bluuebunny/crossref_metadata_2025_split huggingface dataset:
Caffeine but not acetaminophen increases 4-km cycling time-trial performance
Authors: Tomazini Fabiano , Mariano Ana Carla S. , Andrade-Souza Victor A. , Sebben Viviane C. , de Maria Carlos A. B. , Coelho Daniel B. , Bertuzzi Romulo , Silva-Cavalcante Marcos D. , Lima-Silva Adriano E. 
Published: March 2019

AbstractAcetaminophen has been combined with caffeine for therapeutic purpose, but the effect of co-ingestion of acetaminophen and caffeine on exercise performance has not been investigated. The aim of this study was to determine the effect of isolated and combined ingestion of caffeine and acetaminophen on performance during a 4-km cycling time-trial. In a double-blind, crossover design, eleven men, accustomed to cycling recreationally, completed a 4-km cycling time-trial one hour after the ingestion of cellulose (PLA), acetaminophen (20 mg·kg−1body mass, ACT), caffeine (5 mg·kg−1body mass, CAF) or combined acetaminophen and caffeine (20 and 5 mg·kg−1body mass, respectively, ACTCAF). The perception of pain and rating of perceived exertion were recorded every 1-km, and electromyography and oxygen uptake were continually recorded and averaged each 1-km. Plasma lactate concentration was measured before and immediately after the trial. The time and mean power during the 4-km cycling time-trial was significantly improved (P< 0.05) in CAF (407.9 ± 24.5 s, 241.4 ± 16.1 W) compared to PLA (416.1 ± 34.1 s, 234.1 ± 19.2 W) and ACT (416.2 ± 26.6 s, 235.8 ± 19.7 W). However, there was no difference between ACTCAF (411.6 ± 27.7 s, 238.7 ± 18.7 W) and the other conditions (P> 0.05). The perception of pain, rating of perceived exertion, electromyography, oxygen uptake, and plasma lactate were similar across the conditions (P> 0.05). In conclusion, caffeine but not acetaminophen increases power output ultimately increasing performance during a 4-km cycling time-trial.
About samples, giving examples: Optimized Single Molecule Localization Microscopy
Authors: Jimenez Angélique , Friedl Karoline , Leterrier Christophe 
Published: March 2019

AbstractSuper-resolution microscopy has profoundly transformed how we study the architecture of cells, revealing unknown structures and refining our view of cellular assemblies. Among the various techniques, the resolution of Single Molecule Localization Microscopy (SMLM) can reach the size of macromolecular complexes and offer key insights on their nanoscale arrangement in situ. SMLM is thus a demanding technique and taking advantage of its full potential requires specifically optimized procedures. Here we describe how we perform the successive steps of an SMLM workflow, focusing on single-color Stochastic Optical Reconstruction Microscopy (STORM) as well as multicolor DNA Points Accumulation for imaging in Nanoscale Topography (DNA-PAINT) of fixed samples. We provide detailed procedures for careful sample fixation and immunostaining of typical cellular structures: cytoskeleton, clathrin-coated pits, and organelles. We then offer guidelines for optimal imaging and processing of SMLM data in order to optimize reconstruction quality and avoid the generation of artifacts. We hope that the tips and tricks we discovered over the years and detail here will be useful for researchers looking to make the best possible SMLM images, a pre-requisite for meaningful biological discovery.
TheKlebsiella pneumoniaecitrate synthase gene,gltA, influences site specific fitness during infection
Authors: Sun Yuang , Vornhagen Jay , Breen Paul , Forsyth Valerie , Zhao Lili , Mobley Harry L.T. , Bachman Michael A. 
Published: March 2019

AbstractKlebsiella pneumoniae(Kp), one of the most common causes of healthcare-associated infections, increases patient morbidity, mortality and hospitalization costs. Kp must acquire nutrients from the host for successful infection. However, the host is able to prevent bacterial nutrient acquisition through multiple systems, including the innate immune protein lipocalin 2 (Lcn2) that prevents Kp iron acquisition by sequestering the siderophore enterobactin. To identify novel Kp factors that mediate evasion of nutritional immunity during lung infection, we undertook an InSeq study using a pool of >20,000 transposon mutants administered toLcn2+/+andLcn2-/-mice. Comparing mutant frequencies between mouse genotypes, this genome-wide screen identified the Kp citrate synthase GltA as potentially interacting with Lcn2, and this novel finding was independently validated. Interestingly,in vitrostudies suggest that this interaction is not direct. Given that GltA is involved in oxidative metabolism, we screened the ability of this mutant to use a variety of carbon and nitrogen sources. The results indicated that thegltAmutant has a distinct amino acid auxotrophy and is unable to use a variety of carbon sources. Specifically, we show thatgltAis necessary for growth in bronchioloalveolar lavage fluid, which is amino acid-limited, but dispensable in serum, which is amino acid rich. Deletion ofLcn2from the host leads to increased amino acid levels in bronchioloalveolar lavage fluid, and thus abrogates the loss ofgltAduring pneumonia in theLcn2-/-background. GltA was also required for gut colonization, but dispensable in the bloodstream in a bacteremia model, demonstrating that deletion ofgltAleads to an organ-specific fitness defect. Together, this study is the first to mechanistically describe a role forgltAin Kp infection and provide unique insight into how metabolic flexibility impacts bacterial fitness during infection.Author SummaryThe bacteriaKlebsiella pneumoniae(Kp) is an important cause of infection in healthcare settings. These infections can be difficult to treat, as they frequently occur in chronically ill patients and the bacteria has the ability to acquire multiple antibiotic resistance markers. Kp is a common colonizer of the intestinal tract in hospitalized patients, and can progress to infections of the bloodstream, respiratory and urinary tract. However, the bacterial factors that allow Kp to replicate in these different body sites is unclear. In this study, we found that the Kp citrate synthase, GltA, enables bacterial replication in the lung and intestine by enhancing the ability of Kp to use diverse nutrients, in a mechanism known as metabolic flexibility. Kp lacking GltA require specific amino acids that are abundant in blood, but not other body sites. The work in this study provides novel insight into why Kp is a successful hospital pathogen that can colonize and infect multiple body sites.
Constitutional Principle, the Rule of Law and Political Reality: The European Union (Withdrawal) Act 2018
Authors: Craig Paul 
Published: March 2019

AbstractThe European Union (Withdrawal) Act 2018 is the cornerstone of UK legislation designed to accomplish the legal dimension of Brexit. It brings the entire acquis of EU law into UK law in order to avoid regulatory black holes that would otherwise occur. The Act embodies a twofold legislative strategy: EU law brought into UK law thereby is to be made fit for purpose by exit day, with necessary changes being made by statutory instrument; Parliament can then decide at greater leisure thereafter whether it wishes to retain, amend or repeal this legislation. The burden placed on Parliament is unprecedented, all the more so given the exigencies of time in which the changes are to be made. This article explicates the principal provisions of the 2018 Act, and the concerns as to constitutional principle and the rule of law raised by the legislation. The tensions in the drafting process are made apparent, and uncertainties in the resulting text are revealed.
An Assessment of Grant‐based Multilateral Funding Flows from 2014 to 2016
Authors: McArthur John W , Rasmussen Krista 
Published: March 2019

AbstractThis paper presents a global snapshot of how all countries, plus the Bill & Melinda Gates Foundation, allocated approximately $63 billion per year across 54 major multilateral organizations during the 2014–16 period. We assess direct funding to United Nations and non‐UN organizations to examine three key questions. First, how much does each funder contribute to each organization? Second, what is the relative importance of each funder to each organization? Third, how do funding allocations compare to objective benchmarks like share of donor country income, share of world income and share of world population? We find that a small number of countries provide a majority of total funding and a small number of organizations account for a majority of total resources received. Only a handful of countries are the top funders to at least one organization, but a variety of mid‐ and smaller‐sized economies play larger relative roles in some smaller organizations. Estimating funders’ flows across organizations allows for assessment of their revealed preferences among multilateral priorities and enables comparison against objective benchmarks for burden‐sharing. To our knowledge, this is the first study to provide a comprehensive mapping of all countries’ recent annual grant funding across the majority of large multilateral institutions.
Nontuberculous mycobacterium M. avium infection predisposes aged mice to cardiac abnormalities and inflammation
Authors: Headley Colwyn A. , Gerberick Abigail , Mehta Sumiran , Wu Qian , Yu Lianbo , Fadda Paolo , Khan Mahmood , Ganesan Latha Prabha , Turner Joanne , Rajaram Murugesan V. S. 
Published: March 2019

AbstractBiological aging dynamically alters normal immune and cardiac function, favoring the production of pro‐inflammatory cytokines (IL‐1β, IL‐6, and TNF‐α) and increased instances of cardiac distress. Cardiac failure is the primary reason for hospitalization of the elderly (65+ years). The elderly are also increasingly susceptible to developing chronic bacterial infections due to aging associated immune abnormalities. Since bacterial infections compound the rates of cardiac failure in the elderly, and this phenomenon is not entirely understood, the interplay between the immune system and cardiovascular function in the elderly is of great interest. Using Mycobacterium avium, an opportunistic pathogen, we investigated the effect of mycobacteria on cardiac function in aged mice. Young (2–3 months) and old (18–20 months) C57BL/6 mice were intranasally infected with M. avium strain 104, and we compared the bacterial burden, immune status, cardiac electrical activity, pathology, and function of infected mice against uninfected age‐matched controls. Herein, we show that biological aging may predispose old mice infected with M. avium to mycobacterial dissemination into the heart tissue and this leads to cardiac dysfunction. M. avium infected old mice had significant dysrhythmia, cardiac hypertrophy, increased recruitment of CD45+ leukocytes, cardiac fibrosis, and increased expression of inflammatory genes in isolated heart tissue. This is the first study to report the effect of mycobacteria on cardiac function in an aged model. Our findings are critical to understanding how nontuberculous mycobacterium (NTM) and other mycobacterial infections contribute to cardiac dysfunction in the elderly population.
Peripheral inflammation induces neuroinflammation that alters neurotransmission and cognitive and motor function in hepatic encephalopathy: Underlying mechanisms and therapeutic implications
Authors: Cabrera‐Pastor Andrea , Llansola Marta , Montoliu Carmina , Malaguarnera Michele , Balzano Tiziano , Taoro‐Gonzalez Lucas , García‐García Raquel , Mangas‐Losada Alba , Izquierdo‐Altarejos Paula , Arenas Yaiza M. , Leone Paola , Felipo Vicente 
Published: March 2019

AbstractSeveral million patients with liver cirrhosis suffer minimal hepatic encephalopathy (MHE), with mild cognitive and coordination impairments that reduce their quality of life and life span. Hyperammonaemia and peripheral inflammation act synergistically to induce these neurological alterations. We propose that MHE appearance is because of the changes in peripheral immune system, which are transmitted to brain, leading to neuroinflammation that alters neurotransmission leading to cognitive and motor alterations. We summarize studies showing that MHE in cirrhotic patients is associated with alterations in the immune system and that patients died with HE show neuroinflammation in cerebellum, with microglial and astrocytic activation and Purkinje cell loss. We also summarize studies in animal models of MHE on the role of peripheral inflammation in neuroinflammation induction, how neuroinflammation alters neurotransmission and how this leads to cognitive and motor alterations. These studies identify therapeutic targets and treatments that improve cognitive and motor function. Rats with MHE show neuroinflammation in hippocampus and altered NMDA and AMPA receptor membrane expression, which impairs spatial learning and memory. Neuroinflammation in cerebellum is associated with altered GABA transporters and extracellular GABA, which impair motor coordination and learning in a Y maze. These alterations are reversed by treatments that reduce peripheral inflammation (anti‐TNFα, ibuprofen), neuroinflammation (sulphoraphane, p38 inhibitors), GABAergic tone (bicuculline, pregnenolone sulphate) or increase extracellular cGMP (sildenafil or cGMP). The mechanisms identified would also occur in other chronic diseases associated with inflammation, aging and some mental and neurodegenerative diseases. Treatments that improve MHE may also be beneficial to treat these pathologies.
Daratumumab, bortezomib, cyclophosphamide and dexamethasone in newly diagnosed and relapsed multiple myeloma: LYRA study
Authors: Yimer Habte , Melear Jason , Faber Edward , Bensinger William I. , Burke John M. , Narang Mohit , Stevens Don , Gunawardena Sriya , Lutska Yana , Qi Keqin , Ukropec Jon , Qi Ming , Lin Thomas S. , Rifkin Robert M. 
Published: March 2019

SummaryThis United States community study evaluated the combination of daratumumab, bortezomib, cyclophosphamide and dexamethasone (D‐VCd) in newly diagnosed multiple myeloma (NDMM) and relapsed multiple myeloma (RMM). Patients received 4–8 induction cycles of bortezomib 1·5 mg/m2, cyclophosphamide 300 mg/m2 and dexamethasone 40 mg weekly. Intravenous daratumumab 16 mg/kg was administered as approved except for a split‐first dose in Cycle 1. Eligible patients underwent autologous stem cell transplantation. All patients received ≤12 daratumumab maintenance doses monthly. Eighty‐six NDMM and 14 RMM patients received ≥1 treatment dose. In NDMM patients, very good partial response or better (≥VGPR) and overall response rates after 4 induction cycles were 44% (primary endpoint) and 79%, respectively, and 56% and 81% at end of induction. The 12‐month progression‐free survival (PFS) rate was 87%. Efficacy was also observed in RMM patients. Fatigue (59%) and neutropenia (13%) were the most frequent treatment‐emergent adverse event (TEAE) and grade 3/4 TEAE, respectively. Infusion reactions occurred in 54% of patients, primarily during the first dose, and were mild (2% grade 3). The first 2 daratumumab infusions were 4·5 and 3·8 h (median). Overall, D‐VCd was well tolerated, split‐first daratumumab dosing was feasible, the ≥VGPR rate after 4 cycles was 44% and the 1‐year PFS rate was 87%.
Iron overload in congenital haemolytic anaemias: role of hepcidin and cytokines and predictive value of ferritin and transferrin saturation
Authors: Barcellini Wilma , Zaninoni Anna , Gregorini Anna I. , Soverini Giulia , Duca Lorena , Fattizzo Bruno , Giannotta Juri A. , Pedrotti Patrizia , Vercellati Cristina , Marcello Anna P. , Fermo Elisa , Bianchi Paola , Cappellini Maria Domenica 
Published: March 2019

SummaryIron overload (IO) is poorly investigated in the congenital haemolytic anaemias (CHAs), a heterogeneous group of rare inherited diseases encompassing abnormalities of the erythrocyte membrane and metabolism, and defects of the erythropoiesis. In this study we systematically evaluated routine iron parameters and cardiac and hepatic magnetic resonance imaging, together with erythropoietin, hepcidin, non‐transferrin bound iron (NTBI), and cytokine serum levels in patients with different CHAs. We found that 40% of patients had a liver iron concentration (LIC) >4 mg Fe/g dry weight. Hepatic IO was associated with ferritin levels (P = 0·0025), transferrin saturation (TfSat, P = 0·002) and NTBI (P = 0·003). Moreover, ferritin >500 μg/l plus TfSat >60% was demonstrated as the best combination able to identify increased LIC, and TfSat alteration as more important in cases with discordant values. Possible confounding factors, such as transfusions, hepatic disease, metabolic syndrome and hereditary haemochromatosis‐associated mutations, had negligible effects on IO. Erythropoietin and hepcidin levels were increased in CHAs compared with controls, correlating with LIC and ferritin, respectively. Regarding cytokines, γ‐interferon (IFN‐γ) was increased, and both interleukin 6 and IFN‐γ levels positively correlated with ferritin and hepcidin levels. Overall, these findings suggest the existence of a vicious cycle between chronic haemolysis, inflammatory response and IO in CHAs.
Hypomethylating agent alters the immune microenvironment in acute myeloid leukaemia (AML) and enhances the immunogenicity of a dendritic cell/AML vaccine
Authors: Nahas Myrna R. , Stroopinsky Dina , Rosenblatt Jacalyn , Cole Leandra , Pyzer Athalia R. , Anastasiadou Eleni , Sergeeva Anna , Ephraim Adam , Washington Abigail , Orr Shira , McMasters Malgorzata , Weinstock Matthew , Jain Salvia , Leaf Rebecca K. , Ghiasuddin Haider , Rahimian Maryam , Liegel Jessica , Molldrem Jeffrey J. , Slack Frank , Kufe Donald , Avigan David 
Published: March 2019

SummaryAcute myeloid leukaemia (AML) is a lethal haematological malignancy characterized by an immunosuppressive milieu in the tumour microenvironment (TME) that fosters disease growth and therapeutic resistance. Hypomethylating agents (HMAs) demonstrate clinical efficacy in AML patients and exert immunomodulatory activities. In the present study, we show that guadecitabine augments both antigen processing and presentation, resulting in increased AML susceptibility to T cell‐mediated killing. Exposure to HMA results in the activation of the endogenous retroviral pathway with concomitant downstream amplification of critical mediators of inflammation. In an immunocompetent murine leukaemia model, guadecitabine negatively regulates inhibitory accessory cells in the TME by decreasing PD‐1 (also termed PDCD1) expressing T cells and reducing AML‐mediated expansion of myeloid‐derived suppressor cells. Therapy with guadecitabine results in enhanced leukaemia‐specific immunity, as manifested by increased CD4 and CD8 cells targeting syngeneic leukaemia cells. We have previously reported that vaccination with AML/dendritic cell fusions elicits the expansion of leukaemia‐specific T cells and protects against disease relapse. In the present study, we demonstrate that vaccination in conjunction with HMA therapy results in enhanced anti‐leukaemia immunity and survival. The combination of a novel personalized dendritic cell/AML fusion vaccine and an HMA has therapeutic potential, and a clinical trial investigating this combination is planned.
Online Assessment of Preschool Anxiety: description and initial validation of a new diagnostic tool
Authors: Morgan Amy J. , Tamir Elli , Rapee Ronald M. , Lyneham Heidi J. , McLellan Lauren F. , Bayer Jordana K. 
Published: March 2019

BackgroundThe Online Assessment of Preschool Anxiety (OAPA) is a newly developed measure that assesses anxiety disorders in preschool children aged 3–6 years. This study aimed to explore the OAPA's initial psychometric properties with a particular focus on examining its construct validity, both convergent and discriminant.MethodThe OAPA was completed online by a community sample of 319 Australian parents of temperamentally inhibited preschool children (M: 5.3 years). Preliminary diagnoses were automatically generated before assessment reports were reviewed by a psychologist. Construct validity was examined by assessing the degree of agreement between the OAPA and existing valid questionnaire measures that were simultaneously administered online.ResultsNearly half of participants met criteria for a child anxiety disorder according to the OAPA, most commonly social phobia. Findings supported convergent validity with the Revised Preschool Anxiety Scale (an anxiety symptom measure), the Children's Anxiety Life Interference Scale – Preschool Version (a measure of life interference from anxiety), the Emotional Symptoms scale of the Strengths and Difficulties Questionnaire‐Parent Version (a measure of broader internalizing symptoms), as well as an over‐involved/protective parenting scale. Findings also supported initial discriminant validity with the Conduct Problems scale of the Strengths and Difficulties Questionnaire‐Parent Version.ConclusionsResults of this study provide evidence for the OAPA's preliminary construct validity. With further research into the OAPA's reliability (test–retest and interrater) and confirming construct validity, the OAPA may be a useful instrument for use in research settings and clinical practice.
Early intervention programmes for infants at high risk of atypical neurodevelopmental outcome
Authors: Hutchon Betty , Gibbs Deanna , Harniess Phillip , Jary Sally , Crossley Siew‐Lian , Moffat Jane V , Basu Neela , Basu Anna P 
Published: March 2019

The purpose of this review is to present a new framework, EI SMART (early intervention: sensorimotor development, attention and regulation, relationships, and therapist support) for identifying key components that could contribute to more effective interventions for infants at high risk of atypical neurodevelopmental outcome. We present a clinical consensus of current challenges and themes in early intervention, based on multidisciplinary group discussions, including parents of high‐risk infants, supported by a literature review. Components to include in early intervention programmes are: (1) promotion of self‐initiated, developmentally appropriate motor activity; (2) supporting infant self‐regulation and the development of positive parent‐infant relationships; and (3) promotion of early communication skills, parent coaching, responsive parenting, and supporting parental mental well‐being. Such multimodal programmes may need to be evaluated as a package.What this paper adds

Early intervention programmes should address sensorimotor development, attention, self‐regulation, and early communication skills.

Therapist input to the programme should include parent coaching and support for parental mental well‐being.