bluuebunny/crossref_metadata_2025_split huggingface dataset:
SB772077B, A New Rho Kinase Inhibitor Enhances Aqueous Humour Outflow Facility in Human Eyes
Authors: Ashwinbalaji Soundararajan , Senthilkumari Srinivasan , Gowripriya Chidambaranathan , Krishnadas Subbaiah , Gabelt B’ Ann T. , Kaufman Paul L. , Muthukkaruppan Veerappan 
Published: October 2018

AbstractWe investigated the effect of a new Rho kinase inhibitor, SB772077B (SB77) on aqueous outflow facility (OF) in human eyes using human organ-cultured anterior segment (HOCAS). IOP was monitored for 24 h post-treatment with either SB77 (0.1/10/50 µM) or vehicle after a stable baseline pressure. The hydrodynamic pattern of aqueous outflow was analysed by labelling outflow pathway with red fluorescent microspheres. The effect of SB77 on cell morphology, actin stress fibers, focal adhesions, ECM, status of RhoA activation and myosin light chain phosphorylation (p-MLC) were evaluated and compared with Y27632, by immunostaining using primary human trabecular meshwork (HTM) cells. Following 24 h treatment, SB77 increased OF by 16% at 0.1 µM (N = 6), 29% at 10 µM (N = 8; p = 0.018) and 39% at 50 µM (N = 8; p = 0.004) in human eyes. There was an overall increase in tracer quantity and in area along inner wall of Schlemm’s canal. Treatment with SB77 showed no evidence of cytotoxicity and caused a significant reduction in the expression of fibrotic markers compared to Y27632. The present findings indicate that SB77 treatment was effective in enhancing OF and reducing fibrotic markers in an ex vivo model. Thus SB77 may be a potential clinical candidate for the management of glaucoma.
Genome wide mapping of ETV6 binding sites in pre-B leukemic cells
Authors: Neveu Benjamin , Caron Maxime , Lagacé Karine , Richer Chantal , Sinnett Daniel 
Published: October 2018

AbstractGenetic alterations in the transcriptional repressor ETV6 are associated with hematological malignancies. Notably, the t(12;21) translocation leading to an ETV6-AML1 fusion gene is the most common genetic alteration found in childhood acute lymphoblastic leukemia. Moreover, most of these patients also lack ETV6 expression, suggesting a tumor suppressor function. To gain insights on ETV6 DNA-binding specificity and genome wide transcriptional regulation capacities, we performed chromatin immunoprecipitation experiments coupled to deep sequencing in a t(12;21)-positive pre-B leukemic cell line. This strategy led to the identification of ETV6-bound regions that were further associated to gene expression. ETV6 binding is mostly cell type-specific as only few regions are shared with other blood cell subtypes. Peaks localization and motif enrichment analyses revealed that this unique binding profile could be associated with the ETV6-AML1 fusion protein specific to the t(12;21) background. This study underscores the complexity of ETV6 binding and uncovers ETV6 transcriptional network in pre-B leukemia cells bearing the recurrent t(12;21) translocation.
SUMOgo: Prediction of sumoylation sites on lysines by motif screening models and the effects of various post-translational modifications
Authors: Chang Chi-Chang , Tung Chi-Hua , Chen Chi-Wei , Tu Chin-Hau , Chu Yen-Wei 
Published: October 2018

AbstractMost modern tools used to predict sites of small ubiquitin-like modifier (SUMO) binding (referred to as SUMOylation) use algorithms, chemical features of the protein, and consensus motifs. However, these tools rarely consider the influence of post-translational modification (PTM) information for other sites within the same protein on the accuracy of prediction results. This study applied the Random Forest machine learning method, as well as motif screening models and a feature selection combination mechanism, to develop a SUMOylation prediction system, referred to as SUMOgo. With regard to prediction method, PTM sites were coded as new functional features in addition to structural features, such as sequence-based binary coding, encoded chemical features of proteins, and encoded secondary structure information that is important for PTM. Twenty cycles of prediction were conducted with a 1:1 combination of positive test data and random negative data. Matthew’s correlation coefficient of SUMOgo reached 0.511, which is higher than that of current commonly used tools. This study further verified the important role of PTM in SUMOgo and includes a case study on CREB binding protein (CREBBP). The website for the final tool is http://predictor.nchu.edu.tw/SUMOgo.
A systems biology network analysis of nutri(epi)genomic changes in endothelial cells exposed to epicatechin metabolites
Authors: Milenkovic Dragan , Berghe Wim Vanden , Morand Christine , Claude Sylvain , van de Sandt Annette , Gorressen Simone , Monfoulet Laurent-Emmanuel , Chirumamilla Chandra S. , Declerck Ken , Szic Katarzyna Szarc vel , Lahtela-Kakkonen Maija , Gerhauser Clarissa , Merx Marc W. , Kelm Malte 
Published: October 2018

AbstractAlthough vasculo-protective effects of flavan-3-ols are widely accepted today, their impact on endothelial cell functions and molecular mechanisms of action involved is not completely understood. The aim of this study was to characterize the potential endothelium-protective effects of circulating epicatechin metabolites and to define underlying mechanisms of action by an integrated systems biology approach. Reduced leukocyte rolling over vascular endothelium was observed following epicatechin supplementation in a mouse model of inflammation. Integrative pathway analysis of transcriptome, miRNome and epigenome profiles of endothelial cells exposed to epicatechin metabolites revealed that by acting at these different levels of regulation, metabolites affect cellular pathways involved in endothelial permeability and interaction with immune cells. In-vitro experiments on endothelial cells confirmed that epicatechin metabolites reduce monocyte adhesion and their transendothelial migration. Altogether, our in-vivo and in-vitro results support the outcome of a systems biology based network analysis which suggests that epicatechin metabolites mediate their vasculoprotective effects through dynamic regulation of endothelial cell monocyte adhesion and permeability. This study illustrates complex and multimodal mechanisms of action by which epicatechin modulate endothelial cell integrity.
White-nose syndrome is associated with increased replication of a naturally persisting coronaviruses in bats
Authors: Davy Christina M. , Donaldson Michael E. , Subudhi Sonu , Rapin Noreen , Warnecke Lisa , Turner James M. , Bollinger Trent K. , Kyle Christopher J. , Dorville Nicole A. S.-Y. , Kunkel Emma L. , Norquay Kaleigh J. O. , Dzal Yvonne A. , Willis Craig K. R. , Misra Vikram 
Published: October 2018

AbstractSpillover of viruses from bats to other animals may be associated with increased contact between them, as well as increased shedding of viruses by bats. Here, we tested the prediction that little brown bats (Myotis lucifugus) co-infected with the M. lucifugus coronavirus (Myl-CoV) and with Pseudogymnoascus destructans (Pd), the fungus that causes bat white-nose syndrome (WNS), exhibit different disease severity, viral shedding and molecular responses than bats infected with only Myl-CoV or only P. destructans. We took advantage of the natural persistence of Myl-CoV in bats that were experimentally inoculated with P. destructans in a previous study. Here, we show that the intestines of virus-infected bats that were also infected with fungus contained on average 60-fold more viral RNA than bats with virus alone. Increased viral RNA in the intestines correlated with the severity of fungus-related pathology. Additionally, the intestines of bats infected with fungus exhibited different expression of mitogen-activated protein kinase pathway and cytokine related transcripts, irrespective of viral presence. Levels of coronavirus antibodies were also higher in fungal-infected bats. Our results suggest that the systemic effects of WNS may down-regulate anti-viral responses in bats persistently infected with M. lucifugus coronavirus and increase the potential of virus shedding.
16S rRNA amplicon sequencing reveals a polymicrobial nature of complicated claw horn disruption lesions and interdigital phlegmon in dairy cattle
Authors: Bay V. , Griffiths B. , Carter S. , Evans N. J. , Lenzi L. , Bicalho R. C. , Oikonomou G. 
Published: October 2018

AbstractLameness represents an intractable problem for the dairy industry. Complicated claw horn disruption lesions, interdigital hyperplasia, and interdigital phlegmon are important lameness causing foot lesions. Their aetiology is multifactorial, but infectious processes are likely implicated in disease pathogenesis. Our aim was to investigate the bacterial profiles of these lesions using 16S rRNA gene sequencing of samples obtained from 51 cattle across ten farms in the UK. In this study, interdigital hyperplasia, interdigital hyperplasia with signs of interdigital dermatitis, interdigital phlegmon, complicated sole ulcers, complicated toe ulcers lesions, and complicated white line lesions were investigated; corresponding healthy skin control samples were also analysed. All diseased tissues displayed reduced microbial richness and diversity (as described by Chao1, Shannon, and Simpson alpha-diversity indices) compared to their healthy skin control samples. Our results confirm the association ofTreponemaspp with some of these disorders. Other anaerobic bacteria includingFusobacteriumspp.,Fastidiosipilaspp. andPorphyromonasspp. were implicated in the aetiology of all these lesions with the exception of interdigital hyperplasia. Complicated claw horn disruption lesions, and interdigital phlegmon were found to have similar bacterial profiles. Such sharing of bacterial genera suggests many of the infectious agents detected in these foot lesions are acting opportunistically; this finding could contribute towards future treatment and control strategies.
Kinetic control of molecular assembly on surfaces
Authors: Paris Chiara , Floris Andrea , Aeschlimann Simon , Neff Julia , Kling Felix , Kühnle Angelika , Kantorovich Lev 
Published: October 2018

AbstractIt is usually assumed that molecules deposited on surfaces assume the most thermodynamically stable structure. Here we show, by considering a model system of dihydroxybenzoic acid molecules on the (10.4) surface of calcite, that metastable molecular architectures may also be accessed by choosing a suitable initial state of the molecules which defines the observed transformation path. Moreover, we demonstrate that the latter is entirely controlled by kinetics rather than thermodynamics. We argue that molecules are deposited as dimers that undergo, upon increase of temperature, a series of structural transitions from clusters to ordered striped and then dense networks, and finally to a disordered structure. Combining high-resolution dynamic atomic force microscopy experiments and density-functional theory calculations, we provide a comprehensive analysis of the fundamental principles driving this sequence of transitions. Our study may open new avenues based on kinetic control as a promising strategy for achieving tailored molecular architectures on surfaces.
Magnetic bipoles in rotating turbulence with coronal envelope
Authors: Losada I. R. , Warnecke J. , Brandenburg A. , Kleeorin N. , Rogachevskii I. 
Published: October 2018

Context. The formation mechanism of sunspots and starspots is not yet fully understood. It is a major open problem in astrophysics.Aims. Magnetic flux concentrations can be produced by the negative effective magnetic pressure instability (NEMPI). This instability is strongly suppressed by rotation. However, the presence of an outer coronal envelope was previously found to strengthen the flux concentrations and make them more prominent. It also allows for the formation of bipolar regions (BRs). We aim to understand the important issue of whether the presence of an outer coronal envelope also changes the excitation conditions and the rotational dependence of NEMPI.Methods. We have used direct numerical simulations and mean-field simulations. We adopted a simple two-layer model of turbulence that mimics the jump between the convective turbulent and coronal layers below and above the surface of a star, respectively. The computational domain is Cartesian and located at a certain latitude of a rotating sphere. We investigated the effects of rotation on NEMPI by changing the Coriolis number, the latitude, the strengths of the imposed magnetic field, and the box resolution.Results. Rotation has a strong impact on the process of BR formation. Even rather slow rotation is found to suppress BR formation. However, increasing the imposed magnetic field strength also makes the structures stronger and alleviates the rotational suppression somewhat. The presence of a coronal layer itself does not significantly reduce the effects of rotational suppression.
Patient-Specific Restoration of Biomechanics in Total Hip Arthroplasty
Authors: Weber Markus , Grifka Joachim , Renkawitz Tobias 
Published: October 2018

ZusammenfassungEine exakte Rekonstruktion der Biomechanik ist ein wesentlicher Bestandteil in der Hüftendoprothetik für eine gute postoperative Beweglichkeit und Stabilität des Kunstgelenks. Die präoperative Planung des Beinlängen- und Offsetausgleichs wird üblicherweise auf größenskalierten konventionellen Röntgenbildern durchgeführt, die jedoch durch die zweidimensionale Projektion der Gefahr von Fehlberechnungen unterliegen. Insbesondere das femorale Offset wird dabei häufig unterschätzt. Bei der Rekonstruktionsgenauigkeit von Beinlänge und Offset sollten Unterschiede von über 1 cm postoperativ vermieden werden. Analysen der Gangkinematik zeigen jedoch bereits Veränderungen im Gangmuster bei Beinlängen- und Offsetunterschieden von über 5 mm. Neben einer Vielzahl anderer Methoden eignen sich zur intraoperativen Umsetzung der Beinlängen- und Offsetrekonstruktion sowohl die bildfreie Navigation als auch die Fluoroskopie. Eine Abschätzung der Schafttorsion der einliegenden Endoprothese ist neben des Goldstandards CT auch auf konventionellen Röntgenaufnahmen mithilfe der Bestimmung des projizierten CCD-Winkels möglich. Als prädiktiver Parameter eignet sich die Isthmus-Ratio (iRatio), um bereits präoperativ nativradiologisch einen Hinweis der intraoperativ zu erwartenden Schafttorsion zu erhalten. Die Größe des Trochanter minor hilft, eine Abschätzung der nativen Torsion des Femurs treffen zu können.
Heterotopic Ossification – Complication or Chance?
Authors: Roessler Philip Peter , Bornemann Rahel , Jacobs Cornelius , Pflugmacher Robert , Trost Matthias , Hölscher-Doht Stefanie , Jansen Hendrik , Frey Sönke Percy 
Published: October 2018

ZusammenfassungBislang gibt es keine eindeutigen Erklärungen der pathophysiologischen Zusammenhänge in der Entstehung der heterotopen Ossifikation (HO). Es gibt nur wenig experimentelle Daten, die sich mit der posttraumatischen Entzündungsreaktion in Bezug auf die Balance zwischen der Reparatur beschädigter Muskelzellen und der entgegengesetzten Reaktion bei ihrer Entstehung beschäftigen. Es gibt zahlreiche Hinweise in Bezug auf mögliche prädisponierende Faktoren wie das Vorliegen einer Hypoxie im umgebenden Gewebe oder die Funktion von proangiogenen (z. B. VEGF) und osteoinduktiven (z. B. BMP) Faktoren. Diese verschiedenen wissenschaftlichen Ansätze bieten die Möglichkeit, klinisch zu interventionieren. Aus unserer Sicht erscheint das frühe Eingreifen im Hinblick auf die Effektivität sowie das Wiederkehren der HO am sinnvollsten. Ein wichtiger Pathomechanismus scheint die chronische Inflammation zu sein. Derzeit sind die nicht steroidalen Antiphlogistika die am häufigsten verschriebenen Medikamente zur Prophylaxe. Die Effektivität und Wirksamkeit der nicht steroidalen Antiphlogistika ist nicht zuletzt auch durch die zeitlich begrenzte Freisetzung und das Nebenwirkungspotenzial limitiert. Daher ist es interessant, einen Fokus der zukünftigen Forschung in Richtung des Zusammenspiels zwischen immunsuppressiver Herunterregulierung der inflammatorischen Antwort sowie deren Effekt auf die Balance zwischen Muskelregeneration und Entstehung der HO zu richten.
BK 2108 – The Calculation of the Normalized Relative Lumbar Disc Height
Authors: Schwarze Martin , Schiltenwolf Marcus 
Published: October 2018

AbstractThe assessment of the medical conditions (liability-compliant causality) of the BK 2108 is a frequent assessment, which poses a challenge to the medical expert in orthopaedics and trauma surgery. In assessing the load-consistent damage pattern, defined changes in the intervertebral discs as well as the adjacent vertebral bodies must be comprehended in a standardised manner. Of several technical measuring methods, three practicable methods are discussed and their application explained. Thus, methods are provided which allow the medical expert to calculate the normalised relative disc height. In this way, the specifications of the consensus recommendations can be met in order to define the damage profile.
Disorders of Consciousness: Ethical Issues of Diagnosis, Treatment, and Prognostication
Authors: Septien Spencer , Rubin Michael 
Published: October 2018

AbstractConsciousness defines our humanity more than any other biologic phenomena that a clinician might be called upon to examine, diagnose, or treat. When family comes to the bedside of a patient, they hope to find them talking, thinking, and feeling. The complexity of consciousness allows an expansive gradation of dysfunction such that we must consider numerous potential insults, possible interventions, and often an unknown likelihood of recovery. As value-laden questions are more often in the hands of surrogate decision makers, the neurologist is given the herculean task of not only diagnosing and treating alterations of consciousness but also predicting the likely course of the disease to empower surrogates to make a choice most consistent with the preferences of the patient. The degree of uncertainty in the diagnosis and prognosis demands that the clinician consider the ethics of the diagnosis, treatment, and prognostication of disorders of consciousness. Expectations of acute and chronic care, the extent of the formal neurological investigation, the potential of therapeutic trials, the self-fulfilling prophecy that can occur with prognostication, and the challenges of shared decision making are all subjects that we explore.
Contentious Ethical and Legal Aspects of Determination of Brain Death
Authors: Lewis Ariane 
Published: October 2018

AbstractAlthough the concept of death by neurologic criteria is accepted throughout much of the world and death can legally be determined by neurologic criteria throughout the United States, the process is fraught with contentious ethical and legal controversies. I explore historic and contemporary ethical and legal disputes about determination of death by neurologic criteria including the need for consent from patients' surrogates prior to determination of death, the role of religion in determination of death, management of objections to determination of death by neurologic criteria, the approach to patients who are dead by neurologic criteria but are pregnant, and gamete retrieval after determination of death.
Informed Consent for the Human Research Subject with a Neurologic Disorder
Authors: Vaishnav Neil , Chiong Winston 
Published: October 2018

AbstractThe doctrine of informed consent sits at the intersection of law, ethics, and neuroscience, posing unique challenges for human subject research involving neurological patients. These challenges are compounded by the variegated nature of both neurological injury and the law governing research consent. This article provides a framework for investigators likely to encounter subjects with some degree of neurological impairment, whose capacity to consent requires scrupulous assessment prior to enrollment in research trials. We consider several researches and disease contexts—from emergency epilepsy research to long-term dementia research—and clarify the ethical and legal principles governing consent for participation in each. We additionally explore empirical research on consent capacity and survey several areas of emerging ethical import that will require the attention of investigators in decades to come.
Physician-Hastened-Death in Patients with Progressive Neurodegenerative or Neuromuscular Disorders
Authors: Russell James 
Published: October 2018

AbstractPhysician-hastened-death remains a controversial topic for patients and those who care for them. It is a particularly relevant topic for neurologists who currently, or will in the future, reside in jurisdictions where physician-hastened-death is legal. In this article, I attempt to provide a comprehensive and contemporary discussion of hastened-death issues in a measured and respectful fashion. My goal is to provide clinicians with the information necessary to mold their own judgment and conscience in preparation for a time in which one or more of their patients request their participation in physician-hastened-death.
Methemoglobinemia during the Use of Glyceryl Trinitrate Patches in Neonates: Two Case Reports
Authors: Mintoft Alison , Williams Emma , Harris Christopher , Kennea Nigel , Greenough Anne 
Published: October 2018

AbstractMethemoglobinemia can result in severe hypoxia. It has been frequently reported during the use of inhaled nitric oxide, but can occur where nitrate containing medications are used. Glyceryl trinitrate (GTN) patches have been used in the treatment of digital and limb ischemia in prematurely born infants. Little is known about the pharmacokinetics of GTN when incorporated into patches. Studies of other topical forms of nitroglycerine have shown a wide range of absorption. It is likely that the increased permeability of the prematurely born infant's skin would facilitate absorption. We describe the use of GTN patches in two very prematurely born infants used to treat limb/digit ischemia. This resulted in methemoglobinemia and resultant increase in their supplementary oxygen requirements. Removal of the patches was associated with a reduction in their methemoglobin levels and the supplementary oxygen requirements back to baseline levels. In conclusion, routine monitoring of methemoglobin levels should be undertaken when GTN patches are used in very prematurely born infants.
Hypertrophic cardiomyopathy R403Q mutation in rabbit β-myosin reduces contractile function at the molecular and myofibrillar levels
Authors: Lowey Susan , Bretton Vera , Joel Peteranne B. , Trybus Kathleen M. , Gulick James , Robbins Jeffrey , Kalganov Albert , Cornachione Anabelle S. , Rassier Dilson E. 
Published: October 2018

Significance
Familial hypertrophic cardiomyopathy is a major cause of sudden death in young athletes. The mouse model for heart disease showed that the severe R403Q mutation in α-cardiac myosin heavy chain leads to increased ATPase activity and in vitro motility. But the β-myosin heavy chain is the preferred isoform in all larger mammals, leading us to generate a transgenic R403Q rabbit model. In contrast to the mouse model, we find a significant reduction in actin motility by R403Q rabbit myosin. Even more importantly, single myofibrils with the mutant myosin in the environment of a native thick filament showed diminished kinetics, force, and power output, leading to the conclusion that loss-of-function is the initial cause of cardiac hypertrophy.