bluuebunny/crossref_metadata_2025 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

The 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

Diagnosing 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

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.
Author Correction: Efficacy of alprostadil for preventing of contrast-induced nephropathy: A meta-analysis
Authors: Zhang Jing-Zhan , Kang Xiao-Jing , Gao Ying , Zheng Ying-Ying , Wu Ting-Ting , Li Long , Liu Fen , Yang Yi-Ning , Li Xiao-Mei , Ma Yi-Tong , Xie Xiang
Published: May 2019

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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

Surgery 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

The 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

Three-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

Strains 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

Lantibiotics 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

In 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

Neuralized 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

Quantifying 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

Cartilage 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

The 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.
Polymeric nanoparticles as an alternative for application of gibberellic acid in sustainable agriculture: a field study
Authors: Pereira Anderson do Espírito Santo , Oliveira Halley Caixeta , Fraceto Leonardo Fernandes
Published: May 2019

Nanocarrier systems for the encapsulation of agrochemicals can contribute to sustainable agriculture, but few nanosystems have been developed for plant growth regulators (PGRs). The present study evaluated the effects of seed priming using alginate/chitosan (nanoALG/CS) and chitosan/tripolyphosphate (nanoCS/TPP) containing GA3 on the growth and productivity of Solanum lycopersicum cultivated under field conditions. The results demonstrated that nanocarrier systems could improve fruit production, with the productivity increasing almost 4-fold using nanoALG/CS-GA3. This pioneering study demonstrates the potential of nanocarrier systems with PGRs for applications in agriculture.
Community profiling of the intestinal microbial community of juvenile Hammerhead Sharks (Sphyrna lewini) from the Rewa Delta, Fiji
Authors: Juste-Poinapen Natacha M. S. , Yang Lu , Ferreira Marta , Poinapen Johann , Rico Ciro
Published: May 2019

Fourteen juvenile scalloped hammerhead sharks (Sphyrna lewini; SHS) were captured between November and December 2014 in the Rewa Delta in Fiji, and assessed for intestinal microflora characterisation using 16S rRNA amplicon sequencing by Illumina Miseq. The microbial population revealed a fluctuating dominance between the Enterobacteriaceae and Vibrionaceae families, namely Citrobacter and Photobacterium spp. Other related marine operational taxonomic units were closely related to Afipia felis, Chloroflexus aggregans, Psychrobacter oceani, Pontibacter actiniarum and Shigella sonnei. Two sharks had distinctive profiles that were dominated by known pathogens, namely Aeromonas salmonicida and Klebsiella pneumonia. The presence of a Methanosaeta species, and of Shigella and Psychrobacter, would suggest sewage contamination because of a spill that occurred on the 6th of December 2014. This study successfully establishes a baseline for future research.
Real-world safety and efficacy of paritaprevir/ritonavir/ombitasvir plus dasabuvir ± ribavirin in patients with hepatitis C virus genotype 1 and advanced hepatic fibrosis or compensated cirrhosis: a multicenter pooled analysis
Authors: Chen Chun-Hsien , Chen Chien-Hung , Lin Chih-Lang , Lin Chun-Yen , Hu Tsung-Hui , Tung Shui-Yi , Hsieh Sen-Yung , Lu Sheng-Nan , Chien Rong-Nan , Hung Chao-Hung , Sheen I-Shyan
Published: May 2019

Paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) with or without ribavirin shows favorable results in hepatitis C virus genotype 1 (HCV-1) patients in terms of safety and efficacy, but real-world data remain limited for those with advanced hepatic fibrosis (fibrosis 3, F3) or compensated cirrhosis (F4). A total of 941 patients treated in four hospitals (the Keelung, the Linkuo, the Chiayi and the Kaohsiung Chang Gung Memorial Hospital) through a nationwide government-funded program in Taiwan were enrolled. Patients with HCV and advanced hepatic fibrosis or compensated cirrhosis received 12 weeks of PrOD in HCV-1b and 12 or 24 weeks of PrOD plus ribavirin therapy in HCV-1a without or with cirrhosis. Advanced hepatic fibrosis or compensated cirrhosis was confirmed by either ultrasonography, fibrosis index based on 4 factors (FIB-4) test, or transient elastography/acoustic radiation force impulse (ARFI). The safety and efficacy (sustained virologic response 12 weeks off therapy, SVR12) were evaluated. An SVR12 was achieved in 887 of 898 (98.8%) patients based on the per-protocol analysis (subjects receiving ≥1 dose of any study medication and HCV RNA data available at post-treatment week 12). Child-Pugh A6 (odds ratio: 0.168; 95% confidence interval (CI): 0.043–0.659, p = 0.011) was the only significant factor of poor SVR12. Fifty-four (5.7%) patients were withdrawn early from the treatment because of hepatic decompensation (n = 18, 1.9%) and other adverse reactions. Multivariate analyses identified old age (odds ratio: 1.062; 95% CI: 1.008–1.119, p = 0.024) and Child-Pugh A6 (odds ratio: 4.957; 95% CI: 1.691–14.528, p = 0.004) were significantly associated with hepatic decompensation. In conclusion, this large real-world cohort proved PrOD with or without ribavirin to be highly effective in chronic hepatitis C patients with advanced hepatic fibrosis or compensated cirrhosis. However, Child-Pugh A6 should be an exclusion criterion for first-line treatment in these patients.
Integration of bilateral nociceptive inputs tunes spinal and cerebral responses
Authors: Rustamov Nabi , Northon Stéphane , Tessier Jessica , Leblond Hugues , Piché Mathieu
Published: May 2019

Together with the nociceptive system, pain protects the body from tissue damage. For instance, when the RIII-reflex is evoked by sural nerve stimulation, nociceptive inputs activate flexor muscles and inhibit extensor muscles of the affected lower limb while producing the opposite effects on the contralateral muscles. But how do the spinal cord and brain integrate concurrent sensorimotor information originating from both limbs? This is critical for evoking coordinated responses to nociceptive stimuli, but has been overlooked. Here we show that the spinal cord integrates spinal inhibitory and descending facilitatory inputs during concurrent bilateral foot stimulation, resulting in facilitation of the RIII-reflex and bilateral flexion. In these conditions, high-gamma oscillation power was also increased in the dorsolateral prefrontal, anterior cingulate and sensorimotor cortex, in accordance with the involvement of these regions in cognitive, motor and pain regulation. We propose that the brain and spinal cord can fine-tune nociceptive and pain responses when nociceptive inputs arise from both lower limbs concurrently, in order to allow adaptable behavioural responses.
Differences in the molecular signatures of mucosal-associated invariant T cells and conventional T cells
Authors: Park Daeui , Kim Hong Gi , Kim Miok , Park Tamina , Ha Hyung-Ho , Lee Dae Ho , Park Kang-Seo , Park Seong Jun , Lim Hwan Jung , Lee Chang Hoon
Published: May 2019

Mucosal-associated invariant T (MAIT) cells exhibit different characteristics from those of TCRα7.2− conventional T cells. They play important roles in various inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. MAIT cells express a single T cell receptor alpha chain, TCRα7.2 segment associated with Jα33 and CDR3 with fixed length, which recognizes bacteria-derived vitamin B metabolites. However, the characteristics of MAIT cells and TCRα7.2+ CD161− T cells have never been compared. Here, we performed RNA sequencing to compare the properties of MAIT cells, TCRα7.2− conventional T cells and TCRα7.2+ CD161− T cells. Genome-wide transcriptomes of MAIT cells, TCRα7.2− conventional T cells, and TCRα7.2+ CD161− T cells were compared and analyzed using causal network analysis. This is the first report comparing the transcriptomes of MAIT cells, TCRα7.2− conventional T cells and TCRα7.2+ CD161− T cells. We also identified the predominant signaling pathways of MAIT cells, which differed from those of TCRα7.2− conventional T cells and TCRα7.2+ CD161− T cells, through a gene set enrichment test and upstream regulator analysis and identified the genes responsible for the characteristic MAIT cell phenotypes. Our study advances the complete understanding of MAIT biology.
GABAergic neurons in the olfactory cortex projecting to the lateral hypothalamus in mice
Authors: Murata Koshi , Kinoshita Tomoki , Fukazawa Yugo , Kobayashi Kenta , Kobayashi Kazuto , Miyamichi Kazunari , Okuno Hiroyuki , Bito Haruhiko , Sakurai Yoshio , Yamaguchi Masahiro , Mori Kensaku , Manabe Hiroyuki
Published: May 2019

Olfaction guides goal-directed behaviours including feeding. To investigate how central olfactory neural circuits control feeding behaviour in mice, we performed retrograde tracing from the lateral hypothalamus (LH), an important feeding centre. We observed a cluster of retrogradely labelled cells distributed in the posteroventral region of the olfactory peduncle. Histochemical analyses revealed that the majority of these retrogradely labelled projection neurons expressed glutamic acid decarboxylase 65/67 (GAD65/67), but not vesicular glutamate transporter 1 (VGluT1). We named this region containing GABAergic projection neurons the ventral olfactory nucleus (VON) to differentiate it from the conventional olfactory peduncle. VON neurons were less immunoreactive for DARPP-32, a striatal neuron marker, compared to neurons in the olfactory tubercle and nucleus accumbens, which distinguished the VON from the ventral striatum. Fluorescent labelling confirmed putative synaptic contacts between VON neurons and olfactory bulb projection neurons. Rabies-virus-mediated trans-synaptic labelling revealed that VON neurons received synaptic inputs from the olfactory bulb, other olfactory cortices, horizontal limb of the diagonal band, and prefrontal cortex. Collectively, these results identify novel GABAergic projection neurons in the olfactory cortex that may integrate olfactory sensory and top-down inputs and send inhibitory output to the LH, which may modulate odour-guided LH-related behaviours.
Heterogeneous flow inside threads of low viscosity fluids leads to anomalous long filament lifetimes
Authors: Recktenwald Steffen M. , Haward Simon J. , Shen Amy Q. , Willenbacher Norbert
Published: May 2019

Formation and breakup of fluid threads is pervasive in nature and technology, where high extensibility of fluid filaments and extended filament lifetimes are commonly observed as a consequence of fluid viscoelasticity. In contrast, threads of low viscous Newtonian fluids like water rupture quickly. Here, we demonstrate that a unique banding instability during filament thinning of model surfactant solutions, with a viscosity close to water and no measurable elasticity, leads to extremely long filament lifetimes and to the formation of remarkably long threads. Complementary measurements in planar extension as well as in shear reveal that this flow instability is characterized by a multivalued stress, arising beyond a critical strain rate, irrespective of flow kinematics. Our work reports the first observation of such phenomena during extensional deformation and provides a unifying view on instabilities in complex flow fields.
Reconfigurable nanoscale spin-wave directional coupler using spin-orbit torque
Authors: Ren Zhiwei , Liu Shuang , Jin Lichuan , Wen Tianlong , Liao Yulong , Tang Xiaoli , Zhang Huaiwu , Zhong Zhiyong
Published: May 2019

We present a reconfigurable nanoscale spin-wave directional coupler based on spin-orbit torque (SOT). By micromagnetic simulations, it is demonstrated that the functionality and operating frequency of proposed device can be dynamically switched by inverting the whole or part of the relative magnetic configuration of the dipolar-coupled waveguides using SOT. Utilizing the effect of sudden change in coupling length, the functionality of power divider can be realized. The proposed reconfigurable spin-wave directional coupler opens a way for two-dimensional planar magnonic integrated circuits.
Interstitial hydrogen atoms in face-centered cubic iron in the Earth’s core
Authors: Ikuta Daijo , Ohtani Eiji , Sano-Furukawa Asami , Shibazaki Yuki , Terasaki Hidenori , Yuan Liang , Hattori Takanori
Published: May 2019

Hydrogen is likely one of the light elements in the Earth’s core. Despite its importance, no direct observation has been made of hydrogen in an iron lattice at high pressure. We made the first direct determination of site occupancy and volume of interstitial hydrogen in a face-centered cubic (fcc) iron lattice up to 12 GPa and 1200 K using the in situ neutron diffraction method. The transition temperatures from the body-centered cubic and the double-hexagonal close-packed phases to the fcc phase were higher than reported previously. At pressures <5 GPa, the hydrogen content in the fcc iron hydride lattice (x) was small at x < 0.3, but increased to x > 0.8 with increasing pressure. Hydrogen atoms occupy both octahedral (O) and tetrahedral (T) sites; typically 0.870(±0.047) in O-sites and 0.057(±0.035) in T-sites at 12 GPa and 1200 K. The fcc lattice expanded approximately linearly at a rate of 2.22(±0.36) Å3 per hydrogen atom, which is higher than previously estimated (1.9 Å3/H). The lattice expansion by hydrogen dissolution was negligibly dependent on pressure. The large lattice expansion by interstitial hydrogen reduced the estimated hydrogen content in the Earth’s core that accounted for the density deficit of the core. The revised analyses indicate that whole core may contain hydrogen of 80(±31) times of the ocean mass with 79(±30) and 0.8(±0.3) ocean mass for the outer and inner cores, respectively.
Mutant huntingtin disturbs circadian clock gene expression and sleep patterns in Drosophila
Authors: Faragó Anikó , Zsindely Nóra , Bodai László
Published: May 2019

Deficiency of the sleep-wake cycle can accelerate the progression of Huntington’s disease (HD) and exacerbate symptoms making it a target of investigation to better understand the molecular pathology of the disorder. In this study we analyzed sleep defects in a Drosophila model of HD and investigated whether disturbed sleep coincides with alterations in the molecular mechanism controlling circadian rhythm. To analyze sleep defects we recorded the daily activity of flies in 12:12 hours light:dark entrainment and in regard to the underlying molecular mechanism measured circadian “clock” gene expression. In HD flies we observed reduced amount of sleep, sleep fragmentation and prolonged sleep latency. We found changes in gene expression patterns of both transcriptional feedback loops of circadian regulation. We detected prolonged expression of the core feedback loop components period and timeless, whilst the secondary feedback loop member vrille had lower expression rates in general. Our results show that the Drosophila HD model recapitulates most of the sleep related symptoms reported in patients therefore it can be a potential tool to study the molecular background of sleep defects in HD. Altered expression of circadian “clock” genes suggests that disturbed sleep pattern in HD might be the consequence of disturbed circadian regulation.
Raptor talon shape and biomechanical performance are controlled by relative prey size but not by allometry
Authors: Tsang Leah R. , Wilson Laura A. B. , Ledogar Justin , Wroe Stephen , Attard Marie , Sansalone Gabriele
Published: May 2019

Most birds of prey (raptors), rely heavily on their talons for capturing prey. However, the relationship between talon shape and the ability to take prey is poorly understood. In this study we investigate whether raptor talons have evolved primarily in response to adaptive pressures exerted by different dietary demands, or if talon morphology is largely constrained by allometric or phylogenetic factors. We focus on the hallux talon and include 21 species in total varying greatly in body mass and feeding ecology, ranging from active predation on relatively large prey to obligate scavenging. To quantify the variation in talon shape and biomechanical performance within a phylogenetic framework, we combined three dimensional (3D) geometric morphometrics, finite element modelling and phylogenetic comparative methods. Our results indicate that relative prey size plays a key role in shaping the raptorial talon. Species that hunt larger prey are characterised by both distinct talon shape and mechanical performance when compared to species that predate smaller prey, even when accounting for phylogeny. In contrast to previous results of skull-based analysis, allometry had no significant effect. In conclusion, we found that raptor talon evolution has been strongly influenced by relative prey size, but not allometry and, that talon shape and mechanical performance are good indicators of feeding ecology.
The selective disruption of presynaptic JNK2/STX1a interaction reduces NMDA receptor-dependent glutamate release
Authors: Marcelli Serena , Iannuzzi Filomena , Ficulle Elena , Mango Dalila , Pieraccini Stefano , Pellegrino Sara , Corbo Massimo , Sironi Maurizio , Pittaluga Anna , Nisticò Robert , Feligioni Marco
Published: May 2019

The neuronal loss caused by excessive glutamate release, or ‘excitotoxicity’, leads to several pathological conditions, including cerebral ischemia, epilepsy, and neurodegenerative diseases. Over-stimulation of presynaptic N-methyl-D-aspartate (NMDA) receptors is known to trigger and support glutamate spillover, while postsynaptic NMDA receptors are responsible for the subsequent apoptotic cascade. Almost all molecules developed so far are unable to selectively block presynaptic or postsynaptic NMDA receptors, therefore a deeper knowledge about intracellular NMDA pathways is required to design more specific inhibitors. Our previous work showed that presynaptic c-Jun N-terminal kinase 2 (JNK2) specifically regulates NMDA-evoked glutamate release and here we demonstrate that an interaction between Syntaxin-1a and JNK2 is fundamental to this mechanism. Based on this evidence, a new cell permeable peptide (CPP), “JGRi1”, has been developed to disrupt the JNK2/STX1a interaction to indirectly, but specifically, inhibit presynaptic NMDA receptor signaling. JGRi1 reduces the NMDA-evoked release of glutamate both in in-vitro and ex-vivo experiments while also being able to widely diffuse throughout brain tissue via intraperitoneal administration. In conclusion, the JNK2/STX1 interaction is involved in presynaptic NMDA-evoked glutamate release and the novel CPP, JGRi1, acts as a pharmacological tool that promotes neuroprotection.
Author Correction: The Src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain
Authors: Appel Camilla Kristine , Gallego-Pedersen Simone , Andersen Line , Blancheflor Kristensen Sophie , Ding Ming , Falk Sarah , Sayilekshmy Manasi , Gabel-Jensen Charlotte , Heegaard Anne-Marie
Published: May 2019

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Author Correction: Beta Trace Protein does not outperform Creatinine and Cystatin C in estimating Glomerular Filtration Rate in Older Adults
Authors: Ebert Natalie , Koep Camilla , Schwarz Kristin , Martus Peter , Mielke Nina , Bartel Jan , Kuhlmann Martin , Gaedeke Jens , Toelle Markus , van der Giet Markus , Schuchardt Mirjam , Schaeffner Elke
Published: May 2019

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Mantle flow and deep electrical anisotropy in a main gateway: MT study in Tierra del Fuego
Authors: González-Castillo Lourdes , Bohoyo Fernando , Junge Andreas , Galindo-Zaldívar Jesús , Cembrowski Marcel , Torres-Carbonell Pablo , Ruiz-Constán Ana , Pedrera Antonio , Ibarra Pedro , Maestro Adolfo , Ruano Patricia
Published: May 2019

Asthenospheric mantle flow drives lithospheric plate motion and constitutes a relevant feature of Earth gateways. It most likely influences the spatial pattern of seismic velocity and deep electrical anisotropies. The Drake Passage is a main gateway in the global pattern of mantle flow. The separation of the South American and Antarctic plates since the Oligocene produced this oceanic and mantle gateway connecting the Pacific and Atlantic oceans. Here we analyze the deep crustal and upper mantle electrical anisotropy of its northern margin using long period magnetotelluric data from Tierra del Fuego (Argentina). The influence of the surrounding oceans was taken into account to constrain the mantle electrical conductivity features. 3D electrical models were calculated to fit 18 sites responses in this area. The phase tensor pattern for the longest periods reveals the existence of a well-defined NW-SE electrical conductivity anisotropy in the upper mantle. This anisotropy would result from the mantle flow related to the 30 to 6 Ma West Scotia spreading, constricted by the subducted slab orientation of the Pacific plate, rather than the later eastward mantle flow across the Drake Passage. Deep electrical anisotropy proves to be a key tool for a better understanding of mantle flow.
VetTag: improving automated veterinary diagnosis coding via large-scale language modeling
Authors: Zhang Yuhui , Nie Allen , Zehnder Ashley , Page Rodney L. , Zou James
Published: May 2019

Unlike human medical records, most of the veterinary records are free text without standard diagnosis coding. The lack of systematic coding is a major barrier to the growing interest in leveraging veterinary records for public health and translational research. Recent machine learning effort is limited to predicting 42 top-level diagnosis categories from veterinary notes. Here we develop a large-scale algorithm to automatically predict all 4577 standard veterinary diagnosis codes from free text. We train our algorithm on a curated dataset of over 100 K expert labeled veterinary notes and over one million unlabeled notes. Our algorithm is based on the adapted Transformer architecture and we demonstrate that large-scale language modeling on the unlabeled notes via pretraining and as an auxiliary objective during supervised learning greatly improves performance. We systematically evaluate the performance of the model and several baselines in challenging settings where algorithms trained on one hospital are evaluated in a different hospital with substantial domain shift. In addition, we show that hierarchical training can address severe data imbalances for fine-grained diagnosis with a few training cases, and we provide interpretation for what is learned by the deep network. Our algorithm addresses an important challenge in veterinary medicine, and our model and experiments add insights into the power of unsupervised learning for clinical natural language processing.
Caffeine-free hawk tea lowers cholesterol by reducing free cholesterol uptake and the production of very-low-density lipoprotein
Authors: Feng Juan , Yang Jian , Chang Yujun , Qiao Liansheng , Dang Honglei , Luo Kun , Guo Hongyan , An Yannan , Ma Chengmei , Shao Hong , Tian Jie , Yuan Yuan , Xie Lan , Xing Wanli , Cheng Jing
Published: May 2019

Medicinal plants show important therapeutic value in chronic disease treatment. However, due to their diverse ingredients and complex biological effects, the molecular mechanisms of medicinal plants are yet to be explored. By means of several high-throughput platforms, here we show hawk tea extract (HTE) inhibits Niemann–Pick C1-like 1 (NPC1L1)-mediated free cholesterol uptake, thereby inducing the transcription of low-density lipoprotein receptor (LDLR) downstream of the sterol response element binding protein 2 (SREBP2) pathway. Meanwhile, HTE suppresses hepatocyte nuclear factor 4α (HNF4α)-mediated transcription of microsomal triglyceride transfer protein (MTP) and apolipoprotein B (APOB), thereby decreasing the production of very-low-density lipoprotein. The catechin EGCG ((−)-epigallocatechin gallate) and the flavonoids kaempferol and quercetin are identified as the bioactive components responsible for the effects on the NPC1L1-SREBP2-LDLR axis and HNF4α-MTP/APOB axis, respectively. Overall, hawk tea works as a previously unrecognized cholesterol-lowering agent in a multi-target and multi-component manner.