When toxin neutralization assays were performed at higher toxin dose levels, the neutralizing capacity of individual antibodies was markedly reduced but this was largely compensated for by using two or more antibodies in combination, resulting in a potency of 79.4 IU/mg in the in vivo intradermal challenge assay. These recombinant antibody combinations are candidates for further clinical and regulatory development to replace equine DAT.
The Japanese herbal medicine Hangeshashinto enhances oral keratinocyte migration to facilitate healing of chemotherapy-induced oral ulcerative mucositis
Authors: Miyano Kanako , Eto Moeko , Hitomi Suzuro , Matsumoto Takashi , Hasegawa Seiya , Hirano Ayane , Nagabuchi Kaori , Asai Noriho , Uzu Miaki , Nonaka Miki , Omiya Yuji , Kaneko Atsushi , Ono Kentaro , Fujii Hideaki , Higami Yoshikazu , Kono Toru , Uezono Yasuhito 
Published: January 2020

AbstractChemotherapy often induces oral ulcerative mucositis (OUM) in patients with cancer, characterized by severe painful inflammation. Mouth-washing with the Japanese herbal medicine hangeshashinto (HST) ameliorates chemotherapy-induced OUM in patients with colorectal cancer. Previously, we demonstrated that HST decreased interleukin 1β-induced prostaglandin E2 production in human oral keratinocytes (HOKs) and OUM-induced mechanical or spontaneous pain in rats. However, HST effects on tissue repair functions in HOKs remain unclear. Here, we examined the effects of HST on scratch-induced wound healing in vitro and in vivo. In vitro, HST enhanced wound healing mainly through scratch-induced HOK migration. Screening of the seven constituent medicinal herbs and their major components revealed that Scutellaria root, processed ginger, and Glycyrrhiza components mainly induced the scratch-induced HOK migration. Pharmacokinetic analyses indicated that the active ingredient concentrations in rat plasma following oral HST administration were below the effective doses for HOK migration, suggesting direct effects of HST in OUM. Mitogen-activated protein kinase and C-X-C chemokine receptor 4 inhibitors significantly suppressed HST-induced HOK migration. Moreover, HST enhanced tissue repair in our OUM rat model. Thus, HST likely enhanced OUM tissue repair through oral keratinocyte migration upon MAPK and CXCR4 activation and may be useful in patients with cancer-associated OUM.
Monitoring canid scent marking in space and time using a biologging and machine learning approach
Authors: Bidder Owen R. , di Virgilio Agustina , Hunter Jennifer S. , McInturff Alex , Gaynor Kaitlyn M. , Smith Alison M. , Dorcy Janelle , Rosell Frank 
Published: January 2020

AbstractFor canid species, scent marking plays a critical role in territoriality, social dynamics, and reproduction. However, due in part to human dependence on vision as our primary sensory modality, research on olfactory communication is hampered by a lack of tractable methods. In this study, we leverage a powerful biologging approach, using accelerometers in concert with GPS loggers to monitor and describe scent-marking events in time and space. We performed a validation experiment with domestic dogs, monitoring them by video concurrently with the novel biologging approach. We attached an accelerometer to the pelvis of 31 dogs (19 males and 12 females), detecting raised-leg and squat posture urinations by monitoring the change in device orientation. We then deployed this technique to describe the scent marking activity of 3 guardian dogs as they defend livestock from coyote depredation in California, providing an example use-case for the technique. During validation, the algorithm correctly classified 92% of accelerometer readings. High performance was partly due to the conspicuous signatures of archetypal raised-leg postures in the accelerometer data. Accuracy did not vary with the weight, age, and sex of the dogs, resulting in a method that is broadly applicable across canid species’ morphologies. We also used models trained on each individual to detect scent marking of others to emulate the use of captive surrogates for model training. We observed no relationship between the similarity in body weight between the dog pairs and the overall accuracy of predictions, although models performed best when trained and tested on the same individual. We discuss how existing methods in the field of movement ecology can be extended to use this exciting new data type. This paper represents an important first step in opening new avenues of research by leveraging the power of modern-technologies and machine-learning to this field.
5-hydroxymethylcytosine and gene activity in mouse intestinal differentiation
Authors: Uribe-Lewis Santiago , Carroll Thomas , Menon Suraj , Nicholson Anna , Manasterski Piotr J. , Winton Douglas J. , Buczacki Simon J. A. , Murrell Adele 
Published: January 2020

AbstractCytosine hydroxymethylation (5hmC) in mammalian DNA is the product of oxidation of methylated cytosines (5mC) by Ten-Eleven-Translocation (TET) enzymes. While it has been shown that the TETs influence 5mC metabolism, pluripotency and differentiation during early embryonic development, the functional relationship between gene expression and 5hmC in adult (somatic) stem cell differentiation is still unknown. Here we report that 5hmC levels undergo highly dynamic changes during adult stem cell differentiation from intestinal progenitors to differentiated intestinal epithelium. We profiled 5hmC and gene activity in purified mouse intestinal progenitors and differentiated progeny to identify 43425 differentially hydroxymethylated regions and 5325 differentially expressed genes. These differentially marked regions showed both losses and gains of 5hmC after differentiation, despite lower global levels of 5hmC in progenitor cells. In progenitors, 5hmC did not correlate with gene transcript levels, however, upon differentiation the global increase in 5hmC content showed an overall positive correlation with gene expression level as well as prominent associations with histone modifications that typify active genes and enhancer elements. Our data support a gene regulatory role for 5hmC that is predominant over its role in controlling DNA methylation states.
Association of patient-reported outcomes and heart rate trends in heart failure: a report from the Chiron project
Authors: Monzo Luca , Schiariti Michele , Calvisi Pietro Fedele , Bonfiglio Silvio , Luštrek Mitja , Puddu Paolo E. 
Published: January 2020

AbstractPatient-reported outcomes (PROs) have been previously considered “soft” end-points because of the lack of association of the reported outcome to measurable biological parameters. The present study aimed to assess whether electrocardiographic measures are associated to PROs changes. We evaluated the association between heart rate (HR), QRS and QT/QTc durations and PROs, classified as “good” or “bad” according to the patients’ overall feeling of health, in patients from the Chiron project. Twenty-four chronic heart failure (HF) patients were enrolled in the study (71% male, mean age 62.9 ± 9.4 years, 42% ischemic etiology, 15 NYHA class II and 9 class III) providing 1086 days of usable physiological recordings (4 hours/day). The mean HR was significantly higher in the “bad” than in the “good” PROs class (74.0 ± 6.4 bpm vs 68.0 ± 7.2 bpm; p < 0.001). Conversely, the ratio between movement and rest activities showed significantly higher values in “good” compared to “bad” PROs. We also found significantly longer QTc and QRS durations in patients with “bad” PROs compared to patients with “good” PROs. That in patients with mild to moderate HF, higher HR, wider QRS and longer QTc, as well as a reduced HR ratio between movement and rest, were associated with “bad” PROs is clinically noteworthy because the association of worse PROs with measurable variations of biological parameters may help physicians in evaluating PROs reliability itself and in their clinical decisions. Whether a timely intervention on these biological parameters may prevent adverse outcomes is important and deserves to be investigated in further studies.
Global vulnerability of marine mammals to global warming
Authors: Albouy Camille , Delattre Valentine , Donati Giulia , Frölicher Thomas L. , Albouy-Boyer Severine , Rufino Marta , Pellissier Loïc , Mouillot David , Leprieur Fabien 
Published: January 2020

AbstractAlthough extinctions due to climate change are still uncommon, they might surpass those caused by habitat loss or overexploitation over the next few decades. Among marine megafauna, mammals fulfill key and irreplaceable ecological roles in the ocean, and the collapse of their populations may therefore have irreversible consequences for ecosystem functioning and services. Using a trait-based approach, we assessed the vulnerability of all marine mammals to global warming under high and low greenhouse gas emission scenarios for the middle and the end of the 21stcentury. We showed that the North Pacific Ocean, the Greenland Sea and the Barents Sea host the species that are most vulnerable to global warming. Future conservation plans should therefore focus on these regions, where there are long histories of overexploitation and there are high levels of current threats to marine mammals. Among the most vulnerable marine mammals were several threatened species, such as the North Pacific right whale (Eubalaena japonica) and the dugong (Dugong dugon), that displayed unique combinations of functional traits. Beyond species loss, we showed that the potential extinctions of the marine mammals that were most vulnerable to global warming might induce a disproportionate loss of functional diversity, which may have profound impacts on the future functioning of marine ecosystems worldwide.
Δ9-tetrahydrocannabinol exposure during rat pregnancy leads to symmetrical fetal growth restriction and labyrinth-specific vascular defects in the placenta
Authors: Natale Bryony V. , Gustin Katarina N. , Lee Kendrick , Holloway Alison C. , Laviolette Steven R. , Natale David R. C. , Hardy Daniel B. 
Published: January 2020

Abstract1 in 5 women report cannabis use during pregnancy, with nausea cited as their primary motivation. Studies show that (-)-△9–tetrahydrocannabinol (Δ9-THC), the major psychoactive ingredient in cannabis, causes fetal growth restriction, though the mechanisms are not well understood. Given the critical role of the placenta to transfer oxygen and nutrients from mother, to the fetus, any compromise in the development of fetal-placental circulation significantly affects maternal-fetal exchange and thereby, fetal growth. The goal of this study was to examine, in rats, the impact of maternal Δ9-THC exposure on fetal development, neonatal outcomes, and placental development. Dams received a daily intraperitoneal injection (i.p.) of vehicle control or Δ9-THC (3 mg/kg) from embryonic (E)6.5 through 22. Dams were allowed to deliver normally to measure pregnancy and neonatal outcomes, with a subset sacrificed at E19.5 for placenta assessment via immunohistochemistry and qPCR. Gestational Δ9-THC exposure resulted in pups born with symmetrical fetal growth restriction, with catch up growth by post-natal day (PND)21. During pregnancy there were no changes to maternal food intake, maternal weight gain, litter size, or gestational length. E19.5 placentas from Δ9-THC-exposed pregnancies exhibited a phenotype characterized by increased labyrinth area, reduced Epcam expression (marker of labyrinth trophoblast progenitors), altered maternal blood space, decreased fetal capillary area and an increased recruitment of pericytes with greater collagen deposition, when compared to vehicle controls. Further, at E19.5 labyrinth trophoblast had reduced glucose transporter 1 (GLUT1) and glucocorticoid receptor (GR) expression in response to Δ9-THC exposure. In conclusion, maternal exposure to Δ9-THC effectively compromised fetal growth, which may be a result of the adversely affected labyrinth zone development. These findings implicate GLUT1 as a Δ9-THC target and provide a potential mechanism for the fetal growth restriction observed in women who use cannabis during pregnancy.
Statin use, HMGCR expression, and breast cancer survival – The Malmö Diet and Cancer Study
Authors: Bjarnadottir Olöf , Feldt Maria , Inasu Maria , Bendahl Pär-Ola , Elebro Karin , Kimbung Siker , Borgquist Signe 
Published: January 2020

AbstractStatins, commonly used to treat hypercholesterolemia, have also been proposed as anti-cancer agents. The identification of a predictive marker is essential. The 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR), which is inhibited by statins, might serve as such a marker. Thorough antibody validation was performed for four different HMGCR antibodies. Tumor expression of HMGCR (#AMAb90619, CL0260, Atlas Antibodies, Stockholm, Sweden) was evaluated in the Malmö Diet and Cancer Study breast cancer cohort. Statin use and cause of death data were retrieved from the Swedish Prescribed Drug Register and Swedish Death Registry, respectively. Breast cancer-specific mortality (BCM) according to statin use and HMGCR expression were analyzed using Cox regression models. Three-hundred-twelve of 910 breast cancer patients were prescribed statins; 74 patients before and 238 after their breast cancer diagnosis. HMGCR expression was assessable for 656 patients; 119 showed negative, 354 weak, and 184 moderate/strong expressions. HMGCR moderate/strong expression was associated with prognostically adverse tumor characteristics as higher histological grade, high Ki67, and ER negativity. HMGCR expression was not associated with BCM. Neither was statin use associated with BCM in our study. Among breast cancer patients on statins, no or weak HMGCR expression predicted favorable clinical outcome. These suggested associations need further testing in larger cohorts.
Better brain connectivity is associated with higher total fat mass and lower visceral adipose tissue in military pilots
Authors: Cárdenas David , Madinabeitia Iker , Vera Jesús , de Teresa Carlos , Alarcón Francisco , Jiménez Raimundo , Catena Andrés 
Published: January 2020

AbstractA lack of exercise leads to being overweight or obese affecting regional brain structure and functional connectivity associated with impaired cognitive function and dementia. In recent decades, several studies of healthy individuals suggest that adiposity may also produce negative independent effects on the brain. We aimed to investigate the relationship between body composition – total fat mass (TFM) and visceral adipose tissue (VAT) – with white matter (WM) integrity using a whole-brain approach in military pilots. Twenty-three military helicopter pilots (Mage = 36.79; SD = 8.00; MBMI = 25.48; SD = 2.49) took part in the study. Brain volumes were studied using diffusion tensor imaging technique by means of a 3T Magnetom Tim Trio. Measurements of body mass index (BMI), TFM and VAT were obtained using Dual-energy X-ray Absorptiometry (DXA). The results showed that, on one hand, higher TFM was associated with higher white matter fractional anisotropy (FA) and, on the other hand, higher VAT was associated with lower FA. Data showed that TFM and VAT are the critical factors underlying WM integrity in combat helicopter pilots. The authors suggest that fat presence enhance brain connectivity while there is no excess, specifically in VAT.
The mitochondrial negative regulator MCJ modulates the interplay between microbiota and the host during ulcerative colitis
Authors: Pascual-Itoiz Miguel Angel , Peña-Cearra Ainize , Martín-Ruiz Itziar , Lavín José Luis , Simó Carolina , Rodríguez Héctor , Atondo Estibaliz , Flores Juana María , Carreras-González Ana , Tomás-Cortázar Julen , Barriales Diego , Palacios Ainhoa , García-Cañas Virginia , Pellón Aize , Fullaondo Asier , Aransay Ana Mª , Prados-Rosales Rafael , Martín Rebeca , Anguita Juan , Abecia Leticia 
Published: January 2020

AbstractRecent evidences indicate that mitochondrial genes and function are decreased in active ulcerative colitis (UC) patients, in particular, the activity of Complex I of the electron transport chain is heavily compromised. MCJ is a mitochondrial inner membrane protein identified as a natural inhibitor of respiratory chain Complex I. The induction of experimental colitis in MCJ-deficient mice leads to the upregulation ofTimp3expression resulting in the inhibition of TACE activity that likely inhibitsTnfandTnfr1shedding from the cell membrane in the colon. MCJ-deficient mice also show higher expression ofMyd88andTlr9, proinflammatory genes and disease severity. Interestingly, the absence of MCJ resulted in distinct microbiota metabolism and composition, including a member of the gut community in UC patients,Ruminococcus gnavus. These changes provoked an effect on IgA levels. Gene expression analyses in UC patients showed decreased levels ofMCJand higher expression ofTIMP3, suggesting a relevant role of mitochondrial genes and function among active UC. The MCJ deficiency disturbs the regulatory relationship between the host mitochondria and microbiota affecting disease severity. Our results indicate that mitochondria function may be an important factor in the pathogenesis. All together support the importance of MCJ regulation during UC.