bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics, safety, and tolerability of the 2‐ and 3‐direct‐acting antiviral combination of AL‐335, odalasvir, and simeprevir in healthy subjects
Authors: Kakuda Thomas N. , McClure Matthew W. , Westland Christopher , Vuong Jennifer , Homery Marie‐Claude , Poizat Gwendoline , Viguerie Laure , Denot Caroline , Patat Alain , Zhang Qingling , Hui James , Apelian David , Smith David B. , Chanda Sushmita M. , Fry John 
Published: April 2018

AbstractThis Phase I, open‐label, two‐group, fixed‐sequence study evaluated the pharmacokinetics and safety of AL‐335, odalasvir, and simeprevir in healthy subjects. Group 1 (n = 16) received AL‐335 800 mg once daily (QD) (days 1‐3, 11‐13, and 21‐23), simeprevir 150 mg QD (days 4‐23), and odalasvir 150 mg (day 14) followed by 50 mg QD (days 15‐23). Group 2 (n = 16) received the same AL‐335 regimen as in Group 1 plus odalasvir 150 mg (day 4) followed by 50 mg QD (days 5‐23) and simeprevir 150 mg QD (days 14‐23). Blood samples were collected to determine plasma concentrations of AL‐335 (prodrug) and its metabolites, ALS‐022399 (monophosphate precursor) and ALS‐022227 (parent nucleoside), odalasvir, and simeprevir. Thirty‐two subjects were enrolled. Odalasvir and simeprevir given alone, or in combination, increased AL‐335 area under plasma concentration‐time curve over 24 hours (AUC0‐24 h) 3‐, 4‐, and 7‐ to 8‐fold, respectively; ALS‐022399 AUC0‐24 h increased 2‐, 2‐, and 3‐fold, respectively. Simeprevir had no effect on ALS‐022227 AUC0‐24 h, whereas odalasvir with/without simeprevir increased ALS‐022227 AUC0‐24 h 1.5‐fold. AL‐335 had no effect on odalasvir or simeprevir pharmacokinetics. Odalasvir and simeprevir AUC0‐24 h increased 1.5‐ to 2‐fold for both drugs when coadministered irrespective of AL‐335 coadministration. Study medications were well tolerated with no serious adverse events. One subject prematurely discontinued study drugs (unrelated event). This study defined the preliminary pharmacokinetic and safety profiles of the combination of AL‐335, odalasvir, and simeprevir in healthy subjects. These data support the further evaluation of this combination for the treatment of chronic hepatitis C virus infection.
Pharmacological properties of revefenacin (TD‐4208), a novel, nebulized long‐acting, and lung selective muscarinic antagonist, at human recombinant muscarinic receptors and in rat, guinea pig, and human isolated airway tissues
Authors: Hegde Sharath S. , Pulido‐Rios M. Teresa , Luttmann Mark A. , Foley James J. , Hunsberger Gerald E. , Steinfeld Tod , Lee TaeWeon , Ji Yuhua , Mammen Mathai M. , Jasper Jeffrey R. 
Published: April 2018

AbstractRevefenacin (TD‐4208) is a novel, long‐acting, and lung‐selective muscarinic cholinergic receptor (mAChR) antagonist in development as a nebulized inhalation solution for the treatment of chronic obstructive pulmonary disease (COPD) patients. This study evaluated the pharmacology of revefenacin at human recombinant mAChRs and in airway tissues from rats, guinea pigs, and humans. At human recombinant mAChRs, revefenacin displayed high affinity (pKI = 8.2‐9.8) and behaved as a competitive antagonist (pKI, apparent = 9.4‐10.9) at the five human recombinant mAChRs. Kinetic studies demonstrated that revefenacin dissociated significantly slower from the hM3 (t1/2 = 82 minutes) compared to the hM2 (t1/2 = 6.9 minutes) mAChR at 37°C, thereby making it kinetically selective for the former subtype. Similarly, in functional studies, revefenacin‐mediated antagonism of acetylcholine (ACh)‐evoked calcium mobilization responses were reversed less rapidly at hM3 compared to the hM2 mAChR. In isolated tracheal tissues from rat and guinea pig and isolated bronchial tissues from humans, revefenacin potently antagonized mAChR‐mediated contractile responses. Furthermore, the antagonistic effects of revefenacin in rat, guinea pig, and human airway tissues were slowly reversible (t1/2 of 13.3, >16, and >10 hours, respectively). These data demonstrate that revefenacin is a potent, high affinity, and selective functional mAChR antagonist with kinetic selectivity for the hM3 receptor and produces potent and long‐lasting antagonism of mAChR‐mediated contractile responses in rat, guinea pig, and human airway tissue. These data suggest that revefenacin has the potential to be a potent once‐daily dosed inhaled bronchodilator in COPD patients.
The moist parcel‐in‐cell method for modelling moist convection
Authors: Dritschel David G. , Böing Steven J. , Parker Douglas J. , Blyth Alan M. 
Published: April 2018

We describe a promising alternative approach to modelling moist convection and cloud development in the atmosphere. Rather than using a conventional grid‐based approach, we use Lagrangian “parcels” to represent key dynamical and thermodynamical variables. In the prototype model considered, parcels carry vorticity, mass, specific humidity, and liquid‐water potential temperature. In this first study, we ignore precipitation, and many of these parcel “attributes” remain unchanged (i.e. are materially conserved). While the vorticity does change following the parcel motion, the vorticity tendency is readily computed and, crucially, unwanted numerical diffusion can be avoided. The model, called “Moist Parcel‐In‐Cell” (MPIC), is a hybrid approach which uses both parcels and a fixed underlying grid for efficiency: advection (here moving parcels) is Lagrangian whereas inversion (determining the velocity field) is Eulerian. The parcel‐based representation of key variables has several advantages: (a) it allows anexplicitsubgrid representation; (b) it provides a velocity field which isundampedby numerical diffusion all the way down to the grid scale; (c) it does away with the need for eddy viscosity parametrizations and, in their place, it provides for a natural subgrid parcel mixing; (d) it isexactly conservative(i.e. there can be no net loss or gain of any theoretically conserved attribute); and (e) it dispenses with the need to have separate equations for each conserved parcel attribute; attributes are simply labels carried by each parcel. Moreover, the latter advantage increases as more attributes are added, such as the distributions of microphysical properties, chemical composition and aerosol loading.
A Noble‐Metal‐Free CdS/Ni3S2@C Nanocomposite for Efficient Visible‐Light‐Driven Photocatalysis
Authors: Cui Yu , Pan Yun‐Xiang , Qin Haili , Cong Huai‐Ping , Yu Shu‐Hong 
Published: April 2018

AbstractSearching for highly efficient noble‐metal‐free visible‐light‐driven photocatalysts for hydrogen evolution has attracted much attention. Herein, a facile method for synthesis of a noble‐metal‐free CdS/Ni3S2@C nanocomposite by dispersing CdS quantum dots (≤5 nm) on urchin‐like Ni3S2 coated by a 5‐nm‐thick carbon layer is reported. It can be used for highly efficient visible‐light‐driven photocatalytic H2 production from H2O. The H2 production rate on CdS/Ni3S2@C (1164.7 µmol h−1) is about 3.5 times higher than that on the noble‐metal‐based CdS/Pt (325.2 µmol h−1). The CdS–carbon and carbon–Ni3S2 interfaces are favorable for charge separation and the improved visible light absorbance could be the origin for the enhanced photocatalytic activity of CdS/Ni3S2@C. This work provides a model system for rationally designing efficient noble‐metal‐free photocatalysts for visible‐light‐driven photocatalysis.
Optimising lameness detection in dairy cattle by using handheld infrared thermometers
Authors: Lin Yi‐Chun , Mullan Siobhan , Main David C. J. 
Published: April 2018

AbstractLameness is one of the most serious economic and welfare issues in the dairy industry. Early detection of lameness can be difficult, but provision of early treatment is crucial. Previous studies have used infrared thermography to show that increased foot temperature (FT) is associated with lameness and foot lesions. However, poor accuracy has limited the management application potential. This study analysed ambient‐temperature (AT)‐adjusted foot‐surface temperatures and temperature differences between the hind feet of individual cows to enhance lameness detection. Cow FTs were recorded on a 990‐cow farm using an infrared thermometer fortnightly for 6 months. Additionally, mobility level was scored using the AHDB Dairy 4‐point scale. The averages of FTs and ATs were 23.83 ± 0.03°C and 13.99 ± 1.60°C, respectively. The FT of cows with lameness was significantly higher than that of cows without lameness (P < 0.001). Increases in FTs correlated with the mobility score (MS) (P < 0.001). According to receiver operating characteristic (ROC) curves, the optimal threshold based on actual FTs was 23.3°C with 78.5% sensitivity and 39.2% specificity. However, the ROC curve for the AT‐adjusted FT and FT difference parameters showed minimal improvements over the FT in detecting lameness. In conclusion, the infrared thermometer results demonstrated the association between elevated FTs and lameness, but further improvements to this detection technique will be required before it can be implemented as a management tool for detecting cows that could benefit from treatment. With additional validation, the technique could be used as a screening device to identify cows in need of further assessment.
A survey of game theoretic approach for adversarial machine learning
Authors: Zhou Yan , Kantarcioglu Murat , Xi Bowei 
Published: April 2018

The field of machine learning is progressing at a faster pace than ever before. Many organizations leverage machine learning tools to extract useful information from a massive amount of data. In particular, machine learning finds its application in cybersecurity that begins to enter the age of automation. However, machine learning applications in cybersecurity face unique challenges other domains rarely do—attacks from active adversaries. Problems in areas such as intrusion detection, banking fraud detection, spam filtering, and malware detection have to face  challenges of adversarial attacks that modify data so that malicious instances would evade detection by the learning systems. The adversarial learning problem naturally resembles a game between the learning system and the adversary. In such a game, both players would attempt to play their best strategies against each other while maximizing their own payoffs. To solve the game, each player would search for an optimal strategy against the opponent based on the prediction of the opponent's strategy choice. The problem becomes even more complicated in settings where the learning system may have to deal with many adversaries of unknown types. Applying game‐theoretic approach, robust learning techniques have been developed to specifically address adversarial attacks and the preliminary results are promising. In this review, we summarize these results.This article is categorized under:Technologies > Machine LearningFundamental Concepts of Data and Knowledge > Key Design Issues in Data Mining
Anti-NMDA receptor encephalitis in a toddler
Authors: Khundakji Yasmin , Masri Amira , Khuri-Bulos Najwa 
Published: April 2018

Anti N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder and is considered to be one of the most common causes of encephalitis in children. Despite the fact that around half of all reported cases are of children, the number of studies that report infants and toddlers is very small. Furthermore, reports on children from the Middle East particularly are extremely rare.
We report a 21-month-old Jordanian female toddler with NMDAR encephalitis, who initially presented with behavioral changes and some autistic features. She presented a diagnostic challenge due to a concurrent urinary tract infection and gastroenteritis. Multiple investigations were conducted and she was treated with methylprednisolone and intravenous immunoglobulin (IVIg) empirically as well as plasma exchange and rituximab once the diagnosis was confirmed. Her condition improved gradually. We discuss her clinical picture and the diagnostic challenges within this age group; we also review the current related literature.
Ultrasound‐guided intertumoral injection of contrast agents combined with human p53 gene for the treatment of breast cancer
Authors: Guo Jun‐Cheng , Yang Yi‐Jun , Guo Min , Jiang Xiang‐Ling 
Published: April 2018

AbstractThe objective of this study was to investigate the effects of ultrasound‐guided injection of ultrasound contrast agents (UCAs) and the p53 gene on the treatment of rats with breast cancer (BC). Assembly of the p53 expression vector as well as that of a rat model with BC consisted of 200 successfully modeled rats randomly divided into 5 groups: p53 gene introduction, p53 gene introduction + ultrasound irradiation, p53 gene introduction + UCAs, p53 gene introduction + UCA + ultrasound irradiation, and UCA + ultrasound irradiation groups. Expression of p53 was detected via quantitative real‐time polymerase chain reaction (qRT‐PCR), western blotting and immunohistochemical staining. In the p53 gene introduction + ultrasound irradiation group, we observed increased tumor volume with blood flow signals around and necrotic tumor tissues with an inhibition rate of 36.30%, as well as higher expression of p53 than that in the p53 gene introduction group and p53 gene introduction + UCA group. In the p53 gene introduction + UCA + ultrasound irradiation group, tumor volume increased slightly with reduced blood flow signals and massive degenerative necrosis of tumor cells was identified with inhibition rate of 62.62%, and expression of p53 was higher than that in the rest groups. Taken together, the key findings obtained from the present study elucidate that injection of p53 gene and UCA microbubbles guided by ultrasound could increase the expression of p53, thus inhibiting the tumor growth in rats with BC.
Trismus‐pseudocamptodactyly syndrome with bilateral hypoplastic mandibular condyles and shallow mandibular fossa: A case report
Authors: Kusano Chieko , Hori Naoaki , Izawa Kazumi , Kosaki Rika , Nishimura Gen , Hasegawa Tomonobu 
Published: April 2018

AbstractTrismus‐pseudocamptodactyly syndrome (TPS) (OMIM#158300), also known as Hecht syndrome, is a rare autosomal dominant distal arthrogryposis. Bilateral hyperplasia of the coronoid processes has been reported to cause trismus. In this study, we report a case of TPS definitively diagnosed on the basis of clinical signs in a patient who had bilateral hypoplastic mandibular condyles and shallow mandibular fossa; TPS in such patients have never been reported in the literature. On the basis of the present case, we propose that a hypoplastic mandibular condyle and shallow mandibular fossa are also clinical features of TPS.
Putting the MFN Genie Back in the Bottle
Authors: Waibel Michael 
Published: April 2018

This essay underscores the importance of background understandings in general international law for interpreting brief, open-ended clauses such as most favored nation (MFN) clauses. Contrary to Simon Batifort and J. Benton Heath's claim, I suggest that often interpreters of MFN clauses cannot limit themselves to the text, context, and preparatory materials of a specific MFN clause. A common international negotiating technique, including for investment treaties, is to rely on the general background understanding of what a clause typically means in international law—its default meaning. I also argue that MFN clauses have played a surprisingly limited role in the international investment regime to date. In the main, they have functioned as a stepping stone for procedural and substantive guarantees found in third-party investment treaties. This use, and the limited role of MFN clauses in investment treaty awards, stands in sharp contrast to MFN clauses in the trade regime.
Allergic rhinitis and arterial blood pressure: a population-based study
Authors: Sakallioglu O , Polat C , Akyigit A , Cetiner H , Duzer S 
Published: April 2018

AbstractObjectives:To investigate the likelihood of allergic rhinitis and potential co-morbidities, and to assess whether allergic rhinitis is associated with arterial blood pressure and hypertension.Methods:In this population-based study, 369 adults with allergic rhinitis and asthma were assessed via a questionnaire and immunoglobulin E levels. There were four groups: control (n = 90), allergic rhinitis (n = 99), asthma (n = 87) and hypertension (n = 93). Arterial blood pressure was measured in all groups.Results:There were no significant differences in systolic or diastolic blood pressure between males and females in any group. Pairwise comparisons revealed no significant differences between: the control and allergic rhinitis groups, the control and asthma groups, or the allergic rhinitis and asthma groups. The systolic and diastolic blood pressure values of males and females were significantly higher in the hypertension group than the allergic rhinitis group. There were no significant differences in systolic blood pressure or diastolic blood pressure for seasonal and perennial allergic rhinitis patients.Conclusion:Rhinitis was not associated with increased blood pressure. Allergic rhinitis can coincide with asthma and hypertension. The findings do not support the need for blood pressure follow up in allergic rhinitis patients.
Sedimentary breccia and diamictite of the Cambrian Spurs Formation in northern Victoria Land, Antarctica: two kinds of debris flows in a submarine channel system
Authors: Kim Young-Hwan G. , Woo Jusun , Park Tae-Yoon S. , Kihm Ji-Hoon , Lee Jong Ik , Choe Moon Young 
Published: April 2018

AbstractThe submarine channel-fill system of the Cambrian Spurs Formation exhibits unique metre-scale cycles of breccia and diamictite. The studied sections, Eureka Spurs, are located at the Mariner Glacier in the central-eastern part of northern Victoria Land, Antarctica. A facies analysis of the channel-fill deposit has led to the recognition of four main lithofacies: breccia, diamictite, thin-bedded sandstone and mudstone. The channel-fill deposit consists of two architectural elements: hollow-fill (HF) and sheet-like (SL) elements. The SL has wide convex-up geometry and consists solely of a very thick bed of diamictite, and is interpreted as a submarine channel lobe. The HF has a concave-up erosional base and flat upper surface. The HF consists of nine cyclic alternations of underlying breccia (cohesionless debris flow) and overlying diamictite (cohesive debris flow). The deposition of breccia is interpreted to have been controlled by repeated allogenic processes such as earthquakes. In contrast, the abrupt vertical transition from breccia to diamictite in each cycle is interpreted to have resulted from an autogenic, slope instability-related process. The interaction of the allogenic and autogenic factors recorded in the metre-scale unique cyclic deposits provides new criteria to interpret cycles of submarine debris flow.
Urea changes oocyte competence and gene expression in resultant bovine embryo in vitro
Authors: Kowsar Rasoul , Izadi Fatemeh , Sadeghi Nima , Riasi Ahmad , Zadegan Faezeh Ghazvini , Hajian Mehdi , Nasr-Esfahani Mohammad Hossein , Farrokhpour Hossein , Miyamoto Akio 
Published: April 2018

SummaryNutrition influences the microenvironment in the proximity of oocyte and affects early embryonic development. Elevated blood urea nitrogen, even in healthy dairy cows, is associated with reduced fertility and there is high correlation between blood urea levels and follicular fluid urea levels. Using a docking calculation (in silico), urea showed a favorable binding activity towards the ZP-N domain of ZP3, that of ZP2, and towards the predicted full-length sperm receptor ZP3. Supplementation of oocyte maturation medium with nutrition-related levels of urea (20 or 40 mg/dl as seen in healthy dairy cows fed on low or high dietary protein, respectively) dose-dependently increased: (i) the proportion of oocytes that remained uncleaved; and (ii) oocyte degeneration; and reduced cleavage, blastocyst and hatching rates. High levels of urea induced shrinkage in oocytes, visualised using scanning electron microscopy. Urea downregulated NANOG while dose-dependently upregulating OCT4, DNMT1, and BCL2 expression. Urea at 20 mg/dl induced BAX expression. Using mathematical modelling, the rate of oocyte degeneration was sensitive to urea levels; while cleavage, blastocyst and hatching rates exhibited negative sensitivity. The present data imply a novel role for urea in reducing oocyte competence and changing gene expression in the resultant embryos.
Neuropsychological Profiles and Trajectories in Preclinical Alzheimer’s Disease
Authors: Ho Jean K. , Nation Daniel A. ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: April 2018

AbstractObjectives: The present study investigated the independent and synergistic effects of amyloid beta (Aβ1-42) and phosphorylated tau (Ptau) pathologies on neuropsychological profiles and trajectories in cognitively normal older adults. Methods: Alzheimer’s Disease Neuroimaging Initiative participants identified as cognitively normal at baseline underwent longitudinal assessment (N=518; 0, 12, 24, 36 months), baseline lumbar puncture and follow-up cognitive exams. Cerebral spinal fluid (CSF) biomarker profiles (Aβ-Ptau-, Aβ+Ptau-, Aβ-Ptau+, Aβ+Ptau+) were compared on baseline profiles and trajectories for memory (Rey Auditory Verbal Learning Test), attention/executive function (Trail Making Test, A and B), language (Animal Fluency, Vegetable Fluency, Boston Naming Test) and processing speed (Digit Symbol) using multilevel models. Results: The Aβ+Ptau+ group exhibited significantly worse baseline performance on tests of memory and executive function relative to the Aβ-Ptau+ and Aβ-Ptau- groups. The Aβ+Ptau- group fell between the Aβ+Ptau+ participants and the Aβ-Ptau- and Aβ-Ptau+ groups on all three cognitive domains and exhibited worse baseline executive function. The Aβ-Ptau+ group performed worse than Aβ-Ptau- participants on processing speed. Over 36-month follow-up, the Aβ+Ptau+ group exhibited the greatest declines in memory and semantic fluency compared to all other groups. Conclusions: Cognitively normal older adults with both Aβ and Ptau pathology exhibited the weakest profile, marked by the worst memory decline compared to the other groups. Other subtle changes in this group included declines in executive function and semantic fluency. Those with Ptau pathology alone showed slowed processing speed, and those with Aβ pathology alone showed worse attention and executive function compared to biomarker negative participants. (JINS, 2018, 24, 1–10)