bluuebunny/crossref_metadata_2025 huggingface dataset:
COMPUTING IMAGES OF GALOIS REPRESENTATIONS ATTACHED TO ELLIPTIC CURVES
Authors: SUTHERLAND ANDREW V.
Published: February 2016

Let$E$be an elliptic curve without complex multiplication (CM) over a number field$K$, and let$G_{E}(\ell )$be the image of the Galois representation induced by the action of the absolute Galois group of $K$on the$\ell$-torsion subgroup of $E$. We present two probabilistic algorithms to simultaneously determine$G_{E}(\ell )$up to local conjugacy for all primes$\ell$by sampling images of Frobenius elements; one is of Las Vegas type and the other is a Monte Carlo algorithm. They determine$G_{E}(\ell )$up to one of at most two isomorphic conjugacy classes of subgroups of$\mathbf{GL}_{2}(\mathbf{Z}/\ell \mathbf{Z})$that have the same semisimplification, each of which occurs for an elliptic curve isogenous to$E$. Under the GRH, their running times are polynomial in the bit-size$n$of an integral Weierstrass equation for $E$, and for our Monte Carlo algorithm, quasilinear in$n$. We have applied our algorithms to the non-CM elliptic curves in Cremona’s tables and the Stein–Watkins database, some 140 million curves of conductor up to $10^{10}$, thereby obtaining a conjecturally complete list of 63 exceptional Galois images$G_{E}(\ell )$that arise for$E/\mathbf{Q}$without CM. Under this conjecture, we determine a complete list of 160 exceptional Galois images$G_{E}(\ell )$that arise for non-CM elliptic curves over quadratic fields with rational$j$-invariants. We also give examples of exceptional Galois images that arise for non-CM elliptic curves over quadratic fields only when the$j$-invariant is irrational.
Evaluation of a Novel Intervention to Reduce Unnecessary Urine Cultures in Intensive Care Units at a Tertiary Care Hospital in Maryland, 2011–2014
Authors: Epstein Lauren , Edwards Jonathan R. , Halpin Alison Laufer , Preas Michael Anne , Blythe David , Harris Anthony D. , Hunt David , Johnson J. Kristie , Filippell Mala , Gould Carolyn V. , Leekha Surbhi
Published: February 2016

We assessed the impact of a reflex urine culture protocol, an intervention aimed to reduce unnecessary urine culturing, in intensive care units at a tertiary care hospital. Significant decreases in urine culturing rates and reported rates of catheter-associated urinary tract infection followed implementation of the protocol.

Infect Control Hosp Epidemiol 2016;37:606–609
Psychiatric shades of grey: mirtazapine-induced hair discoloration and hair loss
Authors: Osman M. , McCauley M. D.
Published: February 2016

Introduction

Mirtazapine is indicated in the treatment of major depressive disorder particularly in selective serotonin re-uptake inhibitors resistance. Its effect on hair loss is rare with no previous documented effect on hair colour.

Method

Review of relevant literature and description of a case report of a 54-year-old male patient who developed alopecia and hair discoloration after initiation of mirtazapine treatment.

Results

Upon cessation of mirtazapine treatment full restoration of hair colour and regrowth of hair was attained within 10 weeks.

Discussion

There was clear temporal relationship between experiencing hair loss and commencing mirtazapine treatment. No other more likely medical reason to explain such experience was established. A noticeable restoration of the hair colour occurred following mirtazapine cessation.

Conclusion

Mirtazapine is associated with hair discoloration and hair loss. The possibility of such distressing adverse effects needs to be conveyed to patients by clinicians and to be further explored by researchers.
Obstructed and channelized viscoplastic flow in a Hele-Shaw cell
Authors: Hewitt D. R. , Daneshi M. , Balmforth N. J. , Martinez D. M.
Published: February 2016

A theoretical study is presented of the flow of viscoplastic fluid through a Hele-Shaw cell that contains various kinds of obstructions. Circular and elliptical blockages of the cell are considered together with stepwise contractions or expansions in slot width, all within the simplifying approximation of a narrow gap. Specific attention is paid to the flow patterns that develop around the obstacles, particularly any stagnant plugged regions, and the asymptotic limits of relatively small or large yield stress. Periodic arrays of circular contractions or expansions are studied to explore the interference between obstructions. Finally, viscoplastic flow through a cell with randomly roughened walls is examined, and it is shown that constructive interference of local contractions and expansions leads to a pronounced channelization of the flow. An optimization algorithm based on minimization of the pressure drop is derived to construct the path of the channels in the limit of relatively large yield stress or, equivalently, relatively slow flow.
Testing relationships between firm size and perceptions of growth and profitability: An investigation into the practices of Australian ICT SMEs
Authors: Perényi Áron , Yukhanaev Andrey
Published: February 2016

Gibrat’s Law mandates the independence of firm size and growth, while the resource-based view of the firm implies a positive relationship between firm size and profits, to be concluded in a profit–growth trade-off. Empirical studies of entrepreneurial success however, have demonstrated firms’ ability to reach a state of high growth and profitability, despite the trade-offs encapsulated within the profit–growth nexus. Upon assessing the relationships between past profitability, current firm growth and size in Australian ICT SMEs, results demonstrate positive relationships between all three indicators. This suggests that profitability can be considered the most important precursor of entrepreneurial success, and also that successful businesses do not suffer from the trade-offs implied by theory.
A generalisation of a theorem of O. Perron for semilinear evolution equations
Authors: PREDA CIPRIAN
Published: February 2016

We generalise a well-known result of O. Perron from the 30s that connects the asymptotic behavior of a linear homogeneous differential equation with the response of the inhomogeneous associated equation to a certain class of inhomogeneities (for this reason, Perron's result is also referred to as “input-output method”, “test function method” or “admissibility”).

Our extension is twofold, on the one hand, through the means of a (non)linear evolution family, we deal with the mild solution of a nonautonomous semilinear evolution equation and on the other hand, we collect a very general class of inhomogeneities, eligible for a Perron-type approach in this case.

From a technical point of view, the Perron input-output scenario is achieved here by using the Green operator.
A New High-Resolution GPS Multipath Mitigation Technique Using Fast Orthogonal Search
Authors: Tamazin Mohamed , Noureldin Aboelmagd , Korenberg Michael J. , Kamel Ahmed M.
Published: February 2016

The Delay Locked Loop (DLL) tracking algorithm is one of the most widely used in GPS receivers. It uses different correlators such as the Early-Late Slope (ELS) correlator and High-Resolution Correlator (HRC) to mitigate code phase multipath. These techniques are effective for weak multipath environments but they may not be suitable for challenging multipath environments. The Multipath Estimating Delay Lock Loop (MEDLL) shows better performance than the classical methods. However, MEDLL still has limited capabilities in severe multipath environments. This paper introduces a robust multipath mitigation technique based on fast orthogonal search to obtain better delay estimation for GPS receivers. This research utilised a SPIRENT Global Navigation Satellite Systems (GNSS) simulator to compare the performance of the proposed method with other multipath mitigation techniques. Experimental results demonstrated that the performance of the proposed algorithm was better than the classical and advanced techniques under the multipath scenarios tested.
A community mental health team in Northern Ireland: new referrals as a result of civil disorder
Authors: Allen Judith , Cassidy Cahill , Monaghan Clare
Published: February 2016

Objective: Northern Ireland has suffered from civil unrest since 1969. During this time both the nature of violence and the nature of psychiatric services have changed. Considerable variation in incidence figures for psychological consequence of civil unrest exists in the international literature (1). The purpose of our study was to ascertain the workload for a new community mental health team which had accrued solely as a result of civil unrest and the possible implication for the local service. Method: The new patient referrals to a Community Mental Health Team November 1990-91 which were solely and directly consequent on civil disorder were identified. The litigant population was excluded from study. We checked how many still remained in treatment in November 1992 and used Fisher's Exact Test to identify factors associated with still being in treatment at two years. Results: We found that 8.2% of the new referrals satisfied the criteria and 30% remained in treatment at two years. Satisfying criteria for post traumatic stress disorder was not significantly associated with still being in treatment. Remaining in treatment at two years was associated with having received or not received stress management advice in those satisfying post traumatic stress disorder criteria. Conclusion: Civil unrest substantially increased the Community Mental Health Team workload in the first year of existence.
An outbreak of norovirus infection associated with fermented oyster consumption in South Korea, 2013
Authors: CHO H. G. , LEE S. G. , LEE M. Y. , HUR E. S. , LEE J. S. , PARK P. H. , PARK Y. B. , YOON M. H. , PAIK S. Y.
Published: February 2016

An acute gastroenteritis (AGE) outbreak was reported in May 2013 in Gyeonggi Province, South Korea. Eight students who had eaten breakfast on 21 May 2013 at a high-school restaurant exhibited AGE symptoms. Our case-control study showed that a strong association was observed between AGE symptoms and fermented oyster consumption. Virological studies also indicated that noroviruses (NoVs) were detected from both clinical samples and fermented oyster samples, and multiple different genotypes (genogroups GII.4, GII.11 and GII.14) of NoVs were present in both samples. The nucleotide sequence similarity between the strains found in the clinical samples and those in the fermented oysters was more than 99·5%. Therefore, to prevent further outbreaks, proper management of raw oysters is necessary and the food industry should be aware of the risk of viral gastroenteritis posed by fermented oysters contaminated with NoVs.
AVICENNA ON ANIMAL SELF-AWARENESS, COGNITION AND IDENTITY
Authors: Alwishah Ahmed
Published: February 2016

The purpose of this paper is to present a comprehensive and systematic study of Avicenna's account of animal self-awareness and cognition. In the first part, I explain how, for Avicenna, in contrast to human self-awareness, animal self-awareness is taken to be indirect, mixed-up (makhlūṭ), and an intermittent awareness. In his view, animal self-awareness is provided by the faculty of estimation (wahm); hence, in the second part, I explore the cognitive role of the faculty of estimation in animals, and how that relates to self-awareness. The faculty of estimation, according to Avicenna, serves to distinguish one's body and its parts from external objects, and plays a role in connecting the self to its perceptual activities. It follows that animal self-awareness, unlike human self-awareness, is essentially connected to the body. In the third part of the paper, I show that, while Avicenna denies animals awareness of their self-awareness, he explicitly affirms that animals can grasp their individual identity, but, unlike humans, do so incidentally, as part of their perceptual awareness.
GUNDISSALINUS ON NECESSARY BEING: TEXTUAL AND DOCTRINAL ALTERATIONS IN THE EXPOSITION OF AVICENNA'S METAPHYSICA
Authors: Polloni Nicola
Published: February 2016

This article examines the textual alteration strategy carried out by Dominicus Gundissalinus in his original works. One of the most striking examples of this approach can be detected in the large quotation of Ibn Sīnā's Metaphysica I, 6–7 in Gundissalinus’ cosmological treatise De processione mundi, in which the Spanish philosopher variously modifies the text he translated a few years before. After a short presentation of Gundissalinus’ double role as translator and philosopher, the study moves on to the analysis of Ibn Sīnā's doctrine of necessary and possible being, and the five demonstrations of the unrelated uniqueness of necessary being offered by Ibn Sīnā. These arguments are directly quoted by Gundissalinus: nevertheless, the author modifies the text in many passages, here examined through the analysis of some representative excerpts. The results of this enquiry suggest that Gundissalinus is following an effective alteration strategy, envisaging at least two main purposes: the clarification of Ibn Sīnā's line of reasoning, and the doctrinal assimilation of Metaphysica's theories in his original philosophical system. In appendix to this article the whole text of the two versions of Metaphysica I, 6–7 is presented.
Dynamics of heart rate variability analysed through nonlinear and linear dynamics is already impaired in young type 1 diabetic subjects
Authors: Souza Naiara M. , Giacon Thais R. , Pacagnelli Francis L. , Barbosa Marianne P. C. R. , Valenti Vitor E. , Vanderlei Luiz C. M.
Published: February 2016

Background

Autonomic diabetic neuropathy is one of the most common complications of type 1 diabetes mellitus, and studies using heart rate variability to investigate these individuals have shown inconclusive results regarding autonomic nervous system activation.

Aims

To investigate the dynamics of heart rate in young subjects with type 1 diabetes mellitus through nonlinear and linear methods of heart rate variability.

Methods

We evaluated 20 subjects with type 1 diabetes mellitus and 23 healthy control subjects. We obtained the following nonlinear indices from the recurrence plot: recurrence rate (REC), determinism (DET), and Shanon entropy (ES), and we analysed indices in the frequency (LF and HF in ms2 and normalised units – nu – and LF/HF ratio) and time domains (SDNN and RMSSD), through analysis of 1000 R–R intervals, captured by a heart rate monitor.

Results

There were reduced values (p<0.05) for individuals with type 1 diabetes mellitus compared with healthy subjects in the following indices: DET, REC, ES, RMSSD, SDNN, LF (ms2), and HF (ms2). In relation to the recurrence plot, subjects with type 1 diabetes mellitus demonstrated lower recurrence and greater variation in their plot, inter-group and intra-group, respectively.

Conclusion

Young subjects with type 1 diabetes mellitus have autonomic nervous system behaviour that tends to randomness compared with healthy young subjects. Moreover, this behaviour is related to reduced sympathetic and parasympathetic activity of the autonomic nervous system.
Decreased Fronto-Limbic Activation and Disrupted Semantic-Cued List Learning in Major Depressive Disorder
Authors: Kassel Michelle T. , Rao Julia A. , Walker Sara J. , Briceño Emily M. , Gabriel Laura B. , Weldon Anne L. , Avery Erich T. , Haase Brennan D. , Peciña Marta , Considine Ciaran M. , Noll Douglas C. , Bieliauskas Linas A. , Starkman Monica N. , Zubieta Jon-Kar , Welsh Robert C. , Giordani Bruno , Weisenbach Sara L. , Langenecker Scott A.
Published: February 2016

Objectives: Individuals with major depressive disorder (MDD) demonstrate poorer learning and memory skills relative to never-depressed comparisons (NDC). Previous studies report decreased volume and disrupted function of frontal lobes and hippocampi in MDD during memory challenge. However, it has been difficult to dissociate contributions of short-term memory and executive functioning to memory difficulties from those that might be attributable to long-term memory deficits. Methods: Adult males (MDD, n=19; NDC, n=22) and females (MDD, n=23; NDC, n=19) performed the Semantic List Learning Task (SLLT) during functional magnetic resonance imaging. The SLLT Encoding condition consists of 15 lists, each containing 14 words. After each list, a Distractor condition occurs, followed by cued Silent Rehearsal instructions. Post-scan recall and recognition were collected. Groups were compared using block (Encoding-Silent Rehearsal) and event-related (Words Recalled) models. Results: MDD displayed lower recall relative to NDC. NDC displayed greater activation in several temporal, frontal, and parietal regions, for both Encoding-Silent Rehearsal and the Words Recalled analyses. Groups also differed in activation patterns in regions of the Papez circuit in planned analyses. The majority of activation differences were not related to performance, presence of medications, presence of comorbid anxiety disorder, or decreased gray matter volume in MDD. Conclusions: Adults with MDD exhibit memory difficulties during a task designed to reduce the contribution of individual variability from short-term memory and executive functioning processes, parallel with decreased activation in memory and executive functioning circuits. Ecologically valid long-term memory tasks are imperative for uncovering neural correlates of memory performance deficits in adults with MDD. (JINS, 2016, 22, 412–425)
Psychosis and Suicide
Authors: Stefenson Anne , Titelman David
Published: February 2016

Abstract. Background: The life time risk of suicide among patients with long term psychosis is 5-15%. Suicide prevention in this group is a major clinical challenge. Aims: To capture specific characteristics of suicidal communication and critical events preceding suicide in patients with psychosis. Methods: Medical records were examined and a life event inventory applied to a one-year cohort of 21 cases of suicide in the clinical group in Stockholm county. Results: In most cases direct or indirect verbal communication of suicidal thoughts were documented before the suicide. Three months preceeding death, 20 of the 21 subjects had described one or more negative critical experiences, typically physical illness, loss of contact with an important other, loss of "home", and intolerable side effects of medication. In most cases the suicide appeared to be the culmination of prolonged suffering and suicidal deliberations. Conclusions: Suicide prevention among patients with psychosis requires sensitivity, active listening, and responsiveness on the part of the care person to the patient's explicit suicidal communication and perceptions of care-related or other incidents or interactions, even when conveyed in an odd manner or with little emotion. To prevent suicide, attentive and long-term planning in collaboration with the patient is essential.
Symptoms of Alcohol Dependence Predict Suicide Ideation Among Alaskan Undergraduates
Authors: DeCou Christopher R. , Skewes Monica C.
Published: February 2016

Abstract. Background: Previous research has demonstrated an association between alcohol-related problems and suicidal ideation (SI). Aims: The present study evaluated, simultaneously, alcohol consequences and symptoms of alcohol dependence as predictors of SI after adjusting for depressive symptoms and alcohol consumption. Method: A sample of 298 Alaskan undergraduates completed survey measures, including the Young Adult Alcohol Consequences Questionnaire, the Short Alcohol Dependence Data Questionnaire, and the Beck Depression Inventory – II. The association between alcohol problems and SI status was evaluated using sequential logistic regression. Results: Symptoms of alcohol dependence (OR = 1.88, p < .05), but not alcohol-related consequences (OR = 1.01, p = .95), emerged as an independent predictor of SI status above and beyond depressive symptoms (OR = 2.39, p < .001) and alcohol consumption (OR = 1.08, p = .39). Conclusion: Alcohol dependence symptoms represented a unique risk for SI relative to alcohol-related consequences and alcohol consumption. Future research should examine the causal mechanism behind the relationship between alcohol dependence and suicidality among university students. Assessing the presence of dependence symptoms may improve the accuracy of identifying students at risk of SI.
Sea Level and Ice Sheet Changes During Past Warm Periods
Authors: Lecavalier Benoit , Sinclair Gaylen , Vyyerberg Karen
Published: February 2016

PALSEA2 2015 Workshop; Tokyo, Japan, 22–24 July 2015
Radar Technique Shows Magma Flow in 2014 Cape Verde Eruption
Authors: Stanley Sarah
Published: February 2016

The European Space Agency's Sentinel-1 satellite captures volcanic surface changes that reveal the flow below.
Antarctic Meltwater Makes the Ocean Warmer and Fresher
Authors: Sullivan Cody
Published: February 2016

Scientists model how Antarctic meltwater from specific locations could affect the Antarctic Bottom Water, ocean temperatures, and salinity.
Mercury in Rain Increasing in Western and Central United States
Authors: Sullivan Cody
Published: February 2016

Despite tightening emissions rules, mercury concentrations are rising in rainfall wetting western and central regions of the United States. The pollutant may waft in from Asia, scientists speculate.
Correcting the NLRP3 inflammasome deficiency in macrophages from autoimmune NZB mice with exon skipping antisense oligonucleotides
Authors: Thygesen Sara J , Sester David P , Cridland Simon O , Wilton Steve D , Stacey Katryn J
Published: February 2016

Inflammasomes are molecular complexes activated by infection and cellular stress, leading to caspase‐1 activation and subsequent interleukin‐1β (IL‐1β) processing and cell death. The autoimmune NZB mouse strain does not express NLRP3, a key inflammasome initiator mediating responses to a wide variety of stimuli including endogenous danger signals, environmental irritants and a range of bacterial, fungal and viral pathogens. We have previously identified an intronic point mutation in the Nlrp3 gene from NZB mice that generates a splice acceptor site. This leads to inclusion of a pseudoexon that introduces an early termination codon and is proposed to be the cause of NLRP3 inflammasome deficiency in NZB cells. Here we have used exon skipping antisense oligonucleotides (AONs) to prevent aberrant splicing of Nlrp3 in NZB macrophages, and this restored both NLRP3 protein expression and NLRP3 inflammasome activity. Thus, the single point mutation leading to aberrant splicing is the sole cause of NLRP3 inflammasome deficiency in NZB macrophages. The NZB mouse provides a model for addressing a splicing defect in macrophages and could be used to further investigate AON design and delivery of AONs to macrophages in vivo.
Epigenetic re-expression of HIF-2α suppresses soft tissue sarcoma growth
Authors: Nakazawa Michael S. , Eisinger-Mathason T. S. Karin , Sadri Navid , Ochocki Joshua D. , Gade Terence P. F. , Amin Ruchi K. , Simon M. Celeste
Published: February 2016

In soft tissue sarcomas (STS), low intratumoural O2 (hypoxia) is a poor prognostic indicator. HIF-1α mediates key transcriptional responses to hypoxia, and promotes STS metastasis; however, the role of the related HIF-2α protein is unknown. Surprisingly, here we show that HIF-2α inhibits high-grade STS cell growth in vivo, as loss of HIF-2α promotes sarcoma proliferation and increases calcium and mTORC1 signalling in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. We find that most human STS have lower levels of EPAS1 (the gene encoding HIF-2α) expression relative to normal tissue. Many cancers, including STS, contain altered epigenetics, and our findings define an epigenetic mechanism whereby EPAS1 is silenced during sarcoma progression. The clinically approved HDAC inhibitor Vorinostat specifically increases HIF-2α, but not HIF-1α, accumulation in multiple STS subtypes. Vorinostat inhibits STS tumour growth, an effect ameliorated by HIF-2α deletion, implicating HIF-2α as a biomarker for Vorinostat efficacy in STS.
Therapeutically engineered induced neural stem cells are tumour-homing and inhibit progression of glioblastoma
Authors: Bagó Juli R. , Alfonso-Pecchio Adolfo , Okolie Onyi , Dumitru Raluca , Rinkenbaugh Amanda , Baldwin Albert S. , Miller C. Ryan , Magness Scott T. , Hingtgen Shawn D.
Published: February 2016

Transdifferentiation (TD) is a recent advancement in somatic cell reprogramming. The direct conversion of TD eliminates the pluripotent intermediate state to create cells that are ideal for personalized cell therapy. Here we provide evidence that TD-derived induced neural stem cells (iNSCs) are an efficacious therapeutic strategy for brain cancer. We find that iNSCs genetically engineered with optical reporters and tumouricidal gene products retain the capacity to differentiate and induced apoptosis in co-cultured human glioblastoma cells. Time-lapse imaging shows that iNSCs are tumouritropic, homing rapidly to co-cultured glioblastoma cells and migrating extensively to distant tumour foci in the murine brain. Multimodality imaging reveals that iNSC delivery of the anticancer molecule TRAIL decreases the growth of established solid and diffuse patient-derived orthotopic glioblastoma xenografts 230- and 20-fold, respectively, while significantly prolonging the median mouse survival. These findings establish a strategy for creating autologous cell-based therapies to treat patients with aggressive forms of brain cancer.
Supercurrent in van der Waals Josephson junction
Authors: Yabuki Naoto , Moriya Rai , Arai Miho , Sata Yohta , Morikawa Sei , Masubuchi Satoru , Machida Tomoki
Published: February 2016

Supercurrent flow between two superconductors with different order parameters, a phenomenon known as the Josephson effect, can be achieved by inserting a non-superconducting material between two superconductors to decouple their wavefunctions. These Josephson junctions have been employed in fields ranging from digital to quantum electronics, yet their functionality is limited by the interface quality and use of non-superconducting material. Here we show that by exfoliating a layered dichalcogenide (NbSe2) superconductor, the van der Waals (vdW) contact between the cleaved surfaces can instead be used to construct a Josephson junction. This is made possible by recent advances in vdW heterostructure technology, with an atomically flat vdW interface free of oxidation and inter-diffusion achieved by eliminating all heat treatment during junction preparation. Here we demonstrate that this artificially created vdW interface provides sufficient decoupling of the wavefunctions of the two NbSe2 crystals, with the vdW Josephson junction exhibiting a high supercurrent transparency.
A structural and functional magnetic resonance imaging dataset of brain tumour patients
Authors: Pernet Cyril R. , Gorgolewski Krzysztof J. , Job Dominic , Rodriguez David , Whittle Ian , Wardlaw Joanna
Published: February 2016

We collected high resolution structural (T1, T2, DWI) and several functional (BOLD T2*) MRI data in 22 patients with different types of brain tumours. Functional imaging protocols included a motor task, a verb generation task, a word repetition task and resting state. Imaging data are complemented by demographics (age, sex, handedness, and pathology), behavioural results to motor and cognitive tests and direct cortical electrical stimulation data (pictures of stimulation sites with outcomes) performed during surgery. Altogether, these data are suited to test functional imaging methods for single subject analyses, in particular methods that focus on locating eloquent cortical areas, critical functional and/or structural network hubs, and predict patient status based on imaging data (presurgical mapping).
Implication of retinoic acid receptor selective signaling in myogenic differentiation
Authors: Chen Jihong , Li Qiao
Published: February 2016

Signaling molecules are important for committing individual cells into tissue-specific lineages during early vertebrate development. Retinoic acid (RA) is an important vertebrate morphogen, in that its concentration gradient is essential for correct patterning of the vertebrate embryo. RA signaling is mediated through the activation of retinoic acid receptors (RARs), which function as ligand-dependent transcription factors. In this study, we examined the molecular mechanisms of RAR-selective signaling in myogenic differentiation. We found that just like natural ligand RA, a RAR-selective ligand is an effective enhancer in the commitment of skeletal muscle lineage at the early stage of myogenic differentiation. Interestingly, the kinetics and molecular basis of the RAR-selective ligand in myogenic differentiation are similar to that of natural ligand RA. Also similar to natural ligand RA, the RAR-selective ligand enhances myogenic differentiation through β-catenin signaling pathway while inhibiting cardiac differentiation. Furthermore, while low concentrations of natural ligand RA or RAR-selective ligand regulate myogenic differentiation through RAR function and coactivator recruitment, high concentrations are critical to the expression of a model RA-responsive gene. Thus our data suggests that RAR-mediated gene regulation may be highly context-dependent, affected by locus-specific interaction or local chromatin environment.
Graph theoretical analysis of brain connectivity in phantom sound perception
Authors: Mohan Anusha , De Ridder Dirk , Vanneste Sven
Published: February 2016

Tinnitus is a phantom sound commonly thought of to be produced by the brain related to auditory deafferentation. The current study applies concepts from graph theory to investigate the differences in lagged phase functional connectivity using the average resting state EEG of 311 tinnitus patients and 256 healthy controls. The primary finding of the study was a significant increase in connectivity in beta and gamma oscillations and a significant reduction in connectivity in the lower frequencies for the tinnitus group. There also seems to be parallel processing of long-distance information between delta, theta, alpha1 and gamma frequency bands that is significantly stronger in the tinnitus group. While the network reorganizes into a more regular topology in the low frequency carrier oscillations, development of a more random topology is witnessed in the high frequency oscillations. In summary, tinnitus can be regarded as a maladaptive ‘disconnection’ syndrome, which tries to both stabilize into a regular topology and broadcast the presence of a deafferentation-based bottom-up prediction error as a result of a top-down prediction.
Proteolytic and non-proteolytic regulation of collective cell invasion: tuning by ECM density and organization
Authors: Kumar Sandeep , Kapoor Aastha , Desai Sejal , Inamdar Mandar M. , Sen Shamik
Published: February 2016

Cancer cells manoeuvre through extracellular matrices (ECMs) using different invasion modes, including single cell and collective cell invasion. These modes rely on MMP-driven ECM proteolysis to make space for cells to move. How cancer-associated alterations in ECM influence the mode of invasion remains unclear. Further, the sensitivity of the two invasion modes to MMP dynamics remains unexplored. In this paper, we address these open questions using a multiscale hybrid computational model combining ECM density-dependent MMP secretion, MMP diffusion, ECM degradation by MMP and active cell motility. Our results demonstrate that in randomly aligned matrices, collective cell invasion is more efficient than single cell invasion. Although increase in MMP secretion rate enhances invasiveness independent of cell–cell adhesion, sustenance of collective invasion in dense matrices requires high MMP secretion rates. However, matrix alignment can sustain both single cell and collective cell invasion even without ECM proteolysis. Similar to our in-silico observations, increase in ECM density and MMP inhibition reduced migration of MCF-7 cells embedded in sandwich gels. Together, our results indicate that apart from cell intrinsic factors (i.e., high cell–cell adhesion and MMP secretion rates), ECM density and organization represent two important extrinsic parameters that govern collective cell invasion and invasion plasticity.
Skeletal muscle alkaline Pi pool is decreased in overweight-to-obese sedentary subjects and relates to mitochondrial capacity and phosphodiester content
Authors: Valkovič Ladislav , Chmelík Marek , Ukropcová Barbara , Heckmann Thomas , Bogner Wolfgang , Frollo Ivan , Tschan Harald , Krebs Michael , Bachl Norbert , Ukropec Jozef , Trattnig Siegfried , Krššák Martin
Published: February 2016

Defects in skeletal muscle energy metabolism are indicative of systemic disorders such as obesity or type 2 diabetes. Phosphorus magnetic resonance spectroscopy (31P-MRS), in particularly dynamic31P-MRS, provides a powerful tool for the non-invasive investigation of muscular oxidative metabolism. The increase in spectral and temporal resolution of31P-MRS at ultra high fields (i.e., 7T) uncovers new potential for previously implemented techniques, e.g., saturation transfer (ST) or highly resolved static spectra. In this study, we aimed to investigate the differences in muscle metabolism between overweight-to-obese sedentary (Ob/Sed) and lean active (L/Ac) individuals through dynamic, static and ST31P-MRS at 7T. In addition, as the dynamic31P-MRS requires a complex setup and patient exercise, our aim was to identify an alternative technique that might provide a biomarker of oxidative metabolism. The Ob/Sed group exhibited lower mitochondrial capacity, and, in addition, static31P-MRS also revealed differences in the Pi-to-ATP exchange flux, the alkaline Pi-pool and glycero-phosphocholine concentrations between the groups. In addition to these differences, we have identified correlations between dynamically measured oxidative flux and static concentrations of the alkaline Pi-pool and glycero-phosphocholine, suggesting the possibility of using high spectral resolution31P-MRS data, acquired at rest, as a marker of oxidative metabolism.
Distinctive origin of artemisinin-resistant Plasmodium falciparum on the China-Myanmar border
Authors: Ye Run , Hu Dongwei , Zhang Yilong , Huang Yufu , Sun Xiaodong , Wang Jian , Chen Xuedi , Zhou Hongning , Zhang Dongmei , Mungthin Mathirut , Pan Weiqing
Published: February 2016

The artemisinin (ART), discovered in China, has been widely used against malaria in China over the last 30 years. Understanding the emergence and origin of ART resistance in China is therefore of great interest. We analyzed 111 culture-adapted isolates of P. falciparum from China-Myanmar (CM) border for their susceptibility to dihydroartemisinin using the ring stage survival assay (RSA0−3h) and genotyped their K13 genes. Of the isolates, 59 had a wild type of the K13 marker and a median ring survival rate of 0.26% (P95 = 1.005%). Among the remaining isolates harboring single mutations in the K13 marker, 26 survived at >P95(median survival rate = 2.95%). Further, we genotyped the K13 gene of 693 isolates collected from different regions in China and China-Myanmar/Thai-Cambodia/Thai-Myanmar (CM/TC/TM) borders, 308 (44.4%) had K13 mutations and marked differences in the patterns of K13 mutations were observed between the CM and the TC/TM borders. A network diagram showed that majority of the K13 mutant alleles from the CM border clustered together including those harboring the high resistant-associated R539T mutations. The resistant parasites carrying distinct halplotypes suggested the multiple indigenous origins of the resistant alleles, which highlight the importance of surveillance of resistance in all malaria endemic areas where ART has been introduced.
A physiological role of cyclic electron transport around photosystem I in sustaining photosynthesis under fluctuating light in rice
Authors: Yamori Wataru , Makino Amane , Shikanai Toshiharu
Published: February 2016

Plants experience a highly variable light environment over the course of the day. To reveal the molecular mechanisms of their photosynthetic response to fluctuating light, we examined the role of two cyclic electron flows around photosystem I (CEF-PSI)—one depending on PROTON GRADIENT REGULATION 5 (PGR5) and one on NADH dehydrogenase-like complex (NDH)—in photosynthetic regulation under fluctuating light in rice (Oryza sativaL.). The impairment of PGR5-dependent CEF-PSI suppressed the photosynthetic response immediately after sudden irradiation, whereas the impairment of NDH-dependent CEF-PSI did not. However, the impairment of either PGR5-dependent or NDH-dependent CEF-PSl reduced the photosynthetic rate under fluctuating light, leading to photoinhibition at PSI and consequently a reduction in plant biomass. The results highlight that (1) PGR5-dependent CEF-PSI is a key regulator of rapid photosynthetic responses to high light intensity under fluctuating light conditions after constant high light; and (2) both PGR5-dependent and NDH-dependent CEF-PSI have physiological roles in sustaining photosynthesis and plant growth in rice under repeated light fluctuations. The highly responsive regulatory system managed by CEF-PSI appears able to optimize photosynthesis and plant growth under naturally fluctuating light conditions.
The Citrus transcription factor, CitERF13, regulates citric acid accumulation via a protein-protein interaction with the vacuolar proton pump, CitVHA-c4
Authors: Li Shao-jia , Yin Xue-ren , Xie Xiu-lan , Allan Andrew C. , Ge Hang , Shen Shu-ling , Chen Kun-song
Published: February 2016

Organic acids are essential to fruit flavor. The vacuolar H+ transporting adenosine triphosphatase (V-ATPase) plays an important role in organic acid transport and accumulation. However, less is known of V-ATPase interacting proteins and their relationship with organic acid accumulation. The relationship between V-ATPase and citric acid was investigated, using the citrus tangerine varieties ‘Ordinary Ponkan (OPK)’ and an early maturing mutant ‘Zaoshu Ponkan (ZPK)’. Five V-ATPase genes (CitVHA) were predicted as important to citric acid accumulation. Among the genes, CitVHA-c4 was observed, using a yeast two-hybrid screen, to interact at the protein level with an ethylene response factor, CitERF13. This was verified using bimolecular fluorescence complementation assays. A similar interaction was also observed between Arabidopsis AtERF017 (a CitERF13 homolog) and AtVHA-c4 (a CitVHA-c4 homolog). A synergistic effect on citric acid levels was observed between V-ATPase proteins and interacting ERFs when analyzed using transient over-expression in tobacco and Arabidopsis mutants. Furthermore, the transcript abundance of CitERF13 was concomitant with CitVHA-c4. CitERF13 or AtERF017 over-expression leads to significant citric acid accumulation. This accumulation was abolished in an AtVHA-c4 mutant background. ERF-VHA interactions appear to be involved in citric acid accumulation, which was observed in both citrus and Arabidopsis.
The promoter methylomes of monochorionic twin placentas reveal intrauterine growth restriction-specific variations in the methylation patterns
Authors: He Zhiming , Lu Hanlin , Luo Huijuan , Gao Fei , Wang Tong , Gao Yu , Fang Qun , Wang Junwen
Published: February 2016

Intrauterine growth restriction (IUGR) affects the foetus and has a number of pathological consequences throughout life. Recent work has indicated that variations in DNA methylation might cause placental dysfunction, which may be associated with adverse pregnancy complications. Here, we investigated the promoter methylomes of placental shares from seven monochorionic (MC) twins with selective intrauterine growth restriction (sIUGR) using the healthy twin as an ideal control. Our work demonstrated that the IUGR placental shares harboured a distinct DNA hypomethylation pattern and that the methylation variations preferentially occurred in CpG island shores or non-CpG island promoters. The differentially methylated promoters could significantly separate the IUGR placental shares from the healthy ones. Ultra‐performance liquid chromatography/tandem mass spectrometry (UPLC‐MS/MS) further confirmed the genome‐wide DNA hypomethylation and the lower level of hydroxymethylation statuses in the IUGR placental shares. The methylation variations of theLRATandSLC19A1promoters, which are involved in vitamin A metabolism and folate transportation, respectively and theEFSpromoter were further validated in an additional 12 pairs of MC twins with sIUGR. Although the expressions ofLRAT,SLC19A1andEFSwere not affected, we still speculated that DNA methylation and hydroxymethylation might serve a functional role duringin uterofoetal development.
Severe impairment of male reproductive organ development in a low SMN expressing mouse model of spinal muscular atrophy
Authors: Ottesen Eric W. , Howell Matthew D. , Singh Natalia N. , Seo Joonbae , Whitley Elizabeth M. , Singh Ravindra N.
Published: February 2016

Spinal muscular atrophy (SMA) is caused by low levels of survival motor neuron (SMN), a multifunctional protein essential for higher eukaryotes. While SMN is one of the most scrutinized proteins associated with neurodegeneration, its gender-specific role in vertebrates remains unknown. We utilized a mild SMA model (C/C model) to examine the impact of low SMN on growth and development of mammalian sex organs. We show impaired testis development, degenerated seminiferous tubules, reduced sperm count and low fertility in C/C males, but no overt sex organ phenotype in C/C females. Underscoring an increased requirement for SMN expression, wild type testis showed extremely high levels of SMN protein compared to other tissues. Our results revealed severe perturbations in pathways critical to C/C male reproductive organ development and function, including steroid biosynthesis, apoptosis and spermatogenesis. Consistent with enhanced apoptosis in seminiferous tubules of C/C testes, we recorded a drastic increase in cells with DNA fragmentation. SMN was expressed at high levels in adult C/C testis due to an adult-specific splicing switch, but could not compensate for low levels during early testicular development. Our findings uncover novel hallmarks of SMA disease progression and link SMN to general male infertility.
Callous traits in children with and without conduct problems predict reduced connectivity when viewing harm to others
Authors: Yoder Keith J. , Lahey Benjamin B. , Decety Jean
Published: February 2016

The presence of elevated callous unemotional (CU) traits seems to designate a distinct group of children and adolescents with serious conduct problems. However, the extent to which CU traits impact the aversive reaction to harm is still a contentious issue. Here, we examined the effective connectivity seeded in the anterior insula and anterior cingulate cortex in a large number of children (N = 123, age 9–11, 60 females) with various levels of conduct disorder (CD) symptoms in response to visual stimuli depicting other people being physically injured. Perceiving others being harmed was associated with increased hemodynamic activity in the left amygdala and right temporoparietal junction (rTPJ). Children with higher callous traits showed less functional connectivity seeded in anterior cingulate with left amygdala and anterior insula. Conversely, CD symptoms were positively related to connectivity of insula with rTPJ. Overall, these results suggest that callousness is marked by the disruption of widespread cortical networks responsible for detecting and appropriately responding to important environmental cues, such as the distress of others.
Integration or separation in the processing of facial properties - a computational view
Authors: Dahl Christoph D. , Rasch Malte J. , Bülthoff Isabelle , Chen Chien-Chung
Published: February 2016

A face recognition system ought to read out information about the identity, facial expression and invariant properties of faces, such as sex and race. A current debate is whether separate neural units in the brain deal with these face properties individually or whether a single neural unit processes in parallel all aspects of faces. While the focus of studies has been directed toward the processing of identity and facial expression, little research exists on the processing of invariant aspects of faces. In a theoretical framework we tested whether a system can deal with identity in combination with sex, race or facial expression using the same underlying mechanism. We used dimension reduction to describe how the representational face space organizes face properties when trained on different aspects of faces. When trained to learn identities, the system not only successfully recognized identities, but also was immediately able to classify sex and race, suggesting that no additional system for the processing of invariant properties is needed. However, training on identity was insufficient for the recognition of facial expressions and vice versa. We provide a theoretical approach on the interconnection of invariant facial properties and the separation of variant and invariant facial properties.
Nifuroxazide exerts potent anti-tumor and anti-metastasis activity in melanoma
Authors: Zhu Yongxia , Ye Tinghong , Yu Xi , Lei Qian , Yang Fangfang , Xia Yong , Song Xuejiao , Liu Li , Deng Hongxia , Gao Tiantao , Peng Cuiting , Zuo Weiqiong , Xiong Ying , Zhang Lidan , Wang Ningyu , Zhao Lifeng , Xie Yongmei , Yu Luoting , Wei Yuquan
Published: February 2016

Melanoma is a highly malignant neoplasm of melanocytes with considerable metastatic potential and drug resistance, explaining the need for new candidates that inhibit tumor growth and metastasis. The signal transducer and activator of the transcription 3 (Stat3) signaling pathway plays an important role in melanoma and has been validated as promising anticancer target for melanoma therapy. In this study, nifuroxazide, an antidiarrheal agent identified as an inhibitor of Stat3, was evaluated for its anti-melanoma activity in vitro and in vivo. It had potent anti-proliferative activity against various melanoma cell lines and could induce G2/M phase arrest and cell apoptosis. Moreover, nifuroxazide markedly impaired melanoma cell migration and invasion by down-regulating phosphorylated-Src, phosphorylated-FAK and expression of matrix metalloproteinase (MMP) -2, MMP-9 and vimentin. It also significantly inhibited tumor growth without obvious side effects in the A375-bearing mice model by inducing apoptosis and reducing cell proliferation and metastasis. Notably, nifuroxazide significantly inhibited pulmonary metastases, which might be associated with the decrease of myeloid-derived suppressor cells (MDSCs). These findings suggested that nifuroxazide might be a potential agent for inhibiting the growth and metastasis of melanoma.
A micro-scale simulation of red blood cell passage through symmetric and asymmetric bifurcated vessels
Authors: Wang Tong , Rongin Uwitije , Xing Zhongwen
Published: February 2016

Blood exhibits a heterogeneous nature of hematocrit, velocity and effective viscosity in microcapillaries. Microvascular bifurcations have a significant influence on the distribution of the blood cells and blood flow behavior. This paper presents a simulation study performed on the two-dimensional motions and deformation of multiple red blood cells in microvessels with diverging and converging bifurcations. Fluid dynamics and membrane mechanics were incorporated. Effects of cell shape, hematocrit and deformability of the cell membrane on rheological behavior of the red blood cells and the hemodynamics have been investigated. It was shown that the blood entering the daughter branch with a higher flow rate tended to receive disproportionally more cells. The results also demonstrate that red blood cells in microvessels experienced lateral migration in the parent channel and blunted velocity profiles in both straight section and daughter branches and this effect was influenced by the shape and the initial position of the cells, the hematocrit and the membrane deformability. In addition, a cell free region around the tip of the confluence was observed. The simulation results are qualitatively consistent with existing experimental findings. This study may provide fundamental knowledge for a better understanding of hemodynamic behavior of micro-scale blood flow.