bluuebunny/crossref_metadata_2025_split huggingface dataset:
Follow-up interviews from The Salford Lung Study (COPD) and analyses per treatment and exacerbations
Authors: Whalley Diane , Svedsater Henrik , Doward Lynda , Crawford Rebecca , Leather David , Lay-Flurrie James , Bosanquet Nick 
Published: May 2019

AbstractThe Salford Lung Study in chronic obstructive pulmonary disease (SLS COPD) was a 12-month, Phase III, open-label, randomised study comparing the effectiveness and safety of initiating once-daily fluticasone furoate 100 µg/vilanterol 25 µg (FF/VI) with continuing usual care (UC). Follow-up interviews were conducted among a subset of 400 patients who completed SLS COPD to further understand patients’ experiences with treatment outcomes and the impact of COPD, and potential risk factors associated with higher rates of exacerbations during SLS COPD. Another objective was to explore how such patient-centred outcomes differed by randomised treatment. Patients’ perceived control over COPD and effects on quality of life (QoL) were similar between treatment groups at the time of the follow-up interview, but more patients in the FF/VI group compared with UC reported perceived improvements in COPD control and QoL during the study. Of patients who experienced ≥2 exacerbations during SLS COPD, a greater percentage were women, were unemployed or homemakers, or were on long-term sick leave. Having ≥2 exacerbations also appeared to be associated with smoking, seeing a hospital specialist, a feeling of having no/little control over COPD, perceived worsening of feelings of control and reduced overall QoL since the start of the study, being aware of impending exacerbation occurrence and a more severe last exacerbation. Initiation of FF/VI was associated with a greater perceived improvement in patients’ control of their COPD and QoL throughout SLS COPD than continuation of UC. Suggestions that smoking status and feelings of control are potentially related to exacerbation require further investigation.
Systematic review of clinical prediction models to support the diagnosis of asthma in primary care
Authors: Daines Luke , McLean Susannah , Buelo Audrey , Lewis Steff , Sheikh Aziz , Pinnock Hilary 
Published: May 2019

AbstractDiagnosing asthma is challenging. Misdiagnosis can lead to untreated symptoms, incorrect treatment and avoidable deaths. The best combination of clinical features and tests to achieve a diagnosis of asthma is unclear. As asthma is usually diagnosed in non-specialist settings, a clinical prediction model to aid the assessment of the probability of asthma in primary care may improve diagnostic accuracy. We aimed to identify and describe existing prediction models to support the diagnosis of asthma in children and adults in primary care. We searched Medline, Embase, CINAHL, TRIP and US National Guidelines Clearinghouse databases from 1 January 1990 to 23 November 17. We included prediction models designed for use in primary care or equivalent settings to aid the diagnostic decision-making of clinicians assessing patients with symptoms suggesting asthma. Two reviewers independently screened titles, abstracts and full texts for eligibility, extracted data and assessed risk of bias. From 13,798 records, 53 full-text articles were reviewed. We included seven modelling studies; all were at high risk of bias. Model performance varied, and the area under the receiving operating characteristic curve ranged from 0.61 to 0.82. Patient-reported wheeze, symptom variability and history of allergy or allergic rhinitis were associated with asthma. In conclusion, clinical prediction models may support the diagnosis of asthma in primary care, but existing models are at high risk of bias and thus unreliable for informing practice. Future studies should adhere to recognised standards, conduct model validation and include a broader range of clinical data to derive a prediction model of value for clinicians.
Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia
Authors: Haffner Dieter , Emma Francesco , Eastwood Deborah M. , Biosse Duplan Martin , Bacchetta Justine , Schnabel Dirk , Wicart Philippe , Bockenhauer Detlef , Santos Fernando , Levtchenko Elena , Harvengt Pol , Kirchhoff Martha , Di Rocco Federico , Chaussain Catherine , Brandi Maria Louisa , Savendahl Lars , Briot Karine , Kamenicky Peter , Rejnmark Lars , Linglart Agnès 
Published: May 2019

Abstract
X-linked hypophosphataemia (XLH) is the most common cause of inherited phosphate wasting and is associated with severe complications such as rickets, lower limb deformities, pain, poor mineralization of the teeth and disproportionate short stature in children as well as hyperparathyroidism, osteomalacia, enthesopathies, osteoarthritis and pseudofractures in adults. The characteristics and severity of XLH vary between patients. Because of its rarity, the diagnosis and specific treatment of XLH are frequently delayed, which has a detrimental effect on patient outcomes. In this Evidence-Based Guideline, we recommend that the diagnosis of XLH is based on signs of rickets and/or osteomalacia in association with hypophosphataemia and renal phosphate wasting in the absence of vitamin D or calcium deficiency. Whenever possible, the diagnosis should be confirmed by molecular genetic analysis or measurement of levels of fibroblast growth factor 23 (FGF23) before treatment. Owing to the multisystemic nature of the disease, patients should be seen regularly by multidisciplinary teams organized by a metabolic bone disease expert. In this article, we summarize the current evidence and provide recommendations on features of the disease, including new treatment modalities, to improve knowledge and provide guidance for diagnosis and multidisciplinary care.
Observational study of long-term persistent elevation of neurodegeneration markers after cardiac surgery
Authors: DiMeglio Matthew , Furey William , Hajj Jihane , Lindekens Jordan , Patel Saumil , Acker Michael , Bavaria Joseph , Szeto Wilson Y. , Atluri Pavan , Haber Margalit , Diaz-Arrastia Ramon , Laudanski Krzysztof 
Published: May 2019

AbstractSurgery and anesthesia induce inflammatory changes in the central nervous system, which ultimately lead to neuronal damage concomitant with an increase in the level of neurodegeneration markers. Despite some experimental data showing prolonged activation of the immune system post-surgery, no study has determined the extent of long-term elevation of neurodegeneration markers. The purpose of this study was to investigate the serum levels of tau protein, ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), neurofilament light (NF-L), and glial fibrillary acidic protein (GFAP) after elective cardiac surgery with the implementation of cardiopulmonary bypass (CPB). The serum levels of these markers from 30 patients were compared longitudinally to the baseline (pre-surgery or t0), at 24 hours (t+24), at 7 days (t+7d), and at 3 months (t+3m). The secondary outcome was the production of macrophage-colony stimulating factor (M-CSF) and tumor necrosis factor-α (TNF-α) in vitro by isolated monocytes in response to lipopolysaccharide (LPS) as the measure of immune system activation. The tertiary outcome was the serum level of C-reactive protein (CRP), serum amyloid P (SAP), and α-2-macroglobulin (A2M). Serum levels of tau protein increased 24 hours after surgery (p = 0.0015) and remained elevated at 7 days (p = 0.0017) and three months (p = 0.036). Serum levels of UCH-L1 peaked at 24 hours (p = 0.00055) and normalized at 3 months. In vitro secretion of M-CSF by LPS-stimulated peripheral monocytes, but not TNFα, correlated highly (r = 0.58; p = 0.04) with persistent elevation of serum tau levels at 3 months. The serum CRP and SAP increases correlated with tau post-CPB levels significantly at 3 months. We demonstrated that elevation of serum tau levels at 24 hours, 7 days, and 3 months after heart surgery is concomitant with some traits of inflammation after CPB. The elevation of tau several weeks into recovery is significantly longer than expected.
Context dependency, co-introductions, novel mutualisms, and host shifts shaped the ectomycorrhizal fungal communities of the alien tree Eucalyptus globulus
Authors: Santolamazza-Carbone Serena , Durán-Otero Mónica , Calviño-Cancela María 
Published: May 2019

AbstractThe identity and relevance of the ectomycorrhizal (ECM) fungal partners of Eucalyptus globulus was investigated in NW Spain, to detect which symbionts mainly support its invasiveness. Root tips of E. globulus and of three common native plant species (Quercus robur, Pinus pinaster and Halimium lasianthum) were collected in eucalypt plantations, Q. robur forests, P. pinaster plantations and shrublands. Fungal taxonomical identity was ascertained by use of rDNA and direct sequencing. We studied diversity, composition and colonization rate of the ECM fungal communities of E. globulus to determine if fungal assemblages are host specific (i.e. similar in different habitats) or more dependent on the neighbourhood context. We also identified the type of associations formed (i.e. co-introductions, familiar or novel associations). Twenty-six ECM taxa were associated with E. globulus. Most of them engaged in novel associations with eucalypts, whereas only three fungal species were co-introduced Australian aliens. Eucalypt fungal richness, diversity and colonization rate differed between habitats, being higher in native oak forests, whereas in shrublands E. globulus showed the lowest colonization rate and diversity. The Australian fungus Descolea maculata dominated the eucalypt fungal assemblage and also spread to the native host plants, in all the habitats, posing the risk of further co-invasion.
Short-term 3D culture systems of various complexity for treatment optimization of colorectal carcinoma
Authors: Zoetemelk Marloes , Rausch Magdalena , Colin Didier J. , Dormond Olivier , Nowak-Sliwinska Patrycja 
Published: May 2019

AbstractThree-dimensional (3D) cultures have the potential to increase the predictive value of pre-clinical drug research and bridge the gap towards anticipating clinical outcome of proposed treatments. However, their implementation in more advanced drug-discovery programs is still in its infancy due to the lack of reproducibility and low time- and cost effectiveness. HCT116, SW620 and DLD1 cells, cell lines with distinct mutations, grade and origin, were co-cultured with fibroblasts and endothelial cells (EC) in 3D spheroids. Clinically relevant drugs, i.e. 5-fluorouracil (5−FU), regorafenib and erlotinib, were administered individually to in CRC cell cultures. In this study, we established a robust, low-cost and reproducible short-term 3D culture system addressing the various complexities of the colorectal carcinoma (CRC) microenvironment. We observed a dose-dependent increase of erlotinib sensitivity in 3D (co-)cultures compared to 2D cultures. Furthermore, we compared the drug combination efficacy and drug-drug interactions administered in 2D, 3D and 3D co-cultures. We observed that synergistic/additive drug-drug interactions for drug combinations administered at low doses shifted towards additive and antagonistic when applied at higher doses in metastatic CRC cells. The addition of fibroblasts at various ratios and EC increased the resistance to some drug combinations in SW620 and DLD1 cells, but not in HCT116. Retreatment of SW620 3D co-cultures with a low-dose 3-drug combination was as active (88% inhibition, relative to control) as 5-FU treatment at high dose (100 μM). Moreover, 3D and 3D co-cultures responded variably to the drug combination treatments, and also signalling pathways were differently regulated, probably due to the influence of fibroblasts and ECs on cancer cells. The short-term 3D co-culture system developed here is a powerful platform for screening (combination) therapies. Understanding of signalling in 3D co-cultures versus 3D cultures and the responses in the 3D models upon drug treatment might be beneficial for designing anti-cancer therapies.
Calcium binding to a disordered domain of a type III-secreted protein from a coral pathogen promotes secondary structure formation and catalytic activity
Authors: Hoyer Elisabeth , Knöppel Julius , Liebmann Martina , Steppert Michael , Raiwa Manuel , Herczynski Olivia , Hanspach Erik , Zehner Susanne , Göttfert Michael , Tsushima Satoru , Fahmy Karim , Oertel Jana 
Published: May 2019

AbstractStrains of the Gram-negative bacterium Vibrio coralliilyticus cause the bleaching of corals due to decomposition of symbiotic microalgae. The V. coralliilyticus strain ATCC BAA-450 (Vc450) encodes a type III secretion system (T3SS). The gene cluster also encodes a protein (locus tag VIC_001052) with sequence homology to the T3SS-secreted nodulation proteins NopE1 and NopE2 of Bradyrhizobium japonicum (USDA110). VIC_001052 has been shown to undergo auto-cleavage in the presence of Ca2+ similar to the NopE proteins. We have studied the hitherto unknown secondary structure, Ca2+-binding affinity and stoichiometry of the “metal ion-inducible autocleavage” (MIIA) domain of VIC_001052 which does not possess a classical Ca2+-binding motif. CD and fluorescence spectroscopy revealed that the MIIA domain is largely intrinsically disordered. Binding of Ca2+ and other di- and trivalent cations induced secondary structure and hydrophobic packing after partial neutralization of the highly negatively charged MIIA domain. Mass spectrometry and isothermal titration calorimetry showed two Ca2+-binding sites which promote structure formation with a total binding enthalpy of −110 kJ mol−1 at a low micromolar Kd. Putative binding motifs were identified by sequence similarity to EF-hand domains and their structure analyzed by molecular dynamics simulations. The stoichiometric Ca2+-dependent induction of structure correlated with catalytic activity and may provide a “host-sensing” mechanism that is shared among pathogens that use a T3SS for efficient secretion of disordered proteins.
Prediction and characterisation of lantibiotic structures with molecular modelling and molecular dynamics simulations
Authors: Chakraborty Hirak Jyoti , Gangopadhyay Aditi , Datta Abhijit 
Published: May 2019

AbstractLantibiotics are lanthionine-containing bactericidal peptides produced by gram-positive bacteria as a defence mechanism against other bacterial species. Lantipeptides disrupt the integrity of target cells by forming pores in their cell membranes, or by preventing cell wall biosynthesis, which subsequently results in cell death. Lantibiotics are of immense importance to the food preservation and pharmaceutical industries. The rise in multidrug resistance demands the discovery of novel antimicrobials, and several authors advocate that lantibiotics hold the future of antimicrobial drug discovery. Owing to their amenability to structural modifications, novel lantibiotics with higher efficacy and antimicrobial activity can be constructed by bioengineering and nanoengineering strategies, and is opined to have immense therapeutic success in combating the rise in multidrug resistance. Understanding the structure and dynamics of lantibiotics is therefore crucial for the development of novel lantipeptides, and this study aimed to study the structural properties and dynamics of 37 lantibiotics using computational strategies. The structures of these 37 lantibiotics were constructed from homology, and their structural stability and compactness were analysed by molecular dynamics simulations. The phylogenetic relationships, physicochemical properties, disordered regions, pockets, intramolecular bonds and interactions, and structural diversity of the 37 lantipeptides were studied. The structures of the 37 lantipeptides constructed herein remained stable throughout simulation. The study revealed that the structural diversity of lantibiotics is not significantly correlated to sequence diversity, and this property could be exploited for designing novel lantipeptides with higher efficacy.
Widespread Deposition in a Coastal Bay Following Three Major 2017 Hurricanes (Irma, Jose, and Maria)
Authors: Browning Trevor N. , Sawyer Derek E. , Brooks Gregg R. , Larson Rebekka A. , Ramos-Scharrón Carlos E. , Canals-Silander Miguel 
Published: May 2019

AbstractIn 2017, three major hurricanes (Irma, Jose, and Maria) impacted the Northeastern Caribbean within a 2-week span. Hurricane waves can cause physical damage to coastal ecosystems, re-suspend and transport antecedent seafloor sediment, while the associated intense rainfall can yield large influxes of land-derived sediment to the coast (e.g. burial of ecosystems). To understand sedimentation provenance (terrestrial or marine) and changes induced by the hurricanes, we collected bathymetry surveys and sediment samples of Coral Bay, St. John, US Virgin Islands in August 2017, (pre-storms) and repeated it in November 2017 (post-storms). Comparison reveals morphologic seafloor changes and widespread aggradation with an average of ~25 cm of sediment deposited over a 1.28 km2 benthic zone. Despite an annual amount of precipitation between surveys, sediment yield modeling suggests watersheds contributed <0.2% of the total depositional volume. Considering locally established accumulation rates, this multi-hurricane event equates to ~1–3 centuries of deposition. Critical benthic communities (corals, seagrasses) can be partially or fully buried by deposits of this thickness and previous studies demonstrate that prolonged burial of similar organisms often leads to mortality. This study illuminates how storm events can result in major sediment deposition, which can significantly impact seafloor morphology and composition and benthic ecosystems.
Neuralized family member NEURL1 is a ubiquitin ligase for the cGMP-specific phosphodiesterase 9A
Authors: Taal Kati , Tuvikene Jürgen , Rullinkov Grete , Piirsoo Marko , Sepp Mari , Neuman Toomas , Tamme Richard , Timmusk Tõnis 
Published: May 2019

AbstractNeuralized functions as a positive regulator of the Notch pathway by promoting ubiquitination of Notch ligands via its E3 ligase activity, resulting in their efficient endocytosis and signaling. Using a yeast two-hybrid screen, we have identified a cGMP-hydrolysing phosphodiesterase, PDE9A, as a novel interactor and substrate of Neuralized E3 ubiquitin protein ligase 1 (NEURL1). We confirmed this interaction with co-immunoprecipitation experiments and show that both Neuralized Homology Repeat domains of NEURL1 can interact with PDE9A. We also demonstrate that NEURL1 can promote polyubiquitination of PDE9A that leads to its proteasome-mediated degradation mainly via lysine residue K27 of ubiquitin. Our results suggest that NEURL1 acts as a novel regulator of protein levels of PDE9A.
Widespread population decline in South America correlates with mid-Holocene climate change
Authors: Riris Philip , Arroyo-Kalin Manuel 
Published: May 2019

AbstractQuantifying the impacts of climate change on prehistoric demography is crucial for understanding the adaptive pathways taken by human populations. Archaeologists across South America have pointed to patterns of regional abandonment during the Middle Holocene (8200 to 4200 cal BP) as evidence of sensitivity to shifts in hydroclimate over this period. We develop a unified approach to investigate demography and climate in South America and aim to clarify the extent to which evidence of local anthropic responses can be generalised to large-scale trends. We achieve this by integrating archaeological radiocarbon data and palaeoclimatic time series to show that population decline occurred coeval with the transition to the initial mid-Holocene across South America. Through the analysis of radiocarbon dates with Monte Carlo methods, we find multiple, sustained phases of downturn associated to periods of high climatic variability. A likely driver of the duration and severity of demographic turnover is the frequency of exceptional climatic events, rather than the absolute magnitude of change. Unpredictable levels of tropical precipitation had sustained negative impacts on pre-Columbian populations lasting until at least 6000 cal BP, after which recovery is evident. Our results support the inference that a demographic regime shift in the second half of the Middle Holocene were coeval with cultural practices surrounding Neotropical plant management and early cultivation, possibly acting as buffers when the wild resource base was in flux.
Towards Patient-Specific Computational Modelling of Articular Cartilage on the Basis of Advanced Multiparametric MRI Techniques
Authors: Linka Kevin , Schäfer Amelie , Hillgärtner Markus , Itskov Mikhail , Knobe Matthias , Kuhl Christiane , Hitpass Lea , Truhn Daniel , Thuering Johannes , Nebelung Sven 
Published: May 2019

AbstractCartilage degeneration is associated with tissue softening and represents the hallmark change of osteoarthritis. Advanced quantitative Magnetic Resonance Imaging (qMRI) techniques allow the assessment of subtle tissue changes not only of structure and morphology but also of composition. Yet, the relation between qMRI parameters on the one hand and microstructure, composition and the resulting functional tissue properties on the other hand remain to be defined. To this end, a Finite-Element framework was developed based on an anisotropic constitutive model of cartilage informed by sample-specific multiparametric qMRI maps, obtained for eight osteochondral samples on a clinical 3.0 T MRI scanner. For reference, the same samples were subjected to confined compression tests to evaluate stiffness and compressibility. Moreover, the Mankin score as an indicator of histological tissue degeneration was determined. The constitutive model was optimized against the resulting stress responses and informed solely by the sample-specific qMRI parameter maps. Thereby, the biomechanical properties of individual samples could be captured with good-to-excellent accuracy (mean R2 [square of Pearson’s correlation coefficient]: 0.966, range [min, max]: 0.904, 0.993; mean Ω [relative approximated error]: 33%, range [min, max]: 20%, 47%). Thus, advanced qMRI techniques may be complemented by the developed computational model of cartilage to comprehensively evaluate the functional dimension of non-invasively obtained imaging biomarkers. Thereby, cartilage degeneration can be perspectively evaluated in the context of imaging and biomechanics.
VANGL2 regulates luminal epithelial organization and cell turnover in the mammary gland
Authors: Smith Prestina , Godde Nathan , Rubio Stefany , Tekeste Melawit , Vladar Eszter K. , Axelrod Jeffrey D. , Henderson Deborah J. , Milgrom-Hoffman Michal , Humbert Patrick O. , Hinck Lindsay 
Published: May 2019

AbstractThe VANGL family of planar cell polarity proteins is implicated in breast cancer however its function in mammary gland biology is unknown. Here, we utilized a panel of Vang1 and Vangl2 mouse alleles to examine the requirement of VANGL family members in the murine mammary gland. We show that Vang1CKOΔ/Δ glands display normal branching while Vangl2flox/flox and Vangl2Lp/Lp tissue exhibit several phenotypes. In MMTV-Cre;Vangl2flox/flox glands, cell turnover is reduced and lumens are narrowed. A Vangl2 missense mutation in the Vangl2Lp/Lp tissue leads to mammary anlage sprouting defects and deficient outgrowth with transplantation of anlage or secondary tissue fragments. In successful Vangl2Lp/Lp outgrowths, three morphological phenotypes are observed: distended ducts, supernumerary end buds, and ectopic acini. Layer specific defects are observed with loss of Vangl2 selectively in either basal or luminal layers of mammary cysts. Loss in the basal compartment inhibits cyst formation, but has the opposite effect in the luminal compartment. Candidate gene analysis on MMTV-Cre;Vangl2flox/flox and Vangl2Lp/Lp tissue reveals a significant reduction in Bmi1 expression, with overexpression of Bmi1 rescuing defects in Vangl2 knockdown cysts. Our results demonstrate that VANGL2 is necessary for normal mammary gland development and indicate differential functional requirements in basal versus luminal mammary compartments.