bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural studies of plasmin inhibition
Authors: Wu Guojie , Quek Adam J. , Caradoc-Davies Tom T. , Ekkel Sue M. , Mazzitelli Blake , Whisstock James C. , Law Ruby H.P. 
Published: March 2019

AbstractPlasminogen (Plg) is the zymogen form of the serine protease plasmin (Plm), and it plays a crucial role in fibrinolysis as well as wound healing, immunity, tissue remodeling and inflammation. Binding to the targets via the lysine-binding sites allows for Plg activation by plasminogen activators (PAs) present on the same target. Cellular uptake of fibrin degradation products leads to apoptosis, which represents one of the pathways for cross-talk between fibrinolysis and tissue remodeling. Therapeutic manipulation of Plm activity plays a vital role in the treatments of a range of diseases, whereas Plm inhibitors are used in trauma and surgeries as antifibrinolytic agents. Plm inhibitors are also used in conditions such as angioedema, menorrhagia and melasma. Here, we review the rationale for the further development of new Plm inhibitors, with a particular focus on the structural studies of the active site inhibitors of Plm. We compare the binding mode of different classes of inhibitors and comment on how it relates to their efficacy, as well as possible future developments.
Magnetic braking of supermassive stars through winds
Authors: Haemmerlé L. , Meynet G. 
Published: March 2019

Context. Supermassive stars (SMSs) are candidates for being progenitors of supermassive quasars at high redshifts. However, their formation process requires strong mechanisms that would be able to extract the angular momentum of the gas that the SMSs accrete.
Aims. We investigate under which conditions the magnetic coupling between an accreting SMS and its winds can remove enough angular momentum for accretion to proceed from a Keplerian disc.
Methods. We numerically computed the rotational properties of accreting SMSs that rotate at the ΩΓ-limit and estimated the magnetic field that is required to maintain the rotation velocity at this limit using prescriptions from magnetohydrodynamical simulations of stellar winds.
Results. We find that a magnetic field of 10 kG at the stellar surface is required to satisfy the constraints on stellar rotation from the ΩΓ-limit.
Conclusions. Magnetic coupling between the envelope of SMSs and their winds could allow for SMS formation by accretion from a Keplerian disc, provided the magnetic field is at the upper end of present-day observed stellar fields. Such fields are consistent with primordial origins.
Oscillations in the Sun with SONG: Setting the scale for asteroseismic investigations
Authors: Fredslund Andersen M. , Pallé P. , Jessen-Hansen J. , Wang K. , Grundahl F. , Bedding T. R. , Roca Cortes T. , Yu J. , Mathur S. , Gacia R. A. , Arentoft T. , Régulo C. , Tronsgaard R. , Kjeldsen H. , Christensen-Dalsgaard J. 
Published: March 2019

Context. We present the first high-cadence multiwavelength radial-velocity observations of the Sun-as-a-star, carried out during 57 consecutive days using the stellar échelle spectrograph at the Hertzsprung SONG Telescope operating at the Teide Observatory.
Aims. Our aim was to produce a high-quality data set and reference values for the global helioseismic parameters νmax, ⊙ and Δν⊙ of the solar p-modes using the SONG instrument. The obtained data set or the inferred values should then be used when the scaling relations are applied to other stars showing solar-like oscillations observed with SONG or similar instruments.
Methods. We used different approaches to analyse the power spectrum of the time series to determine νmax, ⊙: simple Gaussian fitting and heavy smoothing of the power spectrum. We determined Δν⊙ using the method of autocorrelation of the power spectrum. The amplitude per radial mode was determined using the method described in Kjeldsen et al. (2008, ApJ, 682, 1370).
Results. We found the following values for the solar oscillations using the SONG spectrograph: νmax, ⊙ = 3141 ± 12 μHz, Δν⊙ = 134.98 ± 0.04 μHz, and an average amplitude of the strongest radial modes of 16.6 ± 0.4 cm s−1. These values are consistent with previous measurements with other techniques.
Therapie der Hypercholesterinämie in der Primärprävention
Authors: Sanin Veronika , Koenig Wolfgang 
Published: March 2019

AbstractAtherosclerotic cardiovascular disease is the leading cause of premature mortality and morbidity worldwide. Dyslipidemia is a commonly encountered clinical condition and is an important determinant of cardiovascular disease. The causality of plasma low-density lipoprotein-cholesterol (LDL-C) in the pathophysiology of cardiovascular disease has been established beyond any reasonable doubt. In this context, individual risk estimation, the determination of target values and lipid-lowering strategies represent an essential part and a challenge in the daily clinical practice to prevent cardiovascular events. Statins are recommended as first-line therapy for patients with hypercholesterolemia in secondary prevention. Controversies remain in the context of primary prevention, however, as to which kind of subjects to treat, the magnitude of the benefit, and potential harm. This article gives a brief overview of the current evidence, guideline recommendations and strategies for lowering of LDL-C in the primary prevention of cardiovascular disease.
Vascular Adaptation to Indoor Cycling Exercise in Premenopausal Women
Authors: Bjarnegård Niclas , Hedman Kristofer , Länne Toste 
Published: March 2019

AbstractThe early vascular adaptation to indoor cycling, a popular activity at many fitness centres, is incompletely evaluated. Forty two healthy women (21–45 years) underwent measurements of arterial wall properties and geometry as well as a maximal bicycle exercise test before and after a 3 months period during which 21 of the women joined indoor cycling classes at a gym 2–3 times per week, while 21 women served as time controls. Peak work load increased by in average 16% (p<0.001) and ascending aortic diameter by 4% (p<0.01) in the exercise group, while unchanged in control group. The exercise intervention had no significant influence on the local intima-media thickness, blood pressure or the pulse pressure wave configuration while the carotid artery distensibility (p<0.05) was higher after the intervention. There was a positive correlation between change in (Δ) peak work load and Δ-diameter of tubular ascending aorta (r=0.42, p<0.01) in the exercise group. In conclusion, after only 3 months of bicycle exercise training, signs of central arterial remodelling were seen in premenopausal women, which was associated to improvement in exercise capacity.
Fingeramputation nach Bagatellverletzung –
versicherungsrechtliche Aspekte in Deutschland und praktische
Herangehensweise
Authors: Wahl Uwe , Siemers Frank , Hofmann Gunther O. , Ernst Friedrich , Schröter Patrick 
Published: March 2019

ZusammenfassungDie Begutachtung ist ein Bestandteil der ärztlichen Tätigkeit. Da die
Subspezialisierung in der Medizin stetig fortschreitet, sind die
Gutachterkollektive für spezielle gutachterliche Fragestellungen häufig klein.
Der ärztliche Gutachter hat Tatsachen im Vollbeweis und Zusammenhänge mit
hinreichender Wahrscheinlichkeit zu bewerten. In der Begutachtung für die
gesetzliche Unfallversicherung spielt in der Erörterung der Haftungsbegründung
die Frage nach Vorerkrankungen/Schadensanlage eine wesentliche Rolle.
Gelegenheitsursachen bzw. Bagatellverletzungen müssen erkannt werden, weil sich
daraus eine Versicherungsrelevanz ergibt.Ein Versicherter mit einer akralen, nicht arteriosklerotischen
Durchblutungsstörung (Thrombangiitis obliterans) erlitt einen Arbeitsunfall mit
einem Haut-Weichteildefekt, in dessen Folge eine Fingeramputation erforderlich
wurde. Das Vorliegen einer Gelegenheitsursache konnte nach gefäßmedizinischer
Begutachtung widerlegt werden. Der handchirurgische Gutachter empfahl eine
Minderung der Erwerbsfähigkeit von 25 von 100. Der Unfallversicherungsträger
folgte der Entscheidung der ärztlichen Gutachter.
Physical immobilization of particles inspired by pollination
Authors: Santos Lúcia F. , Silva A. Sofia , Correia Clara R. , Mano João F. 
Published: March 2019

Significance
Honey bees present a peculiar hairy structure that covers the surface of their body, which is able to transport large quantities of pollen particles for pollination purposes. Inspired by this natural phenomenon and to overcome the current problems associated with drug patches with passive delivery, we propose the concept of a micropatterned surface featuring micropillars with defined spacing and height to mimic the hair of bees for the entrapment of a large quantity of microparticles. We believe that such substrates could be extended to diverse applications that require reversible immobilization of solid particulate objects. In particular, high drug content is required for obtaining more effective drug patches, enabling more sustained and targeted release of the drug.
Transcranial alternating current stimulation entrains single-neuron activity in the primate brain
Authors: Krause Matthew R. , Vieira Pedro G. , Csorba Bennett A. , Pilly Praveen K. , Pack Christopher C. 
Published: March 2019

SignificanceNeurostimulation is a common therapy for a variety of neurological disorders, but the most effective stimulation approaches are often highly invasive, requiring electrodes to be implanted deep within brain structures like the hippocampus and basal ganglia. Here, we show that transcranial electrical stimulation (tES), a neuromodulatory technique that uses electrodes placed outside the scalp, can also affect patterns of neural activity in these areas. We find that tES can reliably control the timing, but not the rate, of spikes in individual neurons. Because changes in spike timing are thought to play a key role in many brain functions, the data shown here suggest that tES may be a valuable tool for clinical and fundamental studies of the human brain.
RIP1 kinase inhibitor halts the progression of an immune-induced demyelination disease at the stage of monocyte elevation
Authors: Zhang Sitao , Su Yaning , Ying Zhengxin , Guo Dejia , Pan Chenjie , Guo Jia , Zou Ziye , Wang Lei , Zhang Ze , Jiang Zhaodi , Zhang Zhiyuan , Wang Xiaodong 
Published: March 2019

Significance
Myelin sheaths insulate the neuronal axons and speed the transmission of electrical impulses. The demyelination process occurs in many human diseases, including multiple sclerosis (MS). Using multiple mouse models of MS, we demonstrate in this study the role of MLKL, a protein known to function in a form of regulated necrosis (necroptosis), in facilitating demyelination in a necroptosis-independent manner in the central nervous system. An RIP1 kinase inhibitor was shown to block the progression of MS in an immune-induced demyelination model, and it does so at the stage after antibody generation but before breakdown of the blood–brain barrier, at a likely step of monocyte elevation. These findings provide insights into the demyelination process and potential new therapeutic agents for MS.
Patterns of genome-wide allele-specific expression in hybrid rice and the implications on the genetic basis of heterosis
Authors: Shao Lin , Xing Feng , Xu Conghao , Zhang Qinghua , Che Jian , Wang Xianmeng , Song Jiaming , Li Xianghua , Xiao Jinghua , Chen Ling-Ling , Ouyang Yidan , Zhang Qifa 
Published: March 2019

Significance
Utilization of heterosis has greatly increased productivity of many crops globally. Allele-specific expression (ASE) has been suggested as a mechanism for causing heterosis. We performed a genome-wide analysis of ASE in three tissues of an elite rice hybrid grown under four conditions. The analysis identified 3,270 genes showing various patterns of ASE in response to developmental and environmental cues, which provides a glimpse of the ASE landscape in the hybrid genome. We showed that the ASE patterns may have distinct implications in the genetic basis of heterosis, especially in light of the classical dominance and overdominance hypotheses. The genes showing ASE provide the candidates for future studies of the genetic and molecular mechanism of heterosis.
AAV
cis
-regulatory sequences are correlated with ocular toxicity
Authors: Xiong Wenjun , Wu David M. , Xue Yunlu , Wang Sean K. , Chung Michelle J. , Ji Xuke , Rana Parimal , Zhao Sophia R. , Mai Shuyi , Cepko Constance L. 
Published: March 2019

Significance
Adeno-associated viral (AAV) gene therapy is becoming an important therapeutic modality, especially for ocular diseases, due to its efficiency of gene delivery and relative lack of pathogenicity. However, AAV sometimes can cause inflammation and toxicity. We explored such effects using injections into the mouse eye. We found a strong correlation of toxicity and inflammation with the use of promoters that were broadly active, or specifically active in the retinal pigment epithelium. AAVs with photoreceptor-specific promoters were found to be nontoxic at all doses tested. These studies reveal that safer vectors can be designed if assays for relevant and specific cell types are developed and tested with a range of vectors with different genomic elements.
Tetraspanin‐decorated extracellular vesicle‐mimetics as a novel adaptable reference material
Authors: Lozano‐Andrés Estefanía , Libregts Sten F. , Toribio Victor , Royo Félix , Morales Sara , López‐Martín Soraya , Valés‐Gómez Mar , Reyburn Hugh T. , Falcón‐Pérez Juan Manuel , Wauben Marca H. , Soto Manuel , Yáñez‐Mó María 
Published: March 2019

ABSTRACTFeatures like small size, low refractive index and polydispersity pose challenges to the currently available detection methods for Extracellular Vesicles (EVs). In addition, the lack of appropriate standards to set up the experimental conditions makes it difficult to compare analyses obtained by different technical approaches. By modifying synthetic nanovesicles with recombinant antigenic regions of EV‐enriched tetraspanins, we aimed to construct an EV‐mimetic that can be used as a suitable standard for EV analyses.To this end, the sequences of the large extracellular loops of the tetraspanins CD9, CD63 and CD81 were tagged with a target sequence for the biotin ligase BirA, and co‐transformed with a BirA expression plasmid into Escherichia coli. GST fusion proteins were then isolated by affinity chromatography and released using thrombin. Biotinylated recombinant tetraspanin‐loops were then coupled to (strept)avidin‐coated synthetic nanovesicles and analysed and characterised by Dot‐blot, Western‐blot, Nanoparticle Tracking Analysis, Flow Cytometry and Transmission Electron Microscopy.With this method, we were able to efficiently produce tetraspanin‐domain decorated nanovesicles that share biophysical properties with natural EVs, can be detected using specific antibodies against common EV markers such as tetraspanins, and can be used as robust reference materials for detection techniques that are often used in the EV field.
When Conflict Cannot be Avoided: Relative Contributions of Early Selection and Frontal Executive Control in Mitigating Stroop Conflict
Authors: Itthipuripat Sirawaj , Deering Sean , Serences John T 
Published: March 2019

Abstract
When viewing familiar stimuli (e.g., common words), processing is highly automatized such that it can interfere with the processing of incompatible sensory information. At least two mechanisms may help mitigate this interference. Early selection accounts posit that attentional processes filter out distracting sensory information to avoid conflict. Alternatively, late selection accounts hold that all sensory inputs receive full semantic analysis and that frontal executive mechanisms are recruited to resolve conflict. To test how these mechanisms operate to overcome conflict induced by highly automatized processing, we developed a novel version of the color-word Stroop task, where targets and distractors were simultaneously flickered at different frequencies. We measured the quality of early sensory processing by assessing the amplitude of steady-state visually evoked potentials (SSVEPs) elicited by targets and distractors. We also indexed frontal executive processes by assessing changes in frontal theta oscillations induced by color-word incongruency. We found that target- and distractor-related SSVEPs were not modulated by changes in the level of conflict whereas frontal theta activity increased on high compared to low conflict trials. These results suggest that frontal executive processes play a more dominant role in mitigating cognitive interference driven by the automatic tendency to process highly familiar stimuli.
Dynamic Causal Modeling of the Relationship between Cognition and Theta–alpha Oscillations in Adults with Down Syndrome
Authors: Hamburg Sarah , Rosch Richard , Startin Carla Marie , Friston Karl John , Strydom André 
Published: March 2019

Abstract
Individuals with Down syndrome (DS) show high inter-subject variability in cognitive ability and have an ultra-high risk of developing dementia (90% lifetime prevalence). Elucidating factors underlying variability in cognitive function can inform us about intellectual disability (ID) and may improve our understanding of factors associated with later cognitive decline. Increased neuronal inhibition has been posited to contribute to ID in DS. Combining electroencephalography (EEG) with dynamic causal modeling (DCM) provides a non-invasive method for investigating excitatory/inhibitory mechanisms. Resting-state EEG recordings were obtained from 36 adults with DS with no evidence of cognitive decline. Theta–alpha activity (4–13 Hz) was characterized in relation to general cognitive ability (raw Kaufmann’s Brief Intelligence Test second Edition (KBIT-2) score). Higher KBIT-2 was associated with higher frontal alpha peak amplitude and higher theta–alpha band power across distributed regions. Modeling this association with DCM revealed intrinsic self-inhibition was the key network parameter underlying observed differences in 4–13 Hz power in relation to KBIT-2 and age. In particular, intrinsic self-inhibition in right V1 was negatively correlated with KBIT-2. Results suggest intrinsic self-inhibition within the alpha network is associated with individual differences in cognitive ability in adults with DS, and may provide a potential therapeutic target for cognitive enhancement.
Incident anaemia in older adults with heart failure: rate, aetiology, and association with outcomes
Authors: Ambrosy Andrew P , Gurwitz Jerry H , Tabada Grace H , Artz Andrew , Schrier Stanley , Rao Sunil V , Barnhart Huiman X , Reynolds Kristi , Smith David H , Peterson Pamela N , Sung Sue Hee , Cohen Harvey Jay , Go Alan S ,   RBC HEART Investigators
Published: March 2019

Abstract

Aims
Limited data exist on the epidemiology, evaluation, and prognosis of otherwise unexplained anaemia of the elderly in heart failure (HF). Thus, we aimed to determine the incidence of anaemia, to characterize diagnostic testing patterns for potentially reversible causes of anaemia, and to evaluate the independent association between incident anaemia and long-term morbidity and mortality.

Methods and results
Within the Cardiovascular Research Network (CVRN), we identified adults age ≥65 years with diagnosed HF between 2005 and 2012 and no anaemia at entry. Incident anaemia was defined using World Health Organization (WHO) haemoglobin thresholds (<13.0 g/dL in men; <12.0 g/dL in women). All-cause death and hospitalizations for HF and any cause were identified from electronic health records. Among 38 826 older HF patients, 22 163 (57.1%) developed incident anaemia over a median (interquartile range) follow-up of 2.9 (1.2–5.6) years. The crude rate [95% confidence interval (CI)] per 100 person-years of incident anaemia was 26.4 (95% CI 26.0–26.7) and was higher for preserved ejection fraction (EF) [29.2 (95% CI 28.6–29.8)] compared with borderline EF [26.5 (95% CI 25.4–27.7)] or reduced EF [26.6 (95% CI 25.8–27.4)]. Iron indices, vitamin B12 level, and thyroid testing were performed in 20.9%, 14.9%, and 40.2% of patients, respectively. Reduced iron stores, vitamin B12 deficiency, and/or hypothyroidism were present in 29.7%, 3.2%, and 18.6% of tested patients, respectively. In multivariable analyses, incident anaemia was associated with excess mortality [hazard ratio (HR) 2.14, 95% CI 2.07–2.22] as well as hospitalization for HF (HR 1.80, 95% CI 1.72–1.88) and any cause (HR 1.77, 95% CI 1.72–1.83).

Conclusion
Among older adults with HF, incident anaemia is common and independently associated with substantially increased risks of morbidity and mortality. Additional research is necessary to clarify the value of routine evaluation and treatment of potentially reversible causes of anaemia.
Accounting for missing data in statistical analyses: multiple imputation is not always the answer
Authors: Hughes Rachael A , Heron Jon , Sterne Jonathan A C , Tilling Kate 
Published: March 2019

Abstract

Background
Missing data are unavoidable in epidemiological research, potentially leading to bias and loss of precision. Multiple imputation (MI) is widely advocated as an improvement over complete case analysis (CCA). However, contrary to widespread belief, CCA is preferable to MI in some situations.

Methods
We provide guidance on choice of analysis when data are incomplete. Using causal diagrams to depict missingness mechanisms, we describe when CCA will not be biased by missing data and compare MI and CCA, with respect to bias and efficiency, in a range of missing data situations. We illustrate selection of an appropriate method in practice.

Results
For most regression models, CCA gives unbiased results when the chance of being a complete case does not depend on the outcome after taking the covariates into consideration, which includes situations where data are missing not at random. Consequently, there are situations in which CCA analyses are unbiased while MI analyses, assuming missing at random (MAR), are biased. By contrast MI, unlike CCA, is valid for all MAR situations and has the potential to use information contained in the incomplete cases and auxiliary variables to reduce bias and/or improve precision. For this reason, MI was preferred over CCA in our real data example.

Conclusions
Choice of method for dealing with missing data is crucial for validity of conclusions, and should be based on careful consideration of the reasons for the missing data, missing data patterns and the availability of auxiliary information.
Impact of Treatment Interruption on HIV Reservoirs and Lymphocyte Subsets in Individuals Who Initiated Antiretroviral Therapy During the Early Phase of Infection
Authors: Huiting Erin D , Gittens Kathleen , Justement J Shawn , Shi Victoria , Blazkova Jana , Benko Erika , Kovacs Colin , Wender Paul A , Moir Susan , Sneller Michael C , Fauci Anthony S , Chun Tae-Wook 
Published: March 2019

Abstract
Therapeutic strategies for achieving sustained virologic remission are being explored in human immunodeficiency virus (HIV)–infected individuals who began antiretroviral therapy (ART) during the early phase of infection. In the evaluation of such therapies, clinical protocols should include analytical treatment interruption (ATI); however, the immunologic and virologic impact of ATI in individuals who initiated ART early has not been fully delineated. We demonstrate that ATI causes neither expansion of HIV reservoirs nor immunologic abnormalities following reinitiation of ART. Our findings support the use of ATI to determine whether sustained virologic remission has been achieved in clinical trials of individuals who initiated ART early during HIV infection.