bluuebunny/crossref_metadata_2025 huggingface dataset:
Exacerbation of myasthenia gravis in a patient with melanoma treated with pembrolizumab
Authors: Lau K. H. Vincent , Kumar Aditya , Yang Irene Hwa , Nowak Richard J.
Published: April 2016

Introduction: While anticancer immunotherapies have traditionally focused on activation of the immune system, there is recent interest in disinhibition of the natural antitumor immune response by targeting immune checkpoints such as cytotoxic T‐lymphocyte associated antigen‐4 (CTLA‐4) and programmed death‐1 (PD‐1). One humanized monoclonal antibody against PD‐1, pembrolizumab, was recently approved for treatment of metastatic malignant melanoma. Methods: We report exacerbation of myasthenia gravis (MG) after treatment with pembrolizumab and provide a brief literature review. Results: We describe a 75‐year‐old man with stable MG who experienced myasthenic crisis in the setting of pembrolizumab treatment. A concurrent azathioprine taper was a possible although unlikely contributor given the short time interval between taper and exacerbation. Conclusions: As long‐term data become available regarding the adverse immune effects of novel checkpoint inhibitors, clinicians should be mindful of their risks/benefits and of possible autoimmune disease exacerbation. Muscle Nerve 54: 157–161, 2016
Delamination growth in composite laminates of variable stiffness
Authors: Yazdani Saleh , Rust Wilhelm J. H. , Wriggers Peter
Published: April 2016

The production of new composite laminates with variable stiffness within the surface of plies was enabled by tow‐placement machines. Because of the variation of stiffness, these materials are called variable stiffness composite laminates (VSCL). Recently, many attempts were made to investigate their structural behaviour. In this contribution, a first‐order shear deformation theory is selected to model the multilayered composite laminates. The adopted theory is enhanced by the extended finite element method (XFEM) to describe discontinuities at element level of any interface of interest. To predict the location of the delamination onset, a traction–separation law is developed that is consistent with the XFEM topology. An exponential softening behaviour is implemented within the interface to model the delamination growth in a mixed‐mode direction. In order to solve the non‐linear equations of the delamination propagation, an arc‐length method is applied. The effect of the curvilinear fibre orientation on the location of the delamination onset is investigated. Subsequently, the structural response of the laminates is computed. According to the simplicity of the new approach using the XFEM; and based on the computational cost for calculating the stiffness of VSCL, the method is able to determine structural response of VSCL with less computational effort. Copyright © 2016 John Wiley & Sons, Ltd.
Outlining the psychopathology behind a case of conversion syndrome: Is a holistic approach beneficial?
Authors: Aquilina Francesca Falzon , Fondacaro Daniel Vella
Published: April 2016

Conversion disorder refers to a set of symptoms where no relevant organic cause is found. These include sensory/motor disturbances, and other neurological symptoms, such as pseudoseizures. Patients with this condition may, by having it, achieve a primary or secondary gain. The condition should be diagnosed when all the relevant investigations are inconclusive. In this case, we use the bio‐psycho‐social model for the interpretation and guidance of treatment. We also demonstrate how a holistic approach is beneficial when it comes to a multi‐dimensional interpretation of such a case. This review outlines a case of a patient with several neurological and orthopedic problems who failed to improve with several treatment plans and surgical interventions. After several years of medical and surgical consultations, a thorough analysis by psychiatrists was made, resulting in a diagnosis of conversion syndrome. The patient gradually improved on psychiatric treatment, including psychotherapy, and with the necessary psychiatric follow‐ups.
Resolution of flashbacks of PTSD with propranolol: a case report
Authors: Chandavarkar Rahul , Sangha Sukhjinder , Khalil Salwa
Published: April 2016

An individual suffering from post‐traumatic stress disorder (PTSD) can continue to re‐experience the traumatic incident, which can involve a sense of extreme fear. In this article, the authors describe the case of a 36‐year‐old gentleman in whom the use of propranolol for the management of these persistent PTSD symptoms proved beneficial and led to the resolution of his flashback symptoms following difficulty in initial management with multiple other first‐line treatment modalities. Propranolol is currently not licensed for use in PTSD.
Flexural strengthening and repair of RC slabs by adding a new RC layer
Authors: Aykac Sabahattin , Kalkan Ilker , Tankut Tugrul
Published: April 2016

The present paper summarizes the findings of an experimental programme to investigate a strengthening/repair technique through the introduction of a new RC layer to an existing slab. Six RC slabs, composed of twelve cantilever and six interior spans, were tested under monotonic transverse loading. The behaviour of statically determinate cantilever spans and indeterminate interior spans was examined by comparing the test results of these specimens to the results of reference slabs, in which the existing and additional layers were cast monolithically. The influences of recovering the permanent slab deformation before repair and the spacing of the shear connectors between the existing and additional layers were investigated. The tests indicated that recovering the permanent deformations of a slab before repair substantially reduces its rigidity while having little influence on the ultimate load. Furthermore, debonding of the reinforcement was observed to considerably decrease the load capacities and rigidities of the slabs.
The monitored and theoretical ultimate moment and ductility of pre‐tensioned HSSCC bridge girders
Authors: Maghsoudi Mohammad , Maghsoudi Aliakbar , Heshmati Arash Ali
Published: April 2016

Self‐compacting concrete (SCC) is defined as highly flowable and non‐segregating concrete that does not require mechanical ‐vibration during application. Load testing of bridge girders was investigated on full scale T‐beams of pre‐tensioned high strength self‐compacting concrete (PHSSCC). The girders were monitored by fixing different types of sensors at different locations.

The results of ultimate moment are compared to evaluate if such girders can be designed using AASHTO Load and Resistance Factor Design (LRFD) Specifications; AASHTO Standard Specifications for Highway Bridges (STD) and the PCI Bridge Design Manual are intended for structures constructed using conventional (non‐vibrated) concrete. It is concluded that good agreement in results exists for the two methods.

Investigations (theoretical and experimental) are needed on the issue of ductility in structural prestressed elements constructed in seismic zones or even, the issue of high strength in SCC. These have also been studied here, with the conclusion that ‐suitable ductility for this type of structure, as would be needed in seismic regions, can be achieved.
Chromosomal microarray analysis in fetuses with aberrant right subclavian artery
Authors: Maya I. , Kahana S. , Yeshaya J. , Tenne T. , Yacobson S. , Agmon‐Fishman I. , Cohen‐Vig L. , Levi A. , Reinstein E. , Basel‐Vanagaite L. , Sharony R.
Published: April 2016

Objective

To evaluate the association between aberrant right subclavian artery (ARSA), with or without additional risk factors for aneuploidy or ultrasound abnormality, and results of chromosomal microarray analysis (CMA).

Methods

This was a multicenter study of fetuses diagnosed with ARSA that underwent genetic analysis by CMA, all samples being analyzed in the same laboratory. Clinical investigation included nuchal translucency measurement, first‐ and second‐trimester maternal serum screening, early and late second‐trimester fetal anatomy scans and fetal echocardiography. Comparative genomic hybridization microarray analysis or single‐nucleotide polymorphism array technology was used for CMA of DNA samples obtained from amniotic fluid.

Results

CMA results were available for 63 fetuses with ARSA. In 36 fetuses, ARSA was an isolated finding, and no pathogenic variant was found. Additional ultrasound findings and/or risk factors for aneuploidy were present in 27 fetuses, five of which had pathogenic CMA results. Of these five, trisomy 21 was detected in a fetus with echogenic intracardiac focus (EIF), 22q11 deletion was detected in a fetus with EIF and an increased risk of trisomy 21 of 1:230 from maternal serum screening, 22q11 duplication was detected in a fetus with hypoplastic right kidney and choroid plexus cyst and 22q11 deletion was detected in a fetus with right aortic arch and clubfoot. The fifth fetus had increased nuchal translucency thickness (4 mm) and a ventricular septal defect, and CMA identified both 22q11 deletion and 1q21 duplication.

Conclusions

In fetuses with isolated ARSA, an invasive procedure for CMA is not indicated. However, CMA is recommended when additional ultrasound abnormalities or risk factors for aneuploidy are observed. The chromosomal findings in four of the five cases with an abnormal CMA result in our study would not have been detected by standard fetal chromosomal testing. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.
Performance Enhancement of Centrifugal Compressors Utilizing Impeller Tip Injection
Authors: Taghavi-Zenouz R. , Solki E. , Afshari H.
Published: April 2016

Effects of air injection on a centrifugal compressor performance are studied numerically and results are presented in this paper. Flow field is simulated based on solution of the Reynolds-Averaged Navier-Stokes equations utilizing the well-known k-ε turbulence modeling. To find optimum arrangement of the air injectors, including their numbers, positions and setting angles and also their mass flow rates, 10 different cases were proposed in this investigation. Results of velocity and pressure fields and streamlines patterns on various blade-to-blade and streamwise planes provided necessary data for analyses and discussions. These results revealed that a proper air tip injection can weaken the tip leakage flow strength and alleviate the blockages to the main stream near the casing. Hence, this technique can be used to extend the stable operating range of the compressor and delay the probable stall commencement. In addition, compressor can produce higher pressure ratios in cases of proper injections in comparison to no-injection case. Optimum injection configuration improved the stall margin of the proposed compressor by nearly 15.8%. Numerical results for no-injection case were compared with those of the authors own experimental works carried out on a proper test rig, which showed close agreement.
The Needham Question Today
Authors: Redding Gordon
Published: April 2016

The Needham Puzzle is part of a larger and very complex historical enigma. What explains the slow-down in scientific innovation in China about five hundred years ago? Also, after a recent forty-year period of growth not heavily dependent on spontaneous innovation, are such inherited influences returning to the surface as significant obstacles at a time when innovativeness is becoming more strategic?
The Diverse Effects of Diversity on Democracy
Authors: Gerring John , Hoffman Michael , Zarecki Dominic
Published: April 2016

Diverse identities coexisting within the same society are often viewed as problematic for economic and political development. This article argues that different types of social diversity have differential effects on regime type. Specifically, ethno-linguistic diversity increases prospects for democracy while religious diversity decreases prospects for democracy. The article presents a variety of reasons why diversity might have divergent causal effects on regime type. Cross-national regressions in a variety of econometric formats – including instrumental variables – provide corroborating evidence for the argument.
Feeding preferences and functional responses ofCalathus granatensisandPterostichus globosus(Coleoptera: Carabidae) on pupae ofBactrocera oleae(Diptera: Tephritidae)
Authors: Dinis A.M. , Pereira J.A. , Benhadi-Marín J. , Santos S.A.P.
Published: April 2016

Carabid beetles are important predators in agricultural landscapes feeding on a range of prey items. However, their role as predators of the olive fruit fly,Bactrocera oleae(Rossi) (Diptera: Tephritidae), one of the most serious pests of olives, is unknown. In this context, the feeding preferences and the functional responses of two carabid beetle species,Calathus granatensis(Vuillefroy) andPterostichus globosus(Fabricius), were studied under laboratory conditions. Feeding preference assays involved exposing carabid beetles to different ratios ofB. oleaepupae and an alternative prey, the Mediterranean fruit fly,Ceratitis capitata(Wiedemann). Both species fed onB. oleaepupae however,C. granatensisalways showed a significant preference for that prey whereasP. globosusswitched toC. capitatapupae when the offered ratio was below 0.5. The total prey biomass consumed was significantly higher forP. globosusthan forC. granatensis. Functional response curves were estimated based on different densities ofB. oleaepupae and both carabid beetle species exhibited a type II functional response using Rogers’ random-predator equation.P. globosusshowed shorter handling time (1.223 ± 0.118 h) onB. oleaepupae thanC. granatensis(3.230 ± 0.627 h). Our results suggest that both species can be important in reducing the densities ofB. oleaein olive groves, althoughP. globosuswas more efficient thanC. granatensis.
Overwintering biology and limits of cold tolerance in larvae of pistachio twig borer,Kermania pistaciella
Authors: Mollaei M. , Izadi H. , Šimek P. , Koštál V.
Published: April 2016

Pistachio twig borer,Kermania pistaciellais an important pest of pistachio trees. It has an univoltine life-cycle and its larvae tunnel and feed inside pistachio twigs for almost 10 months each year. The last larval instars overwinter inside the twigs. Survival/mortality associated with low temperatures during overwintering stage is currently unknown. We found that overwintering larvae of the Rafsanjan (Iran) population ofK. pistaciellarely on maintaining a stably high supercooling capacity throughout the cold season. Their supercooling points (SCPs) ranged between −19.4 and −22.7°C from October to February. Larvae were able to survive 24 h exposures to −15°C anytime during the cold season. During December and January, larvae were undergoing quiescence type of dormancy caused probably by low ambient temperatures and/or changes in host tree physiology (tree dormancy). Larvae attain highest cold tolerance (high survival at −20°C) during dormancy, which offers them sufficient protection against geographically and ecologically relevant cold spells. High cold tolerance during dormancy was not associated with accumulation of any low-molecular mass cryoprotective substances. The SCP sets the limit of cold tolerance in pistachio twig borer, meaning that high mortality of overwintering populations can be expected only in the regions or years where or when the temperatures fall below the average larval SCP (i.e., below −20°C). Partial mortality can be expected also when temperatures repeatedly drop close to the SCP on a diurnal basis.
Status of the ‘Mangrove tunicate’Ecteinascidia turbinata(Ascidiacea: Perophoridae) in the Mediterranean Sea
Authors: Maciver Sutherland K. , Evans Julian , Borg Joseph A. , Ramos-Esplá Alfonso A. , Schembri Patrick J.
Published: April 2016

The ascidianEcteinascidia turbinatais reported from Maltese waters for the first time. Mature colonies were recorded on artificial substrata at two different sites (and on natural substrata at one of these), 4 km apart, during the summer months. The appearance of this ascidian is expected to be seasonal as the winter temperature in Malta may fall below that required for the maintenance of zooid growth. A second species,E. moorei, which was described in 1890 is here confirmed to be the same asE. turbinata, meaning that the species has existed in the Mediterranean since at least ~1880. The possibility that the Mediterranean population is a relic one from warmer periods cannot yet be excluded, so it is best described as being cryptogenic. The species appears to be spreading slowly, perhaps as a result of the rise in surface sea temperature. The Maltese sites offer an opportunity to monitor the species as they are accessible dive sites. This will allow assessment of whether this species remains restricted to these sites, or if it spreads perhaps to impact other species.
Life history traits and population dynamics of the invasive ascidian, Ascidiella aspersa, on cultured scallops in Funka Bay, Hokkaido, northern Japan
Authors: Kanamori Makoto , Baba Katsuhisa , Natsuike Masafumi , Goshima Seiji
Published: April 2016

The European sea squirt, Ascidiella aspersa was first found as an alien species in 2008 from Funka Bay, Hokkaido, northern Japan, causing serious damage to the scallop aquaculture industry. We investigated A. aspersa on cultured scallops and larval occurrence from July 2010 to June 2014 to clarify life history traits and population dynamics, and consider the relation between the life history of A. aspersa and the process of scallop aquaculture. Larvae of A. aspersa were found from June to December, and recruitment on cultured scallops occurred mainly between July and October. The ascidians grew well and their weights increased until February. We found that 60–80% of A. aspersa that had settled in summer had eggs or sperm in autumn, and 90–100% of A. aspersa matured early the following summer. Maturity size in September was 17–20 mm as male, 22–24 mm as female. Scallops in Funka Bay are hung in the spring and harvested from winter to the next spring. Ascidiella aspersa settle as larvae in early summer, and grow well until winter, resulting in overgrowth on scallops in the harvest season. The linking of the process of scallop aquaculture and the life history of A. aspersa explains why this invasive ascidian has caused serious damage to the aquaculture industry in the bay. In comparison to the earlier descriptions of the native population, A. aspersa in Funka Bay has longer reproductive and growth periods, earlier initiation of reproduction, and possibly smaller maturity size.
High energy electron radiography scheme with high spatial and temporal resolution in three dimension based on a e-LINAC
Authors: Zhao Y. , Zhang Z. , Gai W. , Du Y. , Cao S. , Qiu J. , Zhao Q. , Cheng R. , Zhou X. , Ren J. , Huang W. , Tang C. , Xu H. , Zhan W.
Published: April 2016

We present a scheme of electron beam radiography to dynamically diagnose the high energy density (HED) matter in three orthogonal directions simultaneously based on electron Linear Accelerator. The dynamic target information such as, its profile and density could be obtained through imaging the scattered electron beam passing through the target. Using an electron bunch train with flexible time structure, a very high temporal evolution could be achieved. In this proposed scheme, it is possible to obtain 1010 frames/second in one experimental event, and the temporal resolution can go up to 1 ps, spatial resolution to 1 µm. Successful demonstration of this concept will have a major impact for both future inertial confinement fusion science and HED physics research.
CHALLENGES IN CONTEMPORARY HEALTH TECHNOLOGY ASSESSMENT: A VIEW FROM THE OUTSIDE
Authors: Oortwijn Wija , van der Wilt Gert Jan
Published: April 2016

The Special Interest Group on Ethics and HTA (health technology assessment) has invited two renowned philosophers, Norman Daniels from Harvard University and Henry Richardson from Georgetown University to reflect on the role of HTA in healthcare policy making. Both acknowledge its importance, but at the same time warn against a too mechanistic deployment of HTA. In their view, the relevance of HTA to healthcare policy making would considerably be enhanced if it were subsumed within a broader deliberative framework. Why should this be so? What is there to deliberate on, who should do the deliberating, where and when, and how does this relate to the more technical elements of HTA such as evidence synthesis and economic modeling?
A monoidal algebraic model for rational SO(2)-spectra
Authors: BARNES DAVID
Published: April 2016

The category of rational SO(2)–equivariant spectra admits an algebraic model. That is, there is an abelian category ${\mathcal A}$(SO(2)) whose derived category is equivalent to the homotopy category of rational SO(2)–equivariant spectra. An important question is: does this algebraic model capture the smash product of spectra?

The category ${\mathcal A}$(SO(2)) is known as Greenlees' standard model, it is an abelian category that has no projective objects and is constructed from modules over a non–Noetherian ring. As a consequence, the standard techniques for constructing a monoidal model structure cannot be applied. In this paper a monoidal model structure on ${\mathcal A}$(SO(2)) is constructed and the derived tensor product on the homotopy category is shown to be compatible with the smash product of spectra. The method used is related to techniques developed by the author in earlier joint work with Roitzheim. That work constructed a monoidal model structure on Franke's exotic model for the K(p)–local stable homotopy category.

A monoidal Quillen equivalence to a simpler monoidal model category R•-mod that has explicit generating sets is also given. Having monoidal model structures on ${\mathcal A}$(SO(2)) and R•-mod removes a serious obstruction to constructing a series of monoidal Quillen equivalences between the algebraic model and rational SO(2)–equivariant spectra.
Climate change and agricultural productivity in Brazil: future perspectives
Authors: Assunção Juliano , Chein Flávia
Published: April 2016

This paper evaluates the impact of climate change on agricultural productivity. Cross-sectional variation in climate among Brazilian municipalities is used to estimate an equation in which geographical attributes determine agricultural productivity. The Intergovernmental Panel on Climate Change (IPCC) predictions based on atmosphere–ocean, coupled with general circulation models (for 2030–2049), are used to simulate the impacts of climate change. Our estimates suggest that global warming under the current technological standards is expected to decrease the agricultural output per hectare in Brazil by 18 per cent, with the effects on municipalities ranging from−40 to+15 per cent.
DemocracyvHuman Rights? The Strasbourg Court and the Challenge of Power Sharing
Authors: Graziadei Stefan
Published: April 2016

Tension between ‘rights’ and ‘democracy’ principle in highly political cases – ECtHR’s wide margin of appreciation on elections put into question by recent cases –Sejdic-FincivBosnia-Herzegovina (BiH): ethnic criteria for standing in election violate Convention –ZornicvBiH: candidate’s exclusion from standing in election on account of her self-chosen identity violates P-12 –Mathieu-Mohin and ClerfaytvBelgiumoverruled? – ‘Integrative democratic tolerance’ approach: five legal and political principles to reconcile ‘rights’ and ‘democracy’ principle in highly political cases.
Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy
Authors: Freyermuth Fernande , Rau Frédérique , Kokunai Yosuke , Linke Thomas , Sellier Chantal , Nakamori Masayuki , Kino Yoshihiro , Arandel Ludovic , Jollet Arnaud , Thibault Christelle , Philipps Muriel , Vicaire Serge , Jost Bernard , Udd Bjarne , Day John W. , Duboc Denis , Wahbi Karim , Matsumura Tsuyoshi , Fujimura Harutoshi , Mochizuki Hideki , Deryckere François , Kimura Takashi , Nukina Nobuyuki , Ishiura Shoichi , Lacroix Vincent , Campan-Fournier Amandine , Navratil Vincent , Chautard Emilie , Auboeuf Didier , Horie Minoru , Imoto Keiji , Lee Kuang-Yung , Swanson Maurice S. , de Munain Adolfo Lopez , Inada Shin , Itoh Hideki , Nakazawa Kazuo , Ashihara Takashi , Wang Eric , Zimmer Thomas , Furling Denis , Takahashi Masanori P. , Charlet-Berguerand Nicolas
Published: April 2016

Myotonic dystrophy (DM) is caused by the expression of mutant RNAs containing expanded CUG repeats that sequester muscleblind-like (MBNL) proteins, leading to alternative splicing changes. Cardiac alterations, characterized by conduction delays and arrhythmia, are the second most common cause of death in DM. Using RNA sequencing, here we identify novel splicing alterations in DM heart samples, including a switch from adult exon 6B towards fetal exon 6A in the cardiac sodium channel, SCN5A. We find that MBNL1 regulates alternative splicing of SCN5A mRNA and that the splicing variant of SCN5A produced in DM presents a reduced excitability compared with the control adult isoform. Importantly, reproducing splicing alteration of Scn5a in mice is sufficient to promote heart arrhythmia and cardiac-conduction delay, two predominant features of myotonic dystrophy. In conclusion, misregulation of the alternative splicing of SCN5A may contribute to a subset of the cardiac dysfunctions observed in myotonic dystrophy.
The Ku-binding motif is a conserved module for recruitment and stimulation of non-homologous end-joining proteins
Authors: Grundy Gabrielle J. , Rulten Stuart L. , Arribas-Bosacoma Raquel , Davidson Kathryn , Kozik Zuzanna , Oliver Antony W. , Pearl Laurence H. , Caldecott Keith W.
Published: April 2016

The Ku-binding motif (KBM) is a short peptide module first identified in APLF that we now show is also present in Werner syndrome protein (WRN) and in Modulator of retrovirus infection homologue (MRI). We also identify a related but functionally distinct motif in XLF, WRN, MRI and PAXX, which we denote the XLF-like motif. We show that WRN possesses two KBMs; one at the N terminus next to the exonuclease domain and one at the C terminus next to an XLF-like motif. We reveal that the WRN C-terminal KBM and XLF-like motif function cooperatively to bind Ku complexes and that the N-terminal KBM mediates Ku-dependent stimulation of WRN exonuclease activity. We also show that WRN accelerates DSB repair by a mechanism requiring both KBMs, demonstrating the importance of WRN interaction with Ku. These data define a conserved family of KBMs that function as molecular tethers to recruit and/or stimulate enzymes during NHEJ.
PDE6δ-mediated sorting of INPP5E into the cilium is determined by cargo-carrier affinity
Authors: Fansa Eyad Kalawy , Kösling Stefanie Kristine , Zent Eldar , Wittinghofer Alfred , Ismail Shehab
Published: April 2016

The phosphodiesterase 6 delta subunit (PDE6δ) shuttles several farnesylated cargos between membranes. The cargo sorting mechanism between cilia and other compartments is not understood. Here we show using the inositol polyphosphate 5′-phosphatase E (INPP5E) and the GTP-binding protein (Rheb) that cargo sorting depends on the affinity towards PDE6δ and the specificity of cargo release. High-affinity cargo is exclusively released by the ciliary transport regulator Arl3, while low-affinity cargo is released by Arl3 and its non-ciliary homologue Arl2. Structures of PDE6δ/cargo complexes reveal the molecular basis of the sorting signal which depends on the residues at the −1 and −3 positions relative to farnesylated cysteine. Structure-guided mutation allows the generation of a low-affinity INPP5E mutant which loses exclusive ciliary localization. We postulate that the affinity to PDE6δ and the release by Arl2/3 in addition to a retention signal are the determinants for cargo sorting and enrichment at its destination.
Early cranial ultrasound findings among infants with neonatal encephalopathy in Uganda: an observational study
Authors: Tann Cally J. , Nakakeeto Margaret , Hagmann Cornelia , Webb Emily L. , Nyombi Natasha , Namiiro Flaviah , Harvey-Jones Kelly , Muhumuza Anita , Burgoine Kathy , Elliott Alison M. , Kurinczuk Jennifer J. , Robertson Nicola J. , Cowan Frances M.
Published: April 2016

Background:

In sub-Saharan Africa, the timing and nature of brain injury and their relation to mortality in neonatal encephalopathy (NE) are unknown. We evaluated cranial ultrasound (cUS) scans from term Ugandan infants with and without NE for evidence of brain injury.

Methods:

Infants were recruited from a national referral hospital in Kampala. Cases (184) had NE and controls (100) were systematically selected unaffected term infants. All had cUS scans <36 h reported blind to NE status.

Results:

Scans were performed at median age 11.5 (interquartile range (IQR): 5.2–20.2) and 8.4 (IQR: 3.6–13.5) hours, in cases and controls respectively. None had established antepartum injury. Major evolving injury was reported in 21.2% of the cases vs. 1.0% controls (P < 0.001). White matter injury was not significantly associated with bacteremia in encephalopathic infants (odds ratios (OR): 3.06 (95% confidence interval (CI): 0.98–9.60). Major cUS abnormality significantly increased the risk of neonatal death (case fatality 53.9% with brain injury vs. 25.9% without; OR: 3.34 (95% CI: 1.61–6.95)).

Conclusion:

In this low-resource setting, there was no evidence of established antepartum insult, but a high proportion of encephalopathic infants had evidence of major recent and evolving brain injury on early cUS imaging, suggesting prolonged or severe acute exposure to hypoxia–ischemia (HI). Early abnormalities were a significant predictor of death.
X-ray laser diffraction for structure determination of the rhodopsin-arrestin complex
Authors: Zhou X. Edward , Gao Xiang , Barty Anton , Kang Yanyong , He Yuanzheng , Liu Wei , Ishchenko Andrii , White Thomas A. , Yefanov Oleksandr , Han Gye Won , Xu Qingping , de Waal Parker W. , Suino-Powell Kelly M. , Boutet Sébastien , Williams Garth J. , Wang Meitian , Li Dianfan , Caffrey Martin , Chapman Henry N. , Spence John C.H. , Fromme Petra , Weierstall Uwe , Stevens Raymond C. , Cherezov Vadim , Melcher Karsten , Xu H. Eric
Published: April 2016

Serial femtosecond X-ray crystallography (SFX) using an X-ray free electron laser (XFEL) is a recent advancement in structural biology for solving crystal structures of challenging membrane proteins, including G-protein coupled receptors (GPCRs), which often only produce microcrystals. An XFEL delivers highly intense X-ray pulses of femtosecond duration short enough to enable the collection of single diffraction images before significant radiation damage to crystals sets in. Here we report the deposition of the XFEL data and provide further details on crystallization, XFEL data collection and analysis, structure determination, and the validation of the structural model. The rhodopsin-arrestin crystal structure solved with SFX represents the first near-atomic resolution structure of a GPCR-arrestin complex, provides structural insights into understanding of arrestin-mediated GPCR signaling, and demonstrates the great potential of this SFX-XFEL technology for accelerating crystal structure determination of challenging proteins and protein complexes.
Multimodal Image Analysis in Alzheimer’s Disease via Statistical Modelling of Non-local Intensity Correlations
Authors: Lorenzi Marco , Simpson Ivor J. , Mendelson Alex F. , Vos Sjoerd B. , Cardoso M. Jorge , Modat Marc , Schott Jonathan M. , Ourselin Sebastien
Published: April 2016

The joint analysis of brain atrophy measured with magnetic resonance imaging (MRI) and hypometabolism measured with positron emission tomography with fluorodeoxyglucose (FDG-PET) is of primary importance in developing models of pathological changes in Alzheimer’s disease (AD). Most of the current multimodal analyses in AD assume a local (spatially overlapping) relationship between MR and FDG-PET intensities. However, it is well known that atrophy and hypometabolism are prominent in different anatomical areas. The aim of this work is to describe the relationship between atrophy and hypometabolism by means of a data-driven statistical model of non-overlapping intensity correlations. For this purpose, FDG-PET and MRI signals are jointly analyzed through a computationally tractable formulation of partial least squares regression (PLSR). The PLSR model is estimated and validated on a large clinical cohort of 1049 individuals from the ADNI dataset. Results show that the proposed non-local analysis outperforms classical local approaches in terms of predictive accuracy while providing a plausible description of disease dynamics: early AD is characterised by non-overlapping temporal atrophy and temporo-parietal hypometabolism, while the later disease stages show overlapping brain atrophy and hypometabolism spread in temporal, parietal and cortical areas.
FOXC2 regulates the G2/M transition of stem cell-rich breast cancer cells and sensitizes them to PLK1 inhibition
Authors: Pietilä Mika , Vijay Geraldine V. , Soundararajan Rama , Yu Xian , Symmans William F. , Sphyris Nathalie , Mani Sendurai A.
Published: April 2016

Cancer cells with stem cell properties (CSCs) underpin the chemotherapy resistance and high therapeutic failure of triple-negative breast cancers (TNBCs). Even though CSCs are known to proliferate more slowly, they are sensitive to inhibitors of G2/M kinases such as polo-like kinase 1 (PLK1). Understanding the cell cycle regulatory mechanisms of CSCs will help target these cells more efficiently. Herein, we identify a novel role for the transcription factor FOXC2, which is mostly expressed in CSCs, in the regulation of cell cycle of CSC-enriched breast cancer cells. We demonstrate that FOXC2 expression is regulated in a cell cycle-dependent manner, with FOXC2 protein levels accumulating in G2 and rapidly decreasing during mitosis. Knockdown of FOXC2 in CSC-enriched TNBC cells delays mitotic entry without significantly affecting the overall proliferation rate of these cells. Moreover, PLK1 activity is important for FOXC2 protein stability, since PLK1 inhibition reduces FOXC2 protein levels. Indeed, FOXC2 expressing CSC-enriched TNBC cells are sensitive to PLK1 inhibition. Collectively, our findings demonstrate a novel role for FOXC2 as a regulator of the G2/M transition and elucidate the reason for the observed sensitivity of CSC-enriched breast cancer cells to PLK1 inhibitor.
Dissociating the neural correlates of tactile temporal order and simultaneity judgements
Authors: Miyazaki Makoto , Kadota Hiroshi , Matsuzaki Kozue S. , Takeuchi Shigeki , Sekiguchi Hirofumi , Aoyama Takuo , Kochiyama Takanori
Published: April 2016

Perceiving temporal relationships between sensory events is a key process for recognising dynamic environments. Temporal order judgement (TOJ) and simultaneity judgement (SJ) are used for probing this perceptual process. TOJ and SJ exhibit identical psychometric parameters. However, there is accumulating psychophysical evidence that distinguishes TOJ from SJ. Some studies have proposed that the perceptual processes for SJ (e.g., detecting successive/simultaneity) are also included in TOJ, whereas TOJ requires more processes (e.g., determination of the temporal order). Other studies have proposed two independent processes for TOJ and SJ. To identify differences in the neural activity associated with TOJ versus SJ, we performed functional magnetic resonance imaging of participants during TOJ and SJ with identical tactile stimuli. TOJ-specific activity was observed in multiple regions (e.g., left ventral and bilateral dorsal premotor cortices and left posterior parietal cortex) that overlap the general temporal prediction network for perception and motor systems. SJ-specific activation was observed only in the posterior insular cortex. Our results suggest that TOJ requires more processes than SJ and that both TOJ and SJ implement specific process components. The neural differences between TOJ and SJ thus combine features described in previous psychophysical hypotheses that proposed different mechanisms.
Heteroaromatic organic compound with conjugated multi-carbonyl as cathode material for rechargeable lithium batteries
Authors: Lv Meixiang , Zhang Fen , Wu Yiwen , Chen Mujuan , Yao Chunfeng , Nan Junmin , Shu Dong , Zeng Ronghua , Zeng Heping , Chou Shu-Lei
Published: April 2016

The heteroaromatic organic compound, N,N’-diphenyl-1,4,5,8-naphthalenetetra- carboxylic diimide (DP-NTCDI-250) as the cathode material of lithium batteries is prepared through a simple one-pot N-acylation reaction of 1,4,5,8-naphthalenetetra-carboxylic dianhydride (NTCDA) with phenylamine (PA) in DMF solution followed by heat treatment in 250 °C. The as prepared sample is characterized by the combination of elemental analysis, NMR, FT-IR, TGA, XRD, SEM and TEM. The electrochemical measurements show that DP-NTCDI-250 can deliver an initial discharge capacity of 170 mAh g−1 at the current density of 25 mA g−1. The capacity of 119 mAh g−1 can be retained after 100 cycles. Even at the high current density of 500 mA g−1, its capacity still reaches 105 mAh g−1, indicating its high rate capability. Therefore, the as-prepared DP-NTCDI-250 could be a promising candidate as low cost cathode materials for lithium batteries.
Mitochondria-targeted esculetin alleviates mitochondrial dysfunction by AMPK-mediated nitric oxide and SIRT3 regulation in endothelial cells: potential implications in atherosclerosis
Authors: Karnewar Santosh , Vasamsetti Sathish Babu , Gopoju Raja , Kanugula Anantha Koteswararao , Ganji Sai Krishna , Prabhakar Sripadi , Rangaraj Nandini , Tupperwar Nitin , Kumar Jerald Mahesh , Kotamraju Srigiridhar
Published: April 2016

Mitochondria-targeted compounds are emerging as a new class of drugs that can potentially alter the pathophysiology of those diseases where mitochondrial dysfunction plays a critical role. We have synthesized a novel mitochondria-targeted esculetin (Mito-Esc) with an aim to investigate its effect during oxidative stress-induced endothelial cell death and angiotensin (Ang)-II-induced atherosclerosis in ApoE−/− mice. Mito-Esc but not natural esculetin treatment significantly inhibited H2O2- and Ang-II-induced cell death in human aortic endothelial cells by enhancing NO production via AMPK-mediated eNOS phosphorylation. While L-NAME (NOS inhibitor) significantly abrogated Mito-Esc-mediated protective effects, Compound c (inhibitor of AMPK) significantly decreased Mito-Esc-mediated increase in NO production. Notably, Mito-Esc promoted mitochondrial biogenesis by enhancing SIRT3 expression through AMPK activation; and restored H2O2-induced inhibition of mitochondrial respiration. siSIRT3 treatment not only completely reversed Mito-Esc-mediated mitochondrial biogenetic marker expressions but also caused endothelial cell death. Furthermore, Mito-Esc administration to ApoE−/− mice greatly alleviated Ang-II-induced atheromatous plaque formation, monocyte infiltration and serum pro-inflammatory cytokines levels. We conclude that Mito-Esc is preferentially taken up by the mitochondria and preserves endothelial cell survival during oxidative stress by modulating NO generation via AMPK. Also, Mito-Esc-induced SIRT3 plays a pivotal role in mediating mitochondrial biogenesis and perhaps contributes to its anti-atherogenic effects.
C7 genotype of the donor may predict early bacterial infection after liver transplantation
Authors: Zhong Lin , Li Hao , Li Zhiqiang , Shi Baojie , Wang PuSen , Wang ChunGuang , Fan Junwei , Sun Hongcheng , Wang Peiwen , Qin Xuebin , Peng Zhihai
Published: April 2016

Post-transplantation infection causes high mortality and remains a significant challenge. High clinical risk factors for bacterial infection in recipients are often found in critically ill patients. However, for some recipients, bacterial infections are inevitable. It is conceivable that this susceptibility may be related to the genetics of the donor and recipient. Using expression quantitative trait loci (eQTL) analysis, we found that the C7 rs6876739 CC genotypes and mannan-binding lectin (MBL2) gene polymorphisms of liver donors were significantly associated with bacterial infection in recipients. In an extended validation group of 113 patients, donor C7 rs6876739 genetic variation was an independent risk factor for bacterial infection. The donor C7 rs6876739 CC genotype was associated with lower levels of recipient C7 protein, soluble membrane attack complex (MAC) and IL-1β expression compared with the donor C7 rs6876739 TT genotype.In vitro, the MAC significantly triggered NLRP3 inflammasome activation and IL-1β release, suggesting that the mechanism by which C7 defends against bacteria may involve MAC formation, leading to NLRP3 inflammasome activation and IL-1β release. Our findings may be helpful in identifying transplantation recipients at risk of bacterial infection prior to surgery and may contribute to novel infection prevention strategies and the improvement of postoperative outcomes.
The correlation between LDH serum levels and clinical outcome in advanced biliary tract cancer patients treated with first line chemotherapy
Authors: Faloppi Luca , Del Prete Michela , Gardini Andrea Casadei , Santini Daniele , Silvestris Nicola , Bianconi Maristella , Giampieri Riccardo , Valgiusti Martina , Brunetti Oronzo , Bittoni Alessandro , Andrikou Kalliopi , Lai Eleonora , Dessì Alessandra , Cascinu Stefano , Scartozzi Mario
Published: April 2016

LDH may represent an indirect marker of neo-angiogenesis and worse prognosis in many tumour types. We assessed the correlation between LDH and clinical outcome for biliary tract cancer (BTC) patients treated with first-line chemotherapy. Overall, 114 advanced BTC patients treated with first-line gemcitabine and cisplatin were included. Patients were divided into two groups (low vs. high LDH), according to pre-treatment LDH values. Patients were also classified according to pre- and post-treatment variation in LDH serum levels (increased vs. decreased). Median progression free survival (PFS) was 5.0 and 2.6 months respectively in patients with low and high pre-treatment LDH levels (p = 0.0042, HR = 0.56, 95% CI: 0.37–0.87). Median overall survival (OS) was 7.7 and 5.6 months (low vs. high LDH) (p = 0.324, HR = 0.81, 95% CI: 0.54–1.24). DCR was 71% vs. 43% (low vs. high LDH) (p = 0.002). In 38 patients with decreased LDH values after treatment, PFS and OS were respectively 6.2 and 12.1 months, whereas in 76 patients with post-treatment increased LDH levels, PFS and OS were respectively 3.0 and 5.1 months (PFS: p = 0.0009; HR = 0.49; 95% IC: 0.33–0.74; OS: p < 0.0001; HR = 0.42; 95% IC: 0.27–0.63). Our data seem to suggest that LDH serum level may predict clinical outcome in BTC patients receiving first-line chemotherapy.
Pressure-induced topological phases of KNa2Bi
Authors: Sklyadneva I. Yu. , Rusinov I. P. , Heid R. , Bohnen K.-P. , Echenique P. M. , Chulkov E. V.
Published: April 2016

We report an ab initio study of the effect of hydrostatic pressure and uniaxial strain on electronic properties of KNa2Bi, a cubic bialkali bismuthide. It is found that this zero-gap semimetal with an inverted band structure at the Brillouin zone center can be driven into various topological phases under proper external pressure. We show that upon hydrostatic compression KNa2Bi turns into a trivial semiconductor with a conical Dirac-type dispersion of electronic bands at the point of the topological transition while the breaking of cubic symmetry by applying a uniaxial strain converts the compound into a topological insulator or into a three-dimensional Dirac semimetal with nontrivial surface Fermi arcs depending on the sign of strain. The calculated phonon dispersions show that KNa2Bi is dynamically stable both in the cubic structure (at any considered pressures) and in the tetragonal phase (under uniaxial strain).
Implication of Long noncoding RNAs in the endothelial cell response to hypoxia revealed by RNA-sequencing
Authors: Voellenkle C. , Garcia-Manteiga J. M. , Pedrotti S. , Perfetti A. , De Toma I. , Da Silva D. , Maimone B. , Greco S. , Fasanaro P. , Creo P. , Zaccagnini G. , Gaetano C. , Martelli F.
Published: April 2016

Long noncoding RNAs (lncRNAs) are non-protein coding RNAs regulating gene expression. Although for some lncRNAs a relevant role in hypoxic endothelium has been shown, the regulation and function of lncRNAs is still largely unknown in the vascular physio-pathology. Taking advantage of next-generation sequencing techniques, transcriptomic changes induced by endothelial cell exposure to hypoxia were investigated. Paired-end sequencing of polyadenylated RNA derived from human umbilical vein endothelial cells (HUVECs) exposed to 1% O2 or normoxia was performed. Bioinformatics analysis identified ≈2000 differentially expressed genes, including 122 lncRNAs. Extensive validation was performed by both microarray and qPCR. Among the validated lncRNAs, H19, MIR210HG, MEG9, MALAT1 and MIR22HG were also induced in a mouse model of hindlimb ischemia. To test the functional relevance of lncRNAs in endothelial cells, knockdown of H19 expression was performed. H19 inhibition decreased HUVEC growth, inducing their accumulation in G1 phase of the cell cycle; accordingly, p21 (CDKN1A) expression was increased. Additionally, H19 knockdown also diminished HUVEC ability to form capillary like structures when plated on matrigel. In conclusion, a high-confidence signature of lncRNAs modulated by hypoxia in HUVEC was identified and a significant impact of H19 lncRNA was shown.
High magnetic field induced otolith fusion in the zebrafish larvae
Authors: Pais-Roldán Patricia , Singh Ajeet Pratap , Schulz Hildegard , Yu Xin
Published: April 2016

Magnetoreception in animals illustrates the interaction of biological systems with the geomagnetic field (geoMF). However, there are few studies that identified the impact of high magnetic field (MF) exposure from Magnetic Resonance Imaging (MRI) scanners (>100,000 times of geoMF) on specific biological targets. Here, we investigated the effects of a 14 Tesla MRI scanner on zebrafish larvae. All zebrafish larvae aligned parallel to the B0 field, i.e. the static MF, in the MRI scanner. The two otoliths (ear stones) in the otic vesicles of zebrafish larvae older than 24 hours post fertilization (hpf) fused together after the high MF exposure as short as 2 hours, yielding a single-otolith phenotype with aberrant swimming behavior. The otolith fusion was blocked in zebrafish larvae under anesthesia or embedded in agarose. Hair cells may play an important role on the MF-induced otolith fusion. This work provided direct evidence to show that high MF interacts with the otic vesicle of zebrafish larvae and causes otolith fusion in an “all-or-none” manner. The MF-induced otolith fusion may facilitate the searching for MF sensors using genetically amenable vertebrate animal models, such as zebrafish.
Single cell analysis in native tissue: Quantification of the retinoid content of hepatic stellate cells
Authors: Galler Kerstin , Requardt Robert Pascal , Glaser Uwe , Markwart Robby , Bocklitz Thomas , Bauer Michael , Popp Jürgen , Neugebauer Ute
Published: April 2016

Hepatic stellate cells (HSCs) are retinoid storing cells in the liver: The retinoid content of those cells changes depending on nutrition and stress level. There are also differences with regard to a HSC’s anatomical position in the liver. Up to now, retinoid levels were only accessible from bulk measurements of tissue homogenates or cell extracts. Unfortunately, they do not account for the intercellular variability. Herein, Raman spectroscopy relying on excitation by the minimally destructive wavelength 785 nm is introduced for the assessment of the retinoid state of single HSCs in freshly isolated, unprocessed murine liver lobes. A quantitative estimation of the cellular retinoid content is derived. Implications of the retinoid content on hepatic health state are reported. The Raman-based results are integrated with histological assessments of the tissue samples. This spectroscopic approach enables single cell analysis regarding an important cellular feature in unharmed tissue.