bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dietary grape seed procyanidins suppressed weaning stress by improving antioxidant enzyme activity and mRNA expression in weanling piglets
Authors: Fang Luoyun , Li Mingyue , Zhao Luyv , Han Siyv , Li Yi , Xiong Benhai , Jiang Linshu 
Published: March 2020

AbstractThis study was conducted to investigate the effect of grape seed procyanidins (GSP) on growth performance, digestive enzyme activity, antioxidant enzyme activity and mRNA expression in weanling piglets. A total of 96 piglets (Pietrain × Large White) with an average initial body weight (BW) of 8.4 ± 1.7 kg were weaned at 28 days, and randomly divided into 4 groups. Four groups of animals were fed with a basic diet supplemented with various doses of GSP (0, 40, 70 and 100 mg/kg respectively) during the 28‐day treatment period. The results showed that the group receiving 40 mg/kg GSP significantly increased the average daily gain (ADG, p < .05) and decrease the feed/gain ratio (F/G, p < .05). Interestingly, the incidence of diarrhoea was significantly reduced in the groups of 40 and 70 mg/kg GSP, but it was increased in the group of 100 mg/kg GSP. Subsequent biochemical studies indicated that dietary GSP significantly increased the activities of digestive enzymes and antioxidant enzymes, including amylase (Amy), lipase(LPS, p < .05), glutathione peroxidase activity (GSH‐Px, p < .05), superoxide dismutase activity (SOD, p < .05) and total antioxidant capacity (T‐AOC, p < .05) in serum, liver and muscle, increased the expression of GSH‐Px, SOD and CAT genes (p < .05) in the liver, and decreased the level of malondialdehyde (MDA, p < .05) in serum, liver and muscle. Taken together, these studies revealed that low GSP supplement in diets can improve growth performance of weaned piglets, which is associated with increased digestive and antioxidant enzyme activities and enhanced resistance to weanling stress.
Gene editing of three BnITPK genes in tetraploid oilseed rape leads to significant reduction of phytic acid in seeds
Authors: Sashidhar Niharika , Harloff Hans J. , Potgieter Lizel , Jung Christian 
Published: March 2020

SummaryCommercialization of Brassica napus. L (oilseed rape) meal as protein diet is gaining more attention due to its well‐balanced amino acid and protein contents. Phytic acid (PA) is a major source of phosphorus in plants but is considered as anti‐nutritive for monogastric animals including humans due to its adverse effects on essential mineral absorption. The undigested PA causes eutrophication, which potentially threatens aquatic life. PA accounts to 2‐5% in mature seeds of oilseed rape and is synthesized by complex pathways involving multiple enzymes. Breeding polyploids for recessive traits is challenging as gene functions are encoded by several paralogs. Gene redundancy often requires to knock out several gene copies to study their underlying effects. Therefore, we adopted CRISPR‐Cas9 mutagenesis to knock out three functional paralogs of BnITPK. We obtained low PA mutants with an increase of free phosphorus in the canola grade spring cultivar Haydn. These mutants could mark an important milestone in rapeseed breeding with an increase in protein value and no adverse effects on oil contents.
Broker Organizations to Facilitate Cross‐Sector Collaboration: At the Crossroad of Strengthening and Weakening Effects
Authors: Stadtler Lea , Karakulak Özgü 
Published: March 2020

AbstractCross‐sector collaboration has emerged as an important way for public management to address complex social issues. Given the manifold challenges of governing and implementing such collaborations, scholars emphasize the benefits of using broker organizations to facilitate and strengthen cross‐sector collaboration. However, this comparative longitudinal case study of broker organizations that support global health partnerships shows a less straightforward pattern: despite their good intentions, two of the four broker organizations analyzed subtly weakened the collaboration by gradually replacing the partners’ cross‐sector tasks and decision‐making with unilateral, broker‐based ones. By juxtaposing this pattern with the other two broker organizations’ trajectories, this study reveals the processes underlying brokers’ role drift and unintended collaborative weakening and those allowing them to maintain their facilitation role. On this basis, the study exposes overlooked collaboration dynamics to reveal the boundaries of using broker organizations as a mechanism to facilitate cross‐sector collaboration.
Policy Coordination and Integration: A Research Agenda
Authors: Trein Philipp , Biesbroek Robbert , Bolognesi Thomas , Cejudo Guillermo M. , Duffy Robert , Hustedt Thurid , Meyer Iris 
Published: March 2020

AbstractCoordinating and integrating different policies and public sector organizations is a major challenge for practitioners and a continuing topic of interest for researchers. This Viewpoint essay argues that research on this topic needs reorientation to provide better insights for practice and theory of policy making, as well as policy implementation. The authors offer four suggestions on how future research could advance: (1) combining existing conceptual and epistemological approaches more systematically; (2) complementing case studies and surveys with large‐N analyses and novel research tools and methods; (3) more systematic analysis of the causal mechanisms in policy coordination and integration; and (4) more thorough study of the real‐world impact of policy coordination and integration.
Roles for Event Representations in Sensorimotor Experience, Memory Formation, and Language Processing
Authors: Knott Alistair , Takac Martin 
Published: March 2020

AbstractThe unifying theme for the papers in this volume is that event‐predictive representations play an important role in cognitive processes, and they are a particularly fruitful object of study for cognitive scientists. In this paper, we present our own model of event representations that draws together several disparate strands of research into event representations, relating to event perception, event encodings in working memory and their role in prediction, and events as they are reported in language. Our main claim is that the notion of deictic routines originally developed by Ballard et al. (1997) is of great use in explaining how these different types of event representation interface with one another.
Analysis of the Human Middle Ear Dynamics Through Multibody Modeling
Authors: Calero Diego , Lobato Lucas , Paul Stephan , Cordioli Júlio A. 
Published: March 2020

Abstract
The dynamics of the human middle ear (ME) has been studied in the past using several computational and experimental approaches in order to observe the effect on hearing of different conditions, such as conductive disease, corrective surgery, or implantation of a middle ear prosthesis. Multibody (MB) models combine the analysis of flexible structures with rigid body dynamics, involving fewer degrees-of-freedom (DOF) than finite element (FE) models, but a more detailed description than traditional 1D lumped parameter (LP) models. This study describes the reduction of a reference FE model of the human middle ear to a MB model and compares the results obtained considering different levels of model simplification. All models are compared by means of the frequency response of the stapes velocity versus sound pressure at the tympanic membrane (TM), as well as the system natural frequencies and mode shapes. It can be seen that the flexibility of the ossicles has a limited impact on the system frequency response function (FRF) and modes, and the stiffness of the tendons and ligaments only plays a role when above certain levels. On the other hand, the restriction of the stapes footplate movement to a piston-like behavior can considerably affect the vibrational modes, while constraints to the incudomalleolar joint (IMJ) and incudostapedial joint (ISJ) can have a strong impact on the system FRF.
Individual and neighbourhood socioeconomic inequalities in cognitive impairment: cross-sectional findings from the French CONSTANCES cohort
Authors: Letellier Noémie , Carrière Isabelle , Cadot Emmanuelle , Berkman Lisa , Goldberg Marcel , Zins Marie , Berr Claudine 
Published: March 2020

ObjectivesDespite the recent awareness of the environment impact on brain ageing, the influence of the neighbourhood socioeconomic status on cognitive impairment remains unclear. Here, we investigated the effects of individual and neighbourhood deprivation on cognitive impairment in middle-aged and young-old people.DesignCross-sectional study.Settings21 Health Screening Centres in the entire French metropolitan territory.ParticipantsA total of 44 648 participants (age range: 45 to 69 years) from the French CONSTANCES cohort were included in the analyses.Main outcomesAssociations between the overall cognitive score (based on a standardised battery of cognitive tests administered by neuropsychologists) and individual deprivation (Evaluation of Deprivation and Inequalities in Health Screening Centres; EPICES score) and geographical deprivation (French Deprivation Index; FDep index).ResultsBased on the EPICES score (validated cut-off ≥30.17), 12% of participants were considered to be deprived. After mutual adjustment, individual and geographical deprivation were associated with higher cognitive impairment in a multilevel logistic regression analysis that was also adjusted for sociodemographic, lifestyle and health factors. Specifically, individual deprivation was associated with an odds increase of 55% (OR=1.55, 95% CI: 1.45 to 1.66). The risk of global cognitive impairment progressively increased with the neighbourhood deprivation level, evaluated by the FDep index (reference Q1; Q2: OR=1.09, 95% CI: 0.98 to 1.20; Q3: OR=1.15, 95% CI: 1.04 to 1.27; Q4: OR=1.15, 95% CI: 1.04 to 1.28; Q5: OR=1.25, 95% CI: 1.13 to 1.39).ConclusionOur results suggest that the neighbourhood socioeconomic deprivation level is associated with cognitive impairment, independently of the individual deprivation level. A better understanding of this association could help to define new prevention strategies to target high-risk residents and high-risk geographical areas in order to reduce social health inequalities.
Influence of combined vitamin D3supplementation and resistance exercise training on musculoskeletal health in older men and women (EXVITD): protocol for a randomised controlled trial
Authors: Welford Anneka Elizabeth , Lanham-New Susan , Lord Janet , Doyle Alison , Robinson Julie , Nightingale Peter , Gittoes Neil , Greig Carolyn A 
Published: March 2020

IntroductionSarcopenia is a progressive loss in muscle mass, strength and function, the adverse consequences of which are severe, affecting quality of life and placing an increasing burden on social and healthcare systems. Vitamin D status is known to be associated with markers of sarcopenia, namely muscle mass, strength and function. Also, resistance exercise training (RET) is currently the only proven intervention to treat sarcopenia. However, very little data exist on the influence of combining the two interventions of vitamin D supplementation and resistance exercise training, although a recent systematic review provides tentative support for the current study’s hypothesis that the combined intervention may further improve musculoskeletal function above exercise training alone. The aim of the present study is to determine whether vitamin D3supplementation is any more effective in improving musculoskeletal function when combined with RET compared with exercise training alone in older adults.Methods and analysisThis double-blinded randomised placebo-controlled trial will recruit a target of 127 eligible men and women aged ≥65 years living independently or in sheltered housing within the Birmingham area to two groups: (1) 6 months RET and placebo or (2) 6 months RET and 800 IU/d vitamin D3. Measures of muscle power (Nottingham Power Rig), body composition (dual energy X-ray absorptiometry), muscle function (short physical performance battery, timed up and go), falls and fractures as events will be assessed. Assessments will take place at baseline and postintervention, with intermittent monitoring of bone turnover, calcium and vitamin D. The primary outcome will be lower limb extensor power output. Analyses of within-group changes and between-group differences in outcome measures are planned.Ethics and disseminationThe EXVITD study has ethical approval granted by the Black Country National Health Service Research Ethics Committee (14/WM/1220). Results of this trial will be submitted for publication in peer-reviewed journals and presented at conferences. The study is being conducted according to the principles of the Declaration of Helsinki.Trial registration numberNCT02467153; Post-results.
B-decay discrepancies after Moriond 2019
Authors: Aebischer Jason , Altmannshofer Wolfgang , Guadagnoli Diego , Reboud Méril , Stangl Peter , Straub David M. 
Published: March 2020

AbstractFollowing the updated measurement of the lepton flavour universality (LFU) ratio $$R_K$$RK in $$B\rightarrow K\ell \ell $$B→Kℓℓ decays by LHCb, as well as a number of further measurements, e.g. $$R_{K^*}$$RK∗ by Belle and $$B_s \rightarrow \mu \mu $$Bs→μμ by ATLAS, we analyse the global status of new physics in $$b\rightarrow s$$b→s transitions in the weak effective theory at the b-quark scale, in the Standard Model effective theory above the electroweak scale, and in simplified models of new physics. We find that the data continues to strongly prefer a solution with new physics in semi-leptonic Wilson coefficients. A purely muonic contribution to the combination $$C_9 = -C_{10}$$C9=-C10, well suited to UV-complete interpretations, is now favoured with respect to a muonic contribution to $$C_9$$C9 only. An even better fit is obtained by allowing an additional LFU shift in $$C_9$$C9. Such a shift can be renormalization-group induced from four-fermion operators above the electroweak scale, in particular from semi-tauonic operators, able to account for the potential discrepancies in $$b \rightarrow c$$b→c transitions. This scenario is naturally realized in the simplified $$U_1$$U1 leptoquark model. We also analyse simplified models where a LFU effect in $$b\rightarrow s\ell \ell $$b→sℓℓ is induced radiatively from four-quark operators and show that such a setup is on the brink of exclusion by LHC di-jet resonance searches.
Inactivation of the Prolyl Isomerase Pin1 Sensitizes BRCA1-Proficient Breast Cancer to PARP Inhibition
Authors: Luo Man-Li , Zheng Fang , Chen Wenying , Liang Zhi-Mei , Chandramouly Gurushankar , Tan Jianan , Willis Nicholas A. , Chen Chun-Hau , Taveira Mateus de Oliveira , Zhou Xiao Zhen , Lu Kun Ping , Scully Ralph , Wulf Gerburg M. , Hu Hai 
Published: March 2020

Abstract

PARP inhibitor monotherapies are effective to treat patients with breast, ovary, prostate, and pancreatic cancer with BRCA1 mutations, but not to the much more frequent BRCA wild-type cancers. Searching for strategies that would extend the use of PARP inhibitors to BRCA1-proficient tumors, we found that the stability of BRCA1 protein following ionizing radiation (IR) is maintained by postphosphorylational prolyl-isomerization adjacent to Ser1191 of BRCA1, catalyzed by prolyl-isomerase Pin1. Extinction of Pin1 decreased homologous recombination (HR) to the level of BRCA1-deficient cells. Pin1 stabilizes BRCA1 by preventing ubiquitination of Lys1037 of BRCA1. Loss of Pin1, or introduction of a BRCA1-mutant refractory to Pin1 binding, decreased the ability of BRCA1 to localize to repair foci and augmented IR-induced DNA damage. In vitro growth of HR-proficient breast, prostate, and pancreatic cancer cells were modestly repressed by olaparib or Pin1 inhibition using all-trans retinoic acid (ATRA), while combination treatment resulted in near-complete block of cell proliferation. In MDA-MB-231 xenografts and triple-negative breast cancer patient-derived xenografts, either loss of Pin1 or ATRA treatment reduced BRCA1 expression and sensitized breast tumors to olaparib. Together, our study reveals that Pin1 inhibition, with clinical widely used ATRA, acts as an effective HR disrupter that sensitizes BRCA1-proficient tumors to PARP inhibition.

Significance:
PARP inhibitors have been limited to treat homologous recombination–deficient tumors. All-trans retinoic acid, by inhibiting Pin1 and destabilizing BRCA1, extends benefit of PARP inhibitors to patients with homologous recombination–proficient tumors.
See related commentary by Cai, p. 2977
Drug Sensitivity and Allele Specificity of First-Line Osimertinib Resistance EGFR Mutations
Authors: Starrett Jacqueline H. , Guernet Alexis A. , Cuomo Maria Emanuela , Poels Kamrine E. , van Alderwerelt van Rosenburgh Iris K. , Nagelberg Amy , Farnsworth Dylan , Price Kristin S. , Khan Hina , Ashtekar Kumar Dilip , Gaefele Mmaserame , Ayeni Deborah , Stewart Tyler F. , Kuhlmann Alexandra , Kaech Susan M. , Unni Arun M. , Homer Robert , Lockwood William W. , Michor Franziska , Goldberg Sarah B. , Lemmon Mark A. , Smith Paul D. , Cross Darren A.E. , Politi Katerina 
Published: March 2020

Abstract

Osimertinib, a mutant-specific third-generation EGFR tyrosine kinase inhibitor, is emerging as the preferred first-line therapy for EGFR-mutant lung cancer, yet resistance inevitably develops in patients. We modeled acquired resistance to osimertinib in transgenic mouse models of EGFRL858R-induced lung adenocarcinoma and found that it is mediated largely through secondary mutations in EGFR—either C797S or L718V/Q. Analysis of circulating free DNA data from patients revealed that L718Q/V mutations almost always occur in the context of an L858R driver mutation. Therapeutic testing in mice revealed that both erlotinib and afatinib caused regression of osimertinib-resistant C797S-containing tumors, whereas only afatinib was effective on L718Q mutant tumors. Combination first-line osimertinib plus erlotinib treatment prevented the emergence of secondary mutations in EGFR. These findings highlight how knowledge of the specific characteristics of resistance mutations is important for determining potential subsequent treatment approaches and suggest strategies to overcome or prevent osimertinib resistance in vivo.

Significance:
This study provides insight into the biological and molecular properties of osimertinib resistance EGFR mutations and evaluates therapeutic strategies to overcome resistance.
Type 2 Diabetes Mellitus Is Independently Associated With Decreased Neural Baroreflex Sensitivity
Authors: Cseh Domonkos , Climie Rachel E. , Offredo Lucile , Guibout Catherine , Thomas Frédérique , Zanoli Luca , Danchin Nicolas , Sharman James E. , Laurent Stéphane , Jouven Xavier , Boutouyrie Pierre , Empana Jean-Philippe 
Published: March 2020

Objective:
Impaired baroreflex function is an early indicator of cardiovascular autonomic imbalance. Patients with type 2 diabetes mellitus (T2D) have decreased baroreflex sensitivity (BRS), however, whether the neural and/or mechanical component of the BRS (nBRS and mBRS, respectively) is altered in those with high metabolic risk (HMR, impaired fasting glucose and/or metabolic syndrome) or with overt T2D, is unknown. We examined this in a community-based observational study, the Paris Prospective Study III (PPS3).

Approach and Results:

In 7626 adults aged 50 to 75 years, resting nBRS (estimated by low-frequency gain, from carotid distension rate and RR intervals [time intervals between successive R waves]) and mBRS were measured by high-precision carotid echotracking. The associations between overt T2D or HMR as compared with subjects with normal glucose metabolism (NGM) and nBRS or mBRS were quantified using multivariable linear regression analysis. There were 319 subjects with T2D (61±6 years, 77% male), 1450 subjects with HMR (60±6 years, 72% male), and 5857 subjects with NGM (59±6 years, 57% male). Compared with NGM subjects, nBRS was significantly lower in HMR subjects (β=−0.07 [95% CI, −0.12 to −0.01];
P
=0.029) and in subjects with T2D (β=−0.18 [95% CI, −0.29 to −0.07];
P
=0.002) after adjustment for confounding and mediating factors. Subgroup analysis suggests significant and independent alteration in mBRS only among HMR patients who had both impaired fasting glucose and metabolic syndrome.

Conclusions:
In this community-based study of individuals aged 50 to 75, a graded decrease in nBRS was observed in HMR subjects and patients with overt T2D as compared with NGM subjects.
Substrate Spatial Complexity Analysis for the Prediction of Ventricular Arrhythmias in Patients With Ischemic Cardiomyopathy
Authors: Okada David R. , Miller Jason , Chrispin Jonathan , Prakosa Adityo , Trayanova Natalia , Jones Steven , Maggioni Mauro , Wu Katherine C. 
Published: March 2020

Background:
Transition zones between healthy myocardium and scar form a spatially complex substrate that may give rise to reentrant ventricular arrhythmias (VAs). We sought to assess the utility of a novel machine learning approach for quantifying 3-dimensional spatial complexity of grayscale patterns on late gadolinium enhanced cardiac magnetic resonance images to predict VAs in patients with ischemic cardiomyopathy.

Methods:
One hundred twenty-two consecutive ischemic cardiomyopathy patients with left ventricular ejection fraction ≤35% without prior history of VAs underwent late gadolinium enhanced cardiac magnetic resonance images. From raw grayscale data, we generated graphs encoding the 3-dimensional geometry of the left ventricle. A novel technique, adapted to these graphs, assessed global regularity of signal intensity patterns using Fourier-like analysis and generated a substrate spatial complexity profile for each patient. A machine learning statistical algorithm was employed to discern which substrate spatial complexity profiles correlated with VA events (appropriate implantable cardioverter-defibrillator firings and arrhythmic sudden cardiac death) at 5 years of follow-up. From the statistical machine learning results, a complexity score ranging from 0 to 1 was calculated for each patient and tested using multivariable Cox regression models.

Results:

At 5 years of follow-up, 40 patients had VA events. The machine learning algorithm classified with 81% overall accuracy and correctly classified 86% of those without VAs. Overall negative predictive value was 91%. Average complexity score was significantly higher in patients with VA events versus those without (0.5±0.5 versus 0.1±0.2;
P
<0.0001) and was independently associated with VA events in a multivariable model (hazard ratio, 1.5 [1.2–2.0];
P
=0.002).

Conclusions:
Substrate spatial complexity analysis of late gadolinium enhanced cardiac magnetic resonance images may be helpful in refining VA risk in patients with ischemic cardiomyopathy, particularly to identify low-risk patients who may not benefit from prophylactic implantable cardioverter-defibrillator therapy.

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