bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and tolerability of IRL790 in Parkinson’s disease with levodopa-induced dyskinesia—a phase 1b trial
Authors: Svenningsson Per , Johansson Anders , Nyholm Dag , Tsitsi Panagiota , Hansson Fredrik , Sonesson Clas , Tedroff Joakim 
Published: November 2018

AbstractIRL790 is a novel compound with psychomotor stabilizing properties primarily targeting the dopamine D3 receptor. IRL790 is developed as an experimental treatment for levodopa-induced dyskinesia (LID), impulse control disorder, and psychosis in Parkinson’s disease (PD). The primary objective was to investigate the safety and tolerability of IRL790 in PD patients with LID in a randomized controlled trial. PD patients with peak-dose dyskinesia were randomized to placebo or IRL790 treatment (1:3 ratio) for 4 weeks. Study drug was given as an adjunct treatment to the patients’ regular stable antiparkinsonian medication. Dosing was individually titrated for 14 days, whereafter dosing was kept stable for an additional 14 days. Fifteen patients were randomized to treatment and 13 patients completed the 4-week treatment. Adverse events were mostly reported during the titration phase of the trial. They were mainly central nervous system related and could be mitigated by dose adjustments. There were no serious adverse events. There were no clinically significant changes in vital signs, electrocardiogram, and laboratory parameters due to the treatment. The average dose in the stable dose phase was 18 mg daily, yielding a 2-h post-dose plasma concentration of average 229 nM on day 28. Assessments for motor function showed a numeric reduction in dyskinesia. It is concluded that IRL790 can be safely administered to patients with advanced PD. The results will be of guidance for the design of phase 2 studies.
The association between neonatal vitamin D status and risk of schizophrenia
Authors: Eyles Darryl W. , Trzaskowski Maciej , Vinkhuyzen Anna A. E. , Mattheisen Manuel , Meier Sandra , Gooch Helen , Anggono Victor , Cui Xiaoying , Tan Men Chee , Burne Thomas H. J. , Jang Se Eun , Kvaskoff David , Hougaard David M. , Nørgaard-Pedersen Bent , Cohen Arieh , Agerbo Esben , Pedersen Carsten B. , Børglum Anders D. , Mors Ole , Sah Pankaj , Wray Naomi R. , Mortensen Preben B. , McGrath John J. 
Published: November 2018

AbstractClues from the epidemiology of schizophrenia, such as the increased risk in those born in winter/spring, have led to the hypothesis that prenatal vitamin D deficiency may increase the risk of later schizophrenia. We wish to explore this hypothesis in a large Danish case-control study (n = 2602). The concentration of 25 hydroxyvitamin D (25OHD) was assessed from neonatal dried blood samples. Incidence rate ratios (IRR) were calculated when examined for quintiles of 25OHD concentration. In addition, we examined statistical models that combined 25OHD concentration and the schizophrenia polygenic risk score (PRS) in a sample that combined the new sample with a previous study (total n = 3464; samples assayed and genotyped between 2008-2013). Compared to the reference (fourth) quintile, those in the lowest quintile (<20.4 nmol/L) had a significantly increased risk of schizophrenia (IRR = 1.44, 95%CI: 1.12–1.85). None of the other quintile comparisons were significantly different. There was no significant interaction between 25OHD and the PRS. Neonatal vitamin D deficiency was associated with an increased risk for schizophrenia in later life. These findings could have important public health implications related to the primary prevention of schizophrenia.
Computational affinity maturation of camelid single-domain intrabodies against the nonamyloid component of alpha-synuclein
Authors: Mahajan Sai Pooja , Meksiriporn Bunyarit , Waraho-Zhmayev Dujduan , Weyant Kevin B. , Kocer Ilkay , Butler David C. , Messer Anne , Escobedo Fernando A. , DeLisa Matthew P. 
Published: November 2018

AbstractImproving the affinity of protein-protein interactions is a challenging problem that is particularly important in the development of antibodies for diagnostic and clinical use. Here, we used structure-based computational methods to optimize the binding affinity of VHNAC1, a single-domain intracellular antibody (intrabody) from the camelid family that was selected for its specific binding to the nonamyloid component (NAC) of human α-synuclein (α-syn), a natively disordered protein, implicated in the pathogenesis of Parkinson’s disease (PD) and related neurological disorders. Specifically, we performed ab initio modeling that revealed several possible modes of VHNAC1 binding to the NAC region of α-syn as well as mutations that potentially enhance the affinity between these interacting proteins. While our initial design strategy did not lead to improved affinity, it ultimately guided us towards a model that aligned more closely with experimental observations, revealing a key residue on the paratope and the participation of H4 loop residues in binding, as well as confirming the importance of electrostatic interactions. The binding activity of the best intrabody mutant, which involved just a single amino acid mutation compared to parental VHNAC1, was significantly enhanced primarily through a large increase in association rate. Our results indicate that structure-based computational design can be used to successfully improve the affinity of antibodies against natively disordered and weakly immunogenic antigens such as α-syn, even in cases such as ours where crystal structures are unavailable.
Apolipoprotein E genotypes among diverse middle-aged and older Latinos: Study of Latinos-Investigation of Neurocognitive Aging results (HCHS/SOL)
Authors: González Hector M. , Tarraf Wassim , Jian Xueqiu , Vásquez Priscilla M. , Kaplan Robert , Thyagarajan Bharat , Daviglus Martha , Lamar Melissa , Gallo Linda C. , Zeng Donglin , Fornage Myriam 
Published: November 2018

AbstractThe apoE4 isoform is associated with increased cholesterol, cardiovascular risk, and Alzheimer’s Disease risk, however, its distribution is not well-understood among US Latinos. Latinos living in the US are highly Amerindian, European and African admixed, which varies by region and country of origin. However, Latino genetic diversity is understudied and consequently poorly understood, which has significant implications for understanding disease risk in nearly one-fifth of the US population. In this report we describe apoE distributions in a large and representative sample of diverse, genetically determined US Latinos.
Piwi-like 1 and -2 protein expression levels are prognostic factors for muscle invasive urothelial bladder cancer patients
Authors: Eckstein Markus , Jung Rudolf , Weigelt Katrin , Sikic Danijel , Stöhr Robert , Geppert Carol , Agaimy Abbas , Lieb Verena , Hartmann Arndt , Wullich Bernd , Wach Sven , Taubert Helge 
Published: November 2018

AbstractPiwi-like proteins are essential for stem-cell maintenance and self-renewal in multicellular organisms. We analyzed the expression of Piwi-like 1 and Piwi-like 2 by immunohistochemistry (IHC) in 95 muscle invasive bladder cancer (MIBC) samples using tissue microarray. Application of an immunoreactive score (IRS) revealed 37 and 45 patients who were Piwi-like 1 and -2 positive (IRS > 2). IHC results were correlated with clinico-pathological and survival data. The expression of both proteins was positively correlated with each other, lymph node metastasis and expression of CK20 and GATA 3. A negative correlation for both proteins was detected for disease-specific survival (DSS), recurrence, Ki67/MIB1 proliferation index, and CK5 expression. Detection of Piwi-like 1 protein positivity was associated with poor DSS (P = 0.019; log rank test, Kaplan-Meier analysis), and in multivariate Cox’s analysis (adjusted to tumor stage and tumor grade), it was an independent prognostic factor for DSS (RR = 2.16; P = 0.011). Piwi-like 2 positivity was associated with DSS (P = 0.008) and recurrence-free survival (RFS; P = 0.040), and in multivariate Cox’s analysis, Piwi-like 2 positivity was an independent prognostic factor for DSS (RR = 2.46; P = 0.004) and RFS (RR = 3.0; P = 0.003). Most interestingly, in the basal type patient subgroup (CK5+/GATA3−), Piwi-like 2 positivity was associated with poorer DSS, OS and RFS (P < 0.001, P = 0.004 and P = 0.05; log rank test). In multivariate analysis, Piwi-like 2 positivity was an independent prognostic factor for DSS (RR = 12.70; P = 0.001), OS (RR = 6.62;  = 0.008) and RFS (RR=13.0; P = 0.040). In summary, Piwi-like 1 and -2 positivity are associated with clinico-pathological factors and survival. Both Piwi-like proteins are suggested as biomarkers for MIBC patients.
Antimicrobial potential of endocannabinoid and endocannabinoid-like compounds against methicillin-resistant Staphylococcus aureus
Authors: Feldman Mark , Smoum Reem , Mechoulam Raphael , Steinberg Doron 
Published: November 2018

AbstractInfections caused by antibiotic-resistant strains of Staphylococcus aureus have reached epidemic proportions globally. Staphylococcal biofilms are associated with increased antimicrobial resistance and are generally less affected by host immune factors. Therefore, there is an urgent need for novel agents that not only aim at multidrug-resistant pathogens, but also ones that will act as anti biofilms. In the present study, we investigated the antimicrobial activity of the endocannabinoid (EC) anandamide (AEA) and the endocannabinoid-like (EC-like), arachidonoyl serine (AraS) against methicillin resistant S. aureus strains (MRSA). We observed a strong inhibition of biofilm formation of all tested MRSA strains as well as a notable reduction of metabolic activity of pre-formed MRSA biofilms by both agents. Moreover, staphylococcal biofilm-associated virulence determinants such as hydrophobicity, cell aggregation and spreading ability were altered by AEA and AraS. In addition, the agents were able to modify bacterial membrane potential. Importantly, both compounds prevent biofilm formation by altering the surface of the cell without killing the bacteria. Therefore, we propose that EC and EC-like compounds may act as a natural line of defence against MRSA or other antibiotic resistant bacteria. Due to their anti biofilm action these agents could also be a promising alternative to antibiotic therapeutics against biofilm-associated MRSA infections.
Optimism for mitigation of climate warming impacts for sea turtles through nest shading and relocation
Authors: Esteban Nicole , Laloë Jacques-Olivier , Kiggen Fionne S. P. L. , Ubels Selma M. , Becking Leontine E. , Meesters Erik H. , Berkel Jessica , Hays Graeme C. , Christianen Marjolijn J. A. 
Published: November 2018

AbstractIncreasing incubation temperatures may threaten the viability of sea turtle populations. We explored opportunities for decreasing incubation temperatures at a Caribbean rookery with extreme female-biased hatchling production. To investigate the effect of artificial shading, temperatures were measured under simple materials (white sheet, white sand, palm leaves). To test natural drivers of incubation temperature, temperatures were measured at average nest depths with shading on two beaches. Results from a pilot experiment suggest the most effective material was palm leaves. Shading decreased temperatures by a mean of 0.60 °C (SE = 0.10 °C, N = 20). Variation between beaches averaged 1.88 °C (SE = 0.13 °C, N = 20). We used long-term rookery data combined with experimental data to estimate the effect on sex ratio: relocation and shading could shift ratios from current ranges (97–100% female) to 60–90% female. A conservation mitigation matrix summarises our evidence that artificial shading and nest relocation are effective, low-cost, low-technology conservation strategies to mitigate impacts of climate warming for sea turtles.
Dorsolateral and medial prefrontal cortex mediate the influence of incidental priming on economic decision making in obesity
Authors: Morys Filip , Bode Stefan , Horstmann Annette 
Published: November 2018

AbstractObese individuals discount future rewards to a higher degree than lean individuals, which is generally considered disadvantageous. Moreover, their decisions are altered more easily by decision-irrelevant cues. Here, we investigated neural correlates of this phenomenon using functional MRI. We tested 30 lean and 26 obese human subjects on a primed delay discounting paradigm using gustatory and visual cues of positive, neutral and negative valence to bias their intertemporal preferences. We hypothesised that activation differences in reward-related and behavioural control areas, and changes in connectivity between these areas, would reflect the effect of these cues. Here, obese subjects were more susceptible to priming with negative gustatory cues towards delayed choices as opposed to lean subjects. This was related to lower activity in the left dorsolateral prefrontal cortex during priming. Modulation of functional connectivity between the dlPFC and the ventromedial PFC by the behavioural priming effect correlated negatively with BMI. This might indicate that default goals of obese individuals were different from those of lean participants, as the dlPFC has been suggested to be involved in internal goal pursuit. The present results further our understanding of the role of the PFC in decision-making and might inform future weight-management approaches based on non-invasive brain stimulation.
In-situ Measurement of Self-Atom Diffusion in Solids Using Amorphous Germanium as a Model System
Authors: Hüger Erwin , Strauß Florian , Stahn Jochen , Deubener Joachim , Bruns Michael , Schmidt Harald 
Published: November 2018

AbstractWe present in-situ self-diffusion experiments in solids, which were carried out by Focussing Neutron Reflectometry on isotope multilayers. This new approach offers the following advantages in comparison to classical ex-situ measurements: (1) Identification and continuous measurement of a time dependence of diffusivities, (2) significant reduction of error limits of diffusivities, and (3) substantial reduction of the necessary experimental time. In the framework of a case study, yet unknown self-diffusivities in amorphous germanium are measured at various temperatures quasi-continuously, each during isothermal annealing. A significant decrease of diffusivities as a function of annealing time by one order of magnitude is detected that is attributed to structural relaxation accompanied by defect annihilation. In metastable equilibrium the diffusivities follow the Arrhenius law between 375 and 412 °C with an activation energy of Q = (2.11 ± 0.12) eV. The diffusivities are five orders of magnitude higher than in germanium single crystals at 400 °C, mainly due to the lower activation energy.
The spatial epidemiology of sickle-cell anaemia in India
Authors: Hockham Carinna , Bhatt Samir , Colah Roshan , Mukherjee Malay B. , Penman Bridget S. , Gupta Sunetra , Piel Frédéric B. 
Published: November 2018

AbstractSickle-cell anaemia (SCA) is a neglected chronic disorder of increasing global health importance, with India estimated to have the second highest burden of the disease. In the country, SCA is particularly prevalent in scheduled populations, which comprise the most socioeconomically disadvantaged communities. We compiled a geodatabase of a substantial number of SCA surveys carried out in India over the last decade. Using generalised additive models and bootstrapping methods, we generated the first India-specific model-based map of sickle-cell allele frequency which accounts for the district-level distribution of scheduled and non-scheduled populations. Where possible, we derived state- and district-level estimates of the number of SCA newborns in 2020 in the two groups. Through the inclusion of an additional 158 data points and 1.3 million individuals, we considerably increased the amount of data in our mapping evidence-base compared to previous studies. Highest predicted frequencies of up to 10% spanned central India, whilst a hotspot of ~12% was observed in Jammu and Kashmir. Evidence was heavily biased towards scheduled populations and remained limited for non-scheduled populations, which can lead to considerable uncertainties in newborn estimates at national and state level. This has important implications for health policy and planning. By taking population composition into account, we have generated maps and estimates that better reflect the complex epidemiology of SCA in India and in turn provide more reliable estimates of its burden in the vast country. This work was supported by European Union’s Seventh Framework Programme (FP7//2007–2013)/European Research Council [268904 – DIVERSITY]; and the Newton-Bhabha Fund [227756052 to CH]
Human Herpesvirus 6A and 6B inhibit in vitro angiogenesis by induction of Human Leukocyte Antigen G
Authors: Rizzo Roberta , D’Accolti Maria , Bortolotti Daria , Caccuri Francesca , Caruso Arnaldo , Di Luca Dario , Caselli Elisabetta 
Published: November 2018

AbstractWe have previously reported that human herpesvirus 6 (HHV-6) infection of endothelial cells (ECs) induces the loss of angiogenic properties, through the expression of HHV-6 U94, possibly associated to the release of a soluble mediator. It is also known that the soluble isoform of HLA-G exhibits an anti-angiogenic function, important in implantation, transplantation and neoplastic development. In this study, we analyzed the expression of HLA-G in HHV-6 infected ECs, showing that both HHV-6A and HHV-6B infection induce a potent up-modulation of HLA-G, including both membrane and soluble isoforms. Interestingly, HHV-6A and HHV-6B induced different isoforms of HLA-G. The virus-induced increase of HLA-G was likely due to the expression of the U94 viral gene, that by itself was able to reproduce the effect of whole virus. The effect of U94 was mediated by human transcription factor ATF3, that induced HLA-G activation by recognizing a consensus sequence on its promoter. Virus-induced inhibition of ECs angiogenic ability directly correlated to HLA-G expression and release, and the addition of anti-HLA-G antibody restored the angiogenic properties of HHV6-infected ECs. The induction of HLA-G expression in ECs might represent an important mediator of HHV-6 induced effects.
Reduced complexity and near optimum detector for linear‐frequency‐modulated and phase‐modulated LPI radar signals
Authors: Dezfuli Ali Abbasi , Shokouhmand Arash , Oveis Amir Hosein , Norouzi Yaser 
Published: November 2018

Dealing with low probability of intercept (LPI) radar signals in very low signal‐to‐noise ratio (SNR) stages requires reconnaissance systems to employ an effectively practical method for detecting and fully characterising the received signals. Following the aim of LPI signal detection, in this study, a novel method based on concentrating the energy of the signal in one particular row of the time–frequency domain matrix is proposed. It is shown that the proposed method enables to detect and estimate the parameters of multiple low‐power linear‐frequency‐modulated signals. A comparison has been made between the performance of the matched filter and the proposed method, and it is shown the proposed method has approximately the same performance and low computational complexity as matched filters. This method is also able to detect the poly‐phase signals such as Frank‐coded signals and also non‐linear‐frequency‐modulated signals, as well. To show the effectiveness of the method, extensive simulations are carried out with different LPI radar waveforms corrupted with additive white Gaussian noise of SNR down to −25 dB.
Modeling the evection resonance for Trojan satellites: application to the Saturn system
Authors: Giuppone C. A. , Roig F. , Saad-Olivera X. 
Published: November 2018

Context. The stability of satellites in the solar system is affected by the so-called evection resonance. The moons of Saturn, in particular, exhibit a complex dynamical architecture in which co-orbital configurations occur, especially close to the planet where this resonance is present.
Aims. We address the dynamics of the evection resonance, with particular focus on the Saturn system, and compare the known behavior of the resonance for a single moon with that of a pair of moons in co-orbital Trojan configuration.
Methods. We developed an analytic expansion of the averaged Hamiltonian of a Trojan pair of bodies, including the perturbation from a distant massive body. The analysis of the corresponding equilibrium points was restricted to the asymmetric apsidal corotation solution of the co-orbital dynamics. We also performed numerical N-body simulations to construct dynamical maps of the stability of the evection resonance in the Saturn system, and to study the effects of this resonance under the migration of Trojan moons caused by tidal dissipation.
Results. The structure of the phase space of the evection resonance for Trojan satellites is similar to that of a single satellite, differing in that the libration centers are displaced from their standard positions by an angle that depends on the periastron difference ϖ2 −ϖ1 and on the mass ratio m2∕m1 of the Trojan pair. In the Saturn system, the inner evection resonance, located at ~8 RS, may capture a pair of Trojan moons by migration; the stability of the captured system depends on the assumed values of the dissipation factor Q of the moons. On the other hand, the outer evection resonance, located at >0.4 RHill, cannot exist at all for Trojan moons, because Trojan configurations are strongly unstable at distances from Saturn longer than ~0.15 RHill.
Conclusions. The interaction with the inner evection resonance may have been relevant during the early evolution of the Saturn moons Tethys, Dione, and Rhea. In particular, Rhea may have had Trojan companions in the past that were lost when it crossed the evection resonance, while Tethys and Dione may either have retained their Trojans or have never crossed the evection. This may help to constrain the dynamical processes that led to the migration of these satellites and to the evection itself.
Early clinical cxperience with the SIGN hip construct: a retrospective case series
Authors: Roth Justin , Goldman Brian , Zirkle Lewis , Schlechter John , Ibrahim John , Shearer David 
Published: November 2018

Background: As the population ages, the developing world industrializes, and more urban centers emerge, the burden of orthopedic trauma will steadily increase. SIGN Fracture Care International has developed a unique intramedullary device for fixation of hip fractures in low-resource settings lacking fluoroscopy. The purpose of this study is to report the safety profile and complication rate for a consecutive series of hip fracture patients managed using this implant.
Methods: We conducted a retrospective analysis of the first 170 patients treated with the SIGN Hip Construct (SHC) from 2009 to 2014 using the SIGN Online Surgical Database (SOSD). Patients with follow-up greater than 12 weeks and adequate radiographs were included. Data recorded include patient demographics, time-to-surgery, union rate, AO/OTA classification, complications, neck-shaft angle, and clinical outcomes including painless weight bearing and knee flexion greater than 90°.
Results: Of 170 patients, 71 met inclusion criteria with mean follow-up of 39 weeks. Mean age was 49.5 and by WHO, regions were Africa (27), Eastern Mediterranean (21), Western Pacific (17), Americas (3), and Southeast Asia (3). Fractures included intertrochanteric (55), subtrochanteric (7), femoral neck (4), and combined (5). Reduction quality was good in 35 (49%), acceptable in 19 (27%), and poor in 17 (24%). Major complications consisted of varus collapse (6), non- or delayed union (3), intra-articular screw (5), and infection (3). Average postoperative neck-shaft angle was 126° and 119.3° at final follow-up.
Conclusions: This is the first comprehensive report of a novel implant for hip fractures specifically designed for low-resource settings. The early clinical data and outcomes suggest that the SHC can be safely inserted in the absence of fluoroscopy, and facilitates early mobilization while maintaining acceptable reduction until union.