bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of selective IK,ACh inhibition by XAF‐1407 in an equine model of tachypacing‐induced persistent atrial fibrillation
Authors: Fenner Merle Friederike , Carstensen Helena , Dalgas Nissen Sarah , Melis Hesselkilde Eva , Scott Lunddahl Christine , Adler Hess Jensen Maja , Loft‐Andersen Ameli Victoria , Sattler Stefan Michael , Platonov Pyotr , El‐Haou Said , Jackson Claire , Tang Raymond , Kirby Robert , Ford John , Schotten Ulrich , Milnes James , Svane Sørensen Ulrik , Jespersen Thomas , Buhl Rikke 
Published: May 2020

Background and PurposeInhibition of the G‐protein gated ACh‐activated inward rectifier potassium current, IK,ACh may be an effective atrial selective treatment strategy for atrial fibrillation (AF). Therefore, the anti‐arrhythmic and electrophysiological properties of a novel putatively potent and highly specific IK,ACh inhibitor, XAF‐1407 (3‐methyl‐1‐[5‐phenyl‐4‐[4‐(2‐pyrrolidin‐1‐ylethoxymethyl)‐1‐piperidyl]thieno[2,3‐d]pyrimidin‐6‐yl]azetidin‐3‐ol), were characterised for the first time in vitro and investigated in horses with persistent AF.Experimental ApproachThe pharmacological ion channel profile of XAF‐1407 was investigated using cell lines expressing relevant ion channels. In addition, eleven horses were implanted with implantable cardioverter defibrillators enabling atrial tachypacing into self‐sustained AF. The electrophysiological effects of XAF‐1407 were investigated after serial cardioversions over a period of 1 month. Cardioversion success, drug‐induced changes of atrial tissue refractoriness, and ventricular electrophysiology were assessed at baseline (day 0) and days 3, 5, 11, 17, and 29 after AF induction.Key ResultsXAF‐1407 potently and selectively inhibited Kir3.1/3.4 and Kir3.4/3.4, underlying the IK,ACh current. XAF‐1407 treatment in horses prolonged atrial effective refractory period as well as decreased atrial fibrillatory rate significantly (~20%) and successfully cardioverted AF, although with a decreasing efficacy over time. XAF‐1407 shortened atrioventricular‐nodal refractoriness, without effect on QRS duration. QTc prolongation (4%) within 15 min of drug infusion was observed, however, without any evidence of ventricular arrhythmia.Conclusion and ImplicationsXAF‐1407 efficiently cardioverted sustained tachypacing‐induced AF of short duration in horses without notable side effects. This supports IK,ACh inhibition as a potentially safe treatment of paroxysmal AF in horses, suggesting potential clinical value for other species including humans.
Personalized designs of adjuvant radiotherapy for pancreatic cancer based on molecular profiles
Authors: Zhu Xiaofei , Cao Yangsen , Ju Xiaoping , Zhao Xianzhi , Jiang Lingong , Ye Yusheng , Shen Yuxin , Cao Fei , Qing Shuiwang , Zhang Huojun 
Published: May 2020

AbstractThis study aims to identify postoperative recurrence patterns of pancreatic cancer with different molecular profiles, which provides evidence for personalized target volumes of adjuvant radiotherapy. Patients with pathologically confirmed resectable pancreatic ductal adenocarcinoma were included. Recurrences were treated with stereotactic body radiation therapy. Immunohistochemical staining of Ki‐67, P53, and programmed cell death‐ligand 1 (PD‐L1) was carried out. Both of the intensities of Ki‐67 and P53 were classified as 10% or less, 11%‐49%, and 50% or more. Eighty‐nine patients had PD‐L1 tested, stratified as TC0 and IC0, and TC1/2 or IC1/2. Distances with significant differences among different levels or beyond 10 mm were of interest. With the increasing intensity of Ki‐67, the distance from the superior and posterior border of 80% recurrences to the celiac axis (CA) ranged from 10.1 to 13.8 mm and 9.2 to 11.0 mm. The distance from the inferior and posterior border of 80% recurrences to the superior mesenteric artery (SMA) ranged from 9.4 to 9.9 mm and 9.4 to 11.0 mm. Similarly, with the increasing intensity of P53, the distance from the superior and posterior border of 80% recurrences to the CA ranged from 9.7 to 13.2 mm and 10.1 to 10.6 mm. The distance from the inferior and anterior border of 80% recurrences to the SMA ranged from 9.5 to 9.9 mm and 8.6 to 9.4 mm. Regarding the increasing level of PD‐L1, the distance from the superior border of 80% recurrences to the CA ranged from 10.9 to 13.5 mm. A biologically effective dose of more than 65 Gy to local recurrences was predictive of favorable outcomes in all levels of Ki‐67, P53, and PD‐L1. Nonuniform expansions of regions of interest based on different levels of molecular profiles to form target volumes could cover most recurrences, which might be feasible for adjuvant radiotherapy.
Peripubertal high‐fat diet promotes c‐Myc stabilization in mammary gland epithelium
Authors: Kulathunga Nilakshi , Kohno Susumu , Linn Paing , Nishimoto Yuuki , Horike Shin‐ichi , Zaraiskii Mikhail I. , Kumar Sharad , Muranaka Hayato , Takahashi Chiaki 
Published: May 2020

AbstractDietary fat consumption during accelerated stages of mammary gland development, such as peripubertal maturation or pregnancy, is known to increase the risk for breast cancer. However, the underlying molecular mechanisms are not fully understood. Here we examined the gene expression profile of mouse mammary epithelial cells (MMECs) on exposure to a high‐fat diet (HFD) or control diet (CD). Trp53−/− female mice were fed with the experimental diets for 5 weeks during the peripubertal period (3‐8 weeks of age). The treatment showed no significant difference in body weight between the HFD‐fed mice and CD‐fed mice. However, gene set enrichment analysis predicted a significant enrichment of c‐Myc target genes in animals fed HFD. Furthermore, we detected enhanced activity and stabilization of c‐Myc protein in MMECs exposed to a HFD. This was accompanied by augmented c‐Myc phosphorylation at S62 with a concomitant increase in ERK phosphorylation. Moreover, MMECs derived from HFD‐fed Trp53−/− mouse showed increased colony‐ and sphere‐forming potential that was dependent on c‐Myc. Further, oleic acid, a major fatty acid constituent of the HFD, and TAK‐875, an agonist to G protein‐coupled receptor 40 (a receptor for oleic acid), enhanced c‐Myc stabilization and MMEC proliferation. Overall, our data indicate that HFD influences MMECs by stabilizing an oncoprotein, pointing to a novel mechanism underlying dietary fat‐mediated mammary carcinogenesis.
Applications of machine‐learning methods for the discovery of NDM‐1 inhibitors
Authors: Shi Cheng , Dong Fanyi , Zhao Guiling , Zhu Ning , Lao Xingzhen , Zheng Heng 
Published: May 2020

AbstractThe emergence of New Delhi metal beta‐lactamase (NDM‐1)‐producing bacteria and their worldwide spread pose great challenges for the treatment of drug‐resistant bacterial infections. These bacteria can hydrolyze most β‐lactam antibacterials. Unfortunately, there are no clinically useful NDM‐1 inhibitors. In the current work, we manually collected NDM‐1 inhibitors reported in the past decade and established the first NDM‐1 inhibitor database. Four machine‐learning models were constructed using the structural and property characteristics of the collected compounds as input training set to discover potential NDM‐1 inhibitors. In order to distinguish between high active inhibitors and putative positive drugs, a three‐classification strategy was introduced in our study. In detail, the commonly used positive and negative divisions are converted into strongly active, weakly active, and inactive. The accuracy of the best prediction model designed based on this strategy reached 90.5%, compared with 69.14% achieved by the traditional docking‐based virtual screening method. Consequently, the best model was used to virtually screen a natural product library. The safety of the selected compounds was analyzed by the ADMET prediction model based on machine learning. Seven novel NDM‐1 inhibitors were identified, which will provide valuable clues for the discovery of NDM‐1 inhibitors.
The role of Kono‐S anastomosis and mesenteric resection in reducing recurrence after surgery for Crohn’s disease: a systematic review
Authors: Alshantti A. , Hind D. , Hancock L. , Brown S. R. 
Published: May 2020

AbstractAimRecurrence after surgery for Crohn’s disease is common. Anastomotic configuration may influence recurrence and the mesentery may be key. Recently the Kono‐S anastomosis and radical mesenteric excision have been proposed as methods of reducing recurrence. We analysed the literature pertaining to these novel techniques.MethodWe searched MEDLINE, Embase and the Cochrane Library for, and selected, studies evaluating Kono‐S anastomosis and/or radical mesenteric excision in Crohn’s disease. We assessed methodological quality and risk of bias using the Cochrane risk of bias tool for randomized controlled trials and the Joanna Briggs Institute tool for nonrandomized trials. A narrative synthesis was used to summarize the findings.ResultsNine studies (896 patients) were identified. Apart from one randomized controlled trial with a low risk of bias the overall level of evidence was poor (Grade IV). The Kono‐S anastomosis was associated with a lower incidence of endoscopic and surgical recurrence (0%–3.4% vs 15%–24.4% respectively). Complications, particularly anastomotic leak rate, were also lower (1.8% vs 9.3% respectively). Evidence from a single poor quality study suggested that mesenteric excision may reduce surgical recurrence rates compared with mesentery preservation.ConclusionThe existing literature suggests that the Kono‐S anastomosis is safe and may reduce endoscopic and surgical recurrence, but level of evidence is mainly poor. One element of the Kono‐S technique, preservation of the mesentery, may be detrimental to recurrence. Further, higher quality, studies are required to investigate these techniques. Such studies should consider the impact of the degree of mesenteric resection in addition to the anastomosis on disease recurrence.
Country asymmetry, trade agreements, and transfers
Authors: Kilolo Jean‐Marc Malambwe 
Published: May 2020

AbstractUsing a standard 2 × 2 trade agreement model, I show that the welfare effects of a free trade agreement (FTA) depend on the asymmetry on supply and demand functions. When countries are sufficiently asymmetric with respect to the size or the demand functions, the small country tends to be better off, while the large country is worse off. Thus, the small country must compensate the large country for the FTA to be incentive‐compatible. However, in the presence of sufficient asymmetry in the supply functions, the small country is worse off, while the bigger is better off. In this case, the transfer must flow from the large to the small country. This last finding helps explain why some FTAs between rich and poor countries provide for adjustment transfers to the latter.
Real‐world treatment patterns and outcomes in non‐transplant newly diagnosed multiple Myeloma in France, Germany, Italy, and the United Kingdom
Authors: Mohty Mohamad , Knauf Wolfgang , Romanus Dorothy , Corman Shelby , Verleger Katharina , Kwon Youngmin , Cherepanov Dasha , Cambron‐Mellott M. Janelle , Vikis Haris G. , Gonzalez Francisco , Gavini Francois , Ramasamy Karthik 
Published: May 2020

AbstractObjectivesThe treatment paradigm in newly diagnosed multiple myeloma (NDMM) is evolving toward individualized, risk‐directed, and longer duration of therapy (DOT). The objective of this study was to describe treatment patterns and outcomes in non‐transplant NDMM in four European countries.MethodsThis retrospective chart review included adults with NDMM diagnosed between January 1, 2012, and December 31, 2013 (early cohort), or April 1, 2016, and March 31, 2017 (recent cohort).ResultsAmong 836 patients, molecular testing was performed in 21% and 35% patients of early vs recent cohorts; proteasome inhibitor (PI)/alkylator combinations were the principal first‐line (1 L) therapy (39% vs 43%). Use of immunomodulatory drug (IMID)/alkylator combinations declined from early to recent cohort (26% vs 13%) but IMID (7% vs 16%) use increased. Few patients (5%) received 1 L maintenance therapy. Two‐thirds of patients were treated with a fixed duration intent, with a median 7‐month 1 L DOT and progression‐free survival (PFS) of 32.8 months in the early cohort. Both 1 L DOT and PFS were longer with oral compared to injectable regimens.ConclusionsAlthough frontline treatment patterns changed significantly, 1 L DOT is short. The uptake of molecular testing and 1 L maintenance is low. These results highlight areas of unmet need in NDMM.
Transferability of a soil variogram for sampling design: A case study of three grasslands in Ireland
Authors: Sun Xiao‐Lin , Brus Dick J. 
Published: May 2020

AbstractIt is commonly accepted that an estimated soil variogram can be transferred to another similar area for deriving the tolerable spacing of a sampling grid or, more generally, the sample size, given a requirement on the quality of the soil property map of the recipient area. The quality of the derived tolerable grid spacing depends on how similar the population variograms of the donor area and recipient area are. In practice we are uncertain about the variograms of both areas due to sampling errors. Ideally, the uncertainty about the variogram of the donor area is accounted for in deriving the tolerable grid spacing. To assess the transferability, we should also account for uncertainty in the estimated variogram of the recipient area. In this study the transferability of variograms of soil pH, P, Mg and K is analysed for three grassland fields in Ireland, which are similar in soil‐forming factors. One field served as donor area, the other two as recipient area. For all three fields and for each soil property, 500 variograms were sampled from the posterior distribution of the variogram parameters. Results showed that the estimated variogram parameters of the recipient fields differed largely from those of the transferred variograms. The ranges of estimated mean kriging variance values for the various grid spacings, as obtained with the two sets of variograms (one set of the donor field, one set of the recipient field), did not overlap. Even after scaling the transferred variogram with an estimate of the variance of the recipient field, the transferred variogram was of no use for determining the tolerable grid spacing. The difference in the variograms can possibly be explained by the difference in historical land use.Highlights
Transferability of variograms to derive tolerable grid spacing for mapping grassland fields is assessed
Transferability should be based on the uncertainty distributions of the tolerable grid spacings
Due to difference in historical land use, local and transferred variograms differed largely
Transferability of a variogram is very poor, even after scaling the transferred variogram
Experimental determination of sediment transport capacity of concentrated water flow over saturated soil slope
Authors: Huang Yuhan , Li Fahu , Liu Zhiqiang , Li Juan , Gao Xiaofeng 
Published: May 2020

AbstractSediment transport capacity (STC) is an important variable for characterising soil erosion on hillslopes. STC also determines the capability of sediment delivery and solute transportation. An experimental methodological strategy was developed in this study to measure the STC in eroding rills on a saturated soil slope. The STC was ensured by using a slope‐raised flume section to feed sufficient amounts of sediments into the water flow, and a flume section was used to stabilize the water flow and produce sediment concentration at the STC level for measurement. Experiments under four slope gradients of 5°, 10°, 15° and 20° and three unit‐width flow rates of 0.33, 0.67 and 1.33 × 10−3 m3 s−1 m−1 were conducted to measure the STCs on saturated soil slopes, with the experiments on STCs on non‐saturated soil slopes as control treatments. The measured STCs range from 0.16 to 1.41 kg s−1 m−1 over the saturated loess slopes. The STC measurement method for saturated soil slopes was verified as feasible by the small SDs of the measured STCs and the agreement between the trend of rill sediment delivery rate and the STC values at the slope gradient of 20° and three unit‐width discharges. The relationships between STC and slope gradient and those between STC and unit‐width flow rate over saturated soil slopes matched well with the power and linear functions, respectively. Furthermore, the STC values correlated well with the flow velocity. The STC value on the saturated loess slope was approximately 25% larger than that on the non‐saturated loess slope. An empirical power function of slope gradient and unit‐width flow rate was found to predict the STC on saturated loess slopes effectively. Therefore, the measurement method for soil erosion from saturated soil slopes can help to estimate the STC and obtain key parameters for the soil erosion prediction model.Highlights
The sediment feeding by slope‐raised flume section was used to measure sediment transport capacity (STC) of saturated soil slope, and its feasibility was tested.
The STC value over the saturated soil slope was significantly greater than that over non‐saturated soil slope.
The STC over the saturated soil slope could be empirically expressed as the product of power functions of water flow rate and slope gradient.
Trait matching and phenological overlap increase the spatio‐temporal stability and functionality of plant–pollinator interactions
Authors: Peralta Guadalupe , Vázquez Diego P. , Chacoff Natacha P. , Lomáscolo Silvia B. , Perry George L. W. , Tylianakis Jason M. 
Published: May 2020

AbstractMorphology and phenology influence plant–pollinator network structure, but whether they generate more stable pairwise interactions with higher pollination success remains unknown. Here we evaluate the importance of morphological trait matching, phenological overlap and specialisation for the spatio‐temporal stability (measured as variability) of plant–pollinator interactions and for pollination success, while controlling for species' abundance. To this end, we combined a 6‐year plant–pollinator interaction dataset, with information on species traits, phenologies, specialisation, abundance and pollination success, into structural equation models. Interactions among abundant plants and pollinators with well‐matched traits and phenologies formed the stable and functional backbone of the pollination network, whereas poorly matched interactions were variable in time and had lower pollination success. We conclude that phenological overlap could be more useful for predicting changes in species interactions than species abundances, and that non‐random extinction of species with well‐matched traits could decrease the stability of interactions within communities and reduce their functioning.
Aggressive multiple sclerosis: a single‐centre, real‐world treatment experience with autologous haematopoietic stem cell transplantation and alemtuzumab
Authors: Boffa G. , Lapucci C. , Sbragia E. , Varaldo R. , Raiola A. M. , Currò D. , Roccatagliata L. , Capello E. , Laroni A. , Mikulska M. , Gualandi F. , Uccelli A. , Angelucci E. , Mancardi G. L. , Inglese M. 
Published: May 2020

Background and purposeThe best therapeutic approach for aggressive relapsing–remitting multiple sclerosis remains unknown. The objective was to compare the efficacy and safety of autologous haematopoietic stem cell transplantation (aHSCT) and alemtuzumab in aggressive relapsing–remitting multiple sclerosis.MethodsThe time to first relapse, time to confirmed disability worsening, time to first evidence of magnetic resonance imaging (MRI) activity and time to first evidence of disease activity were compared between the two treatment groups. Secondary outcomes included the 12, 24 and 36 month annualized relapse rate (ARR) and the 6‐month confirmed Expanded Disability Status Scale (EDSS) changes at months 12 and 24.ResultsFifty‐seven patients treated with aHSCT (n = 25) or alemtuzumab (n = 32) were included. At baseline, aHSCT patients had a higher EDSS (median score 6 vs. 3; P < 0.001), higher ARR (mean ARR 3.2 vs. 1.7; P = 0.001) and a higher number of baseline T1 gadolinium‐enhancing lesions on MRI (mean number 15.5 vs. 1.6; P < 0.001). NEDA‐3 (no evidence of disease activity) status was more frequently achieved in aHSCT‐treated patients than in alemtuzumab‐treated patients [75% vs. 56% of patients at the end of the observation period; hazard ratio (HR) 0.27, 95% confidence interval (CI) 0.08–0.84; P = 0.023]. aHSCT significantly reduced the risk of relapse (relapse‐free survival 84% vs. 69%; HR 0.13, 95% CI 0.02–0.63; P = 0.012) and MRI activity (MRI‐activity‐free survival 85% vs. 59%; HR 0.13, 95% CI 0.03–0.59; P = 0.009). The ARR at 36 months was significantly lower in the aHSCT group (0.05 vs. 0.35, P = 0.02). A significant effect of aHSCT in promoting EDSS improvement compared with alemtuzumab was noted (P = 0.035).ConclusionsAlemtuzumab and aHSCT are effective treatment choices for aggressive multiple sclerosis. aHSCT seems to be superior to alemtuzumab in inducing complete disease control and in promoting short‐term disability improvement.
Ligand‐centered assessment of SARS‐CoV‐2 drug target models in the Protein Data Bank
Authors: Wlodawer Alexander , Dauter Zbigniew , Shabalin Ivan G. , Gilski Miroslaw , Brzezinski Dariusz , Kowiel Marcin , Minor Wladek , Rupp Bernhard , Jaskolski Mariusz 
Published: May 2020

A bright spot in the SARS‐CoV‐2 (CoV‐2) coronavirus pandemic has been the immediate mobilization of the biomedical community, working to develop treatments and vaccines for COVID‐19. Rational drug design against emerging threats depends on well‐established methodology, mainly utilizing X‐ray crystallography, to provide accurate structure models of the macromolecular drug targets and of their complexes with candidates for drug development. In the current crisis, the structural biological community has responded by presenting structure models of CoV‐2 proteins and depositing them in the Protein Data Bank (PDB), usually without time embargo and before publication. Since the structures from the first‐line research are produced in an accelerated mode, there is an elevated chance of mistakes and errors, with the ultimate risk of hindering, rather than speeding up, drug development. In the present work, we have used model‐validation metrics and examined the electron density maps for the deposited models of CoV‐2 proteins and a sample of related proteins available in the PDB as of April 1, 2020. We present these results with the aim of helping the biomedical community establish a better‐validated pool of data. The proteins are divided into groups according to their structure and function. In most cases, no major corrections were necessary. However, in several cases significant revisions in the functionally sensitive area of protein–inhibitor complexes or for bound ions justified correction, re‐refinement, and eventually reversioning in the PDB. The re‐refined coordinate files and a tool for facilitating model comparisons are available at https://covid-19.bioreproducibility.org.DatabaseValidated models of CoV‐2 proteins are available in a dedicated, publicly accessible web service https://covid-19.bioreproducibility.org