bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel heterozygous C243Y A20/TNFAIP3 gene mutation is responsible for chronic inflammation in autosomal-dominant Behçet's disease
Authors: Shigemura Tomonari , Kaneko Naoe , Kobayashi Norimoto , Kobayashi Keiko , Takeuchi Yusuke , Nakano Naoko , Masumoto Junya , Agematsu Kazunaga 
Published: December 2016

ObjectiveAlthough Behçet's disease (BD) is a chronic inflammatory disorder of uncertain aetiology, the existence of familial BD with autosomal-dominant traits suggests that a responsibility gene (or genes) exists. We investigated a Japanese family with a history of BD to search for pathogenic mutations underlying the biological mechanisms of BD.Methods6 patients over 4 generations who had suffered from frequent oral ulcers, genital ulcers and erythaema nodosum-like lesions in the skin were assessed. Whole-exome sequencing was performed on genomic DNA, and cytokine production was determined from stimulated mononuclear cells. Inflammatory cytokine secretion and Nod2-mediated NF-κB activation were analysed using the transfected cells.ResultsBy whole-exome sequencing, we identified a common heterozygous missense mutation inA20/TNFAIP3, a gene known to regulate NF-κB signalling, for which all affected family members carried a heterozygous C243Y mutation in the ovarian tumour domain. Mononuclear cells obtained from the proband and his mother produced large amounts of interleukin 1β, IL-6 and tumour necrosis factor α (TNF-a) on stimulation as compared with those from normal controls. Although inflammatory cytokine secretion was suppressed by wild-type transfected cells, it was suppressed to a much lesser extent by mutated C243YA20/TNFAIP3-transfected cells. In addition, impaired suppression of Nod2-mediated NF-κB activation by C243YA20/TNFAIP3was observed.ConclusionsA C243Y mutation inA20/TNFAIP3was likely responsible for increased production of human inflammatory cytokines by reduced suppression of NF-κB activation, and may have accounted for the autosomal-dominant Mendelian mode of BD transmission in this family.
Costs of early spondyloarthritis: estimates from the first 3 years of the DESIR cohort
Authors: Harvard Stephanie , Guh Daphne , Bansback Nick , Richette Pascal , Dougados Maxime , Anis Aslam , Fautrel Bruno 
Published: December 2016

ObjectivesTo value health resource utilisation and productivity losses in DESIR, a longitudinal French cohort of 708 patients with early spondyloarthritis (SpA) enrolled between 2007 and 2010, and identify factors associated with costs in the first 3 years of follow-up.MethodsSelf-reported clinical data from DESIR and French public data were used to value health resource utilisation and productivity losses in 2013 Euros. Factors associated with costs, including and excluding biological drugs, were identified in generalised linear models using the generalised estimating equations algorithm to account for repeated observations over participants.ResultsThe mean (±SD) annual cost per patient was €5004±6870 in year 1, decreasing to €4961±7457 in year 3. Patients who never received a biologic had mean 3-year total costs of €4789±6022 compared to €38 206±19 829 among those who received a biologic. Factors associated with increased total costs were peripheral arthritis (rate ratio (RR) 1.19; 95% CI 1.04 to 1.37; p<0.0001), time on biologics (RR 1.23 per month; 1.21, 1.24; p<0.0001), and average BASFI score (RR 1.18/10 point increase; 1.15, 1.25; p<0.0001). Factors associated with increased costs excluding biologics were baseline age (RR 1.10 per 5 year increase; 1.05, 1.16; p<0.0001), peripheral arthritis (RR 1.20; 1.02, 1.40; p<0.0133), time on biologics (RR 1.04 per month; 1.02, 1.05; p<0.0001), and average BASDAI score (RR 1.21 per 10 point increase; 1.16, 1.25; p<0.0001).ConclusionsIn addition to biologics, factors like age, peripheral arthritis and disease activity independently increase SpA-related costs. This study may serve as a benchmark for cost of illness among patients with early SpA in the biologic era.
Clinical joint inactivity predicts structural stability in patients with established rheumatoid arthritis
Authors: Gärtner M , Sigmund I K , Alasti F , Supp G , Radner H , Machold K , Smolen J S , Aletaha D 
Published: December 2016

ObjectivesClinical joint activity is a strong predictor of joint damage in rheumatoid arthritis (RA), but progression of damage might increase despite clinical inactivity of the respective joint (silent progression). The aim of this study was to evaluate the prevalence of silent joint progression, but particularly on the patient level and to investigate the duration of clinical inactivity as a marker for non-progression on the joint level.Methods279 patients with RA with any radiographic progression over an observational period of 3–5 years were included. We obtained radiographic and clinical data of 22 hand/finger joints over a period of at least 3 years. Prevalence of silent progression and associations of clinical joint activity and radiographic progression were evaluated.Results120 (43.0%) of the patients showed radiographic progression in at least one of their joints without any signs of clinical activity in that respective joint. In only 7 (5.8%) patients, such silent joint progression would go undetected, as the remainder had other joints with clinical activity, either with (n=84; 70.0%) or without (n=29; 24.2%) accompanying radiographic progression. Also, the risk of silent progression decreases with duration of clinical activity.ConclusionsSilent progression of a joint without accompanying apparent clinical activity in any other joint of a patient was very rare, and would therefore be most likely detected by the assessment of the patient. Thus, full clinical remission is an excellent marker of structural stability in patients with RA, and the maintenance of this state reduces the risk of progression even further.
Outline of a Permian tetrapod footprint ichnostratigraphy
Authors: Voigt Sebastian , Lucas Spencer G. 
Published: December 2016

Abstract

Tetrapod footprints are among the most common fossil remains in continental Permian strata and thus are of biostratigraphic interest. Based on the vertical distribution of the 13 best-known Permian tetrapod ichnotaxa, three footprint biochrons are suggested for the period: (1)
Dromopus
– latest Carboniferous (approximately Gzhelian) to late Early Permian (approximately Artinskian), representing ichnoassemblages dominated by tracks of temnospondyls, reptiliomorphs, pelycosaurs and early diapsids; (2)
Erpetopus
– late Early Permian (approximately Kungurian) to late Middle Permian (approximately Capitanian), representing ichnoassemblages dominated by tracks of non-diapsid eureptiles; and (3)
Paradoxichnium
– Late Permian (Wuchiapingian and Changhsingian), representing ichnoassemblages dominated by tracks of medium- and large-sized parareptiles, non-diapsid eureptiles and early saurians. This is the most conservative ichnostratigraphic concept, and it may be possible to refine it to almost stage-level resolution by future comprehensive analysis, especially of Permian captorhinomorph and therapsid footprints. Other major tasks to improve Permian tetrapod footprint ichnostratigraphy include enhanced knowledge of Middle Permian tetrapod footprints, and clarification of the palaeoenvironmental factors that may control the distribution of tetrapod footprints in space and time.
Global Permian brachiopod biostratigraphy: an overview
Authors: Shen Shu-Zhong 
Published: December 2016

Abstract

Establishing a Permian brachiopod biochronological scheme for global correlation is difficult because of strong provincialism during the Permian. In this paper, a brief overview of brachiopod successions in five major palaeobiogeographical realms/zones is provided. For Gondwanaland and peri-Gondwanan regions including Cimmerian blocks,
Bandoproductus
and
Punctocyrtella
(or
Cyrtella
) are characteristic of the lower Cisuralian, as is
Cimmeriella
for the middle Cisuralian. As the Cimmerian blocks continued drifting north during the late Kungurian, accompanied by climate amelioration, contemporaneous brachiopods inhabiting these blocks showed a distinct shift from cold-water to mixed or warm-water affinities. However, coeval brachiopods in the Northern Transitional Zone (NTZ) are characterized by warm-water faunas and are associated with fusulinids in the lower Cisuralian. The Guadalupian brachiopods of the NTZ were clearly mixed between the Boreal and palaeoequatorial affinities. The end-Guadalupian is marked by the disappearance of a few characteristic genera, such as
Vediproductus
,
Neoplicatifera
and
Urushtenoidea
, in the Palaeotethyan region. The onset of the end-Permian mass extinction in the latest Changhsingian is clearly exhibited by the occurrence of the dwarfed and thin-shelled brachiopods commonly containing
Paracrurithyris
.
The Permian chronostratigraphic scale: history, status and prospectus
Authors: Lucas Spencer G. , Shen Shu-Zhong 
Published: December 2016

Abstract
In 1841, Murchison coined the term Permian for strata in the Russian Urals. Recognition of the Permian outside of Russia and central Europe soon followed, but it took about a century for the Permian to be accepted globally as a distinct geological system. The work of the Subcommission on Permian Stratigraphy began in the 1970s and resulted in current recognition of nine Permian stages in three series: the Cisuralian (lower Permian) – Asselian, Sakmarian, Artinskian and Kungurian; the Guadalupian (middle Permian) – Roadian, Wordian and Capitanian; and the Lopingian (upper Permian) – Wuchiapingian and Changhsingian. The 1990s saw the rise of Permian conodont biostratigraphy, so that all Permian Global Stratigraphic Sections and Points (GSSPs) use conodont evolutionary events as the primary signal for correlation.
Issues in the development of a Permian chronostratigraphic scale include those of stability and priority of nomenclature and concepts, disagreements over changing taxonomy, ammonoid v. fusulinid v. conodont biostratigraphy, differences in the perceived significance of biotic events for chronostratigraphic classification, and correlation problems between provinces. Further development of the Permian chronostratigraphic scale should focus on GSSP selection for the remaining, undefined stage bases, definition and characterization of substages, and further integration of the Permian chronostratigraphic scale with radioisotopic, magnetostratigraphic and chemostratigraphic tools for calibration and correlation.
A global review of Permian macrofloral biostratigraphical schemes
Authors: Cleal Christopher J. 
Published: December 2016

Abstract
Separate biostratigraphical schemes have been developed for Permian macrofloras in the five main phytochoria (palaeokingdoms), reflecting the essential lack of overlap in taxonomic composition. In Europe two biozones are normally recognized, in North America three zones, in Cathaysia three or four zones, in Gondwana four zones and in Angara five zones. The stratigraphical resolution tends to be far less than that of palynology, and up to an order of magnitude coarser than the macrofloral biozones of the Pennsylvanian subsystem. This is probably due, at least in part, to the lack of rigor in the way that the Permian macrofloral zones have been defined. Nevertheless, the existing zones do provide evidence of the overarching trajectory of change in vegetation through the Permian Period, as it responded at all palaeolatitudes to a combination of climate change, large-scale volcanic eruptions and tectonically driven landscape changes.
Late Pennsylvanian–Early Triassic conchostracan biostratigraphy: a preliminary approach
Authors: Schneider Joerg W. , Scholze Frank 
Published: December 2016

Abstract
Conchostracans are one of the most common fossil animal groups of continental deposits from late Palaeozoic to modern times. Their habitats have ranged from perennial lakes of the Carboniferous and Early Permian to seasonal playa lakes and temporary ponds from the late Early Permian into the Triassic, where they could form mass occurrences. This, together with relatively high speciation rates, makes them ideal guide fossils, especially in otherwise fossil-poor wet and dry red beds. Based on material and data collected since the 1980s from both surface outcrops and well cores in central Europe, a preliminary conchostracan zonation is proposed. We used a conservative approach, erecting assemblage zones comprising two or three species instead of species-range zones with only one or, sometimes, two forms. Assemblage zones are more robust and provide more reliability for each delineated time interval. Isotopically dated occurrences of conchostracan zone species, or co-occurrences of conchostracans, insect zone species and marine index fossils such as conodonts and fusulinids, allow us to correlate our assemblage zones with the marine Standard Global Chronostratigraphic Scale.
A geomagnetic polarity timescale for the Permian, calibrated to stage boundaries
Authors: Hounslow Mark W. , Balabanov Yuri P. 
Published: December 2016

Abstract
The reverse polarity Kiaman Superchron has strong evidence for at least three, or probably four, normal magnetochrons during the early Permian. Normal magnetochrons are during the early Asselian (base CI1r.1n at 297.94±0.33 Ma), late Artinskian (CI2n at 281.24±2.3 Ma), mid-Kungurian (CI3n at 275.86±2.0 Ma) and Roa"dian (CI3r.an at 269.54±1.6 Ma). The mixed-polarity Illawarra Superchron begins in the early Wordian at 266.66±0.76 Ma. The Wordian–Capitanian interval is biased to normal polarity, but the basal Wuchiapingian begins the beginning of a significant reverse polarity magnetochron LP0r, with an overlying mixed-polarity interval through the later Lopingian. No significant magnetostratigraphic data gaps exist in the Permian geomagnetic polarity record. The early Cisuralian magnetochrons are calibrated to a succession of fusulinid zones, the later Cisuralian and Guadalupian to a conodont and fusulinid biostratigraphy, and Lopingian magnetochrons to conodont zonations. Age calibration of the magnetochrons is obtained through a Bayesian approach using 35 radiometric dates, and 95% confidence intervals on the ages and chron durations are obtained. The dating control points are most numerous in the Gzhelian–Asselian, Wordian and Changhsingian intervals. This significant advance should provide a framework for better correlation and dating of the marine and non-marine Permian.
Radon as an anthropogenic indoor air pollutant as exemplified by radium-dial watches and other uranium- and radium-containing artefacts
Authors: Crockett Robin G. M. , Gillmore Gavin K. 
Published: December 2016

Abstract
Radon is generally regarded as a naturally occurring radiological hazard but we report here measurements of significant, hazardous radon concentrations that arise from man-made sources: for example, radium-dial watches. This study is an examination and assessment of health risks from radium and uranium found in historical artefacts, and the radon that emanates from them. This includes radium-dial watches, the main focus, plus clocks, aircraft instruments, and ornaments and artefacts made of uranium glass/uranium-glazed. Such objects were very popular in the 1930s and 1940s, and are still readily available today.

A collection of 30 radium-dial pocket and wrist watches was measured and shown to be capable of giving rise to radon concentrations two orders of magnitude greater than the UK Domestic Action Level of 200 Bq m
−3
in unventilated or poorly ventilated rooms. Furthermore, individual watches are capable of giving rise to radon concentrations in excess of the UK Domestic Action Level. We also highlight a gap in remediation protocols, which are focused on preventing radon entering buildings from outside, with regard to internally generated radon hazards. Radon as arising from man-made objects, such as radium-dial watches, should be considered appropriately in radon protocols and guidelines.
Acute intermittent hypoxia in rats activates muscle proteolytic pathways through a gluccorticoid-dependent mechanism
Authors: Przygodda Franciele , Manfredi Leandro Henrique , Machado Juliano , Gonçalves Dawit A. P. , Zanon Neusa M. , Bonagamba Leni G. H. , Machado Benedito H. , Kettelhut Ísis C. , Navegantes Luiz C. C. 
Published: December 2016

Although it is well known that chronic hypoxia induces muscle wasting, the effects of intermittent hypoxia on skeletal muscle protein metabolism remain unclear. We hypothesized that acute intermittent hypoxia (AIH), a challenge that activates the hypothalamic-pituitary-adrenal axis, would alter muscle protein homeostasis through a glucocorticoid-dependent mechanism. Three-week-old rats were submitted to adrenalectomy (ADX) and exposed to 8 h of AIH (6% O2for 40 s at 9-min intervals). Animals were euthanized, and the soleus and extensor digitorum longus (EDL) muscles were harvested and incubated in vitro for measurements of protein turnover. AIH increased plasma levels of corticosterone and induced insulin resistance as estimated by the insulin tolerance test and lower rates of muscle glucose oxidation and the HOMA index. In both soleus and EDL muscles, rates of overall proteolysis increased after AIH. This rise was accompanied by an increased proteolytic activities of the ubiquitin(Ub)-proteasome system (UPS) and lysosomal and Ca2+-dependent pathways. Furthermore, AIH increased Ub-protein conjugates and gene expression of atrogin-1 and MuRF-1, two key Ub-protein ligases involved in muscle atrophy. In parallel, AIH increased the mRNA expression of the autophagy-related genes LC3b and GABARAPl1. In vitro rates of protein synthesis in skeletal muscles did not differ between AIH and control rats. ADX completely blocked the insulin resistance in hypoxic rats and the AIH-induced activation of proteolytic pathways and atrogene expression in both soleus and EDL muscles. These results demonstrate that AIH induces insulin resistance in association with activation of the UPS, the autophagic-lysosomal process, and Ca2+-dependent proteolysis through a glucocorticoid-dependent mechanism.NEW & NOTEWORTHY Since hypoxia is a condition in which the body is deprived of adequate oxygen supply and muscle wasting is induced, the present work provides evidence linking hypoxia to proteolysis through a glucocorticoid-dependent mechanism. We show that the activation of proteolytic pathways, atrophy-related genes, and insulin resistance in rats exposed to acute intermittent hypoxia was abolished by surgical removal of adrenal gland. This finding will be helpful for understanding of the muscle wasting in hypoxemic conditions.
Novel Hybrid Phenotype Revealed in Small Cell Lung Cancer by a Transcription Factor Network Model That Can Explain Tumor Heterogeneity
Authors: Udyavar Akshata R. , Wooten David J. , Hoeksema Megan , Bansal Mukesh , Califano Andrea , Estrada Lourdes , Schnell Santiago , Irish Jonathan M. , Massion Pierre P. , Quaranta Vito 
Published: December 2016

Abstract
Small cell lung cancer (SCLC) is a devastating disease due to its propensity for early invasion and refractory relapse after initial treatment response. Although these aggressive traits have been associated with phenotypic heterogeneity, our understanding of this association remains incomplete. To fill this knowledge gap, we inferred a set of 33 transcription factors (TF) associated with gene signatures of the known neuroendocrine/epithelial (NE) and non-neuroendocrine/mesenchymal-like (ML) SCLC phenotypes. The topology of this SCLC TF network was derived from prior knowledge and was simulated using Boolean modeling. These simulations predicted that the network settles into attractors, or TF expression patterns, that correlate with NE or ML phenotypes, suggesting that TF network dynamics underlie the emergence of heterogeneous SCLC phenotypes. However, several cell lines and patient tumor specimens failed to correlate with either the NE or ML attractors. By flow cytometry, single cells within these cell lines simultaneously expressed surface markers of both NE and ML differentiation, confirming the existence of a “hybrid” phenotype. Upon exposure to standard-of-care cytotoxic drugs or epigenetic modifiers, NE and ML cell populations converged toward the hybrid state, suggesting possible escape from treatment. Our findings indicate that SCLC phenotypic heterogeneity can be specified dynamically by attractor states of a master regulatory TF network. Thus, SCLC heterogeneity may be best understood as states within an epigenetic landscape. Understanding phenotypic transitions within this landscape may provide insights to clinical applications. Cancer Res; 77(5); 1063–74. ©2016 AACR.
Aspirin Suppresses Growth in PI3K-Mutant Breast Cancer by Activating AMPK and Inhibiting mTORC1 Signaling
Authors: Henry Whitney S. , Laszewski Tyler , Tsang Tiffany , Beca Francisco , Beck Andrew H. , McAllister Sandra S. , Toker Alex 
Published: December 2016

Abstract
Despite the high incidence of oncogenic mutations in PIK3CA, the gene encoding the catalytic subunit of PI3K, PI3K inhibitors have yielded little clinical benefit for breast cancer patients. Recent epidemiologic studies have suggested a therapeutic benefit from aspirin intake in cancers harboring oncogenic PIK3CA. Here, we show that mutant PIK3CA-expressing breast cancer cells have greater sensitivity to aspirin-mediated growth suppression than their wild-type counterparts. Aspirin decreased viability and anchorage-independent growth of mutant PIK3CA breast cancer cells independently of its effects on COX-2 and NF-κB. We ascribed the effects of aspirin to AMP-activated protein kinase (AMPK) activation, mTORC1 inhibition, and autophagy induction. In vivo, oncogenic PIK3CA-driven mouse mammary tumors treated daily with aspirin resulted in decreased tumor growth kinetics, whereas combination therapy of aspirin and a PI3K inhibitor further attenuated tumor growth. Our study supports the evaluation of aspirin and PI3K pathway inhibitors as a combination therapy for targeting breast cancer. Cancer Res; 77(3); 790–801. ©2016 AACR.