bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rheumatoid Arthritis and Risk of Malignant Lymphoma: Is the Risk Still Increased?
Authors: Hellgren K. , Baecklund E. , Backlin C. , Sundstrom C. , Smedby K. E. , Askling J. 
Published: December 2016

ObjectivePatients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas with a strong correlation with RA disease severity. Given the changes in RA therapy over recent decades, this study was undertaken to assess whether lymphoma risk remains increased, and if so, to explore risk predictors and lymphoma subtypes.MethodsWe identified 12,656 cases of incident RA in the Swedish Rheumatology Quality Register 1997–2012 and obtained information on therapy and inflammatory activity during the first year after diagnosis. Each patient was matched to 10 population comparator subjects. Through linkage to the Swedish Cancer Register, lymphomas, including subtypes, were identified. We assessed hazard ratios (HRs) using Cox regression.ResultsOverall, the HR for lymphoma was increased in RA, to 1.6 (95% confidence interval [95% CI] 1.2–2.1). Taking RA duration into account, risks did not appear to have declined over successive calendar years of RA diagnosis. Neither use of methotrexate the first year after RA diagnosis nor ever use of tumor necrosis factor inhibitors (TNFi) increased lymphoma risk (HR 0.9 [95% CI 0.4–1.9]). Use of oral corticosteroids the first year after RA diagnosis was associated with a reduced risk (HR 0.5 [95% CI 0.3–0.9]). Inflammatory activity during the first year after RA diagnosis did not predict future lymphoma risk. Chronic lymphocytic leukemia occurred less frequently, and Hodgkin's lymphoma occurred more frequently, in RA patients than in the general population.ConclusionThe average lymphoma risk in recently diagnosed RA is similar in magnitude to that reported in historical cohorts. Standard antirheumatic treatment including TNFi did not predict future lymphoma risk. Distribution of lymphoma subtypes warrants further investigation.
Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: Amide⋅⋅⋅Heteroarene π‐Stacking Interactions and Chalcogen Bonding in the S3 Pocket
Authors: Giroud Maude , Ivkovic Jakov , Martignoni Mara , Fleuti Marianne , Trapp Nils , Haap Wolfgang , Kuglstatter Andreas , Benz Jörg , Kuhn Bernd , Schirmeister Tanja , Diederich François 
Published: December 2016

AbstractWe report an extensive “heteroarene scan” of triazine nitrile ligands of the cysteine protease human cathepsin L (hCatL) to investigate π‐stacking on the peptide amide bond Gly67–Gly68 at the entrance of the S3 pocket. This heteroarene⋅⋅⋅peptide bond stacking was supported by a co‐crystal structure of an imidazopyridine ligand with hCatL. Inhibitory constants (Ki) are strongly influenced by the diverse nature of the heterocycles and specific interactions with the local environment of the S3 pocket. Binding affinities vary by three orders of magnitude. All heteroaromatic ligands feature enhanced binding by comparison with hydrocarbon analogues. Predicted energetic contributions from the orientation of the local dipole moments of heteroarene and peptide bond could not be confirmed. Binding of benzothienyl (Ki=4 nm) and benzothiazolyl (Ki=17 nm) ligands was enhanced by intermolecular C−S⋅⋅⋅O=C interactions (chalcogen bonding) with the backbone C=O of Asn66 in the S3 pocket. The ligands were also tested for the related enzyme rhodesain.
European Pain Federation position paper on appropriate opioid use in chronic pain management
Authors: O'Brien T. , Christrup L.L. , Drewes A.M. , Fallon M.T. , Kress H.G. , McQuay H.J. , Mikus G. , Morlion B.J. , Perez‐Cajaraville J. , Pogatzki‐Zahn E. , Varrassi G. , Wells J.C.D. 
Published: December 2016

AbstractPoorly controlled pain is a global public health issue. The personal, familial and societal costs are immeasurable. Only a minority of European patients have access to a comprehensive specialist pain clinic. More commonly the responsibility for chronic pain management and initiating opioid therapy rests with the primary care physician and other non‐specialist opioid prescribers. There is much confusing and conflicting information available to non‐specialist prescribers regarding opioid therapy and a great deal of unjustified fear is generated. Opioid therapy should only be initiated by competent clinicians as part of a multi‐faceted treatment programme in circumstances where more simple measures have failed. Throughout, all patients must be kept under close clinical surveillance. As with any other medical therapy, if the treatment fails to yield the desired results and/or the patient is additionally burdened by an unacceptable level of adverse effects, the overall management strategy must be reviewed and revised. No responsible clinician will wish to pursue a failed treatment strategy or persist with an ineffective and burdensome treatment. In a considered attempt to empower and inform non‐specialist opioid prescribers, EFIC convened a European group of experts, drawn from a diverse range of basic science and relevant clinical disciplines, to prepare a position paper on appropriate opioid use in chronic pain. The expert panel reviewed the available literature and harnessed the experience of many years of clinical practice to produce these series of recommendations. Its success will be judged on the extent to which it contributes to an improved pain management experience for chronic pain patients across Europe.SignificanceThis position paper provides expert recommendations for primary care physicians and other non‐ specialist healthcare professionals in Europe, particularly those who do not have ready access to specialists in pain medicine, on the safe and appropriate use of opioid medications as part of a multi‐faceted approach to pain management, in properly selected and supervised patients.
Evolutionary Adaptation and Amyloid Formation: Does the Reduced Amyloidogenicity and Cytotoxicity of Ursine Amylin Contribute to the Metabolic Adaption of Bears and Polar Bears?
Authors: Akter Rehana , Abedini Andisheh , Ridgway Zachary , Zhang Xiaoxue , Kleinberg Joel , Schmidt Ann Marie , Raleigh Daniel P. 
Published: December 2016

AbstractMuch of our knowledge of diabetes is derived from studies of rodent models. An alternative approach explores evolutionary solutions to physiological stress by studying organisms that face challenging metabolic environments. Polar bears eat an enormously lipid‐rich diet without deleterious metabolic consequences. In contrast, transgenic rodents expressing the human neuropancreatic polypeptide hormone amylin develop hyperglycemia and extensive pancreatic islet amyloid when fed a high‐fat diet. The process of islet amyloid formation by human amylin contributes to β‐cell dysfunction and loss of β‐cell mass in type 2 diabetes. We show that ursine amylin is considerably less amyloidogenic and less toxic to β‐cells than human amylin, consistent with the hypothesis that part of the adaptation of bears to metabolic challenges might include protection from islet amyloidosis‐induced β‐cell toxicity. Ursine and human amylin differ at four locations: H18R, S20G, F23L, and S29P. These are interesting from a biophysical perspective, since the S20G mutation accelerates amyloid formation, but the H18R slows it. An H18RS20G double mutant of human amylin behaves similarly to the H18R mutant, indicating that the substitution at position 18 dominates the S20G replacement. These data suggest one possible mechanism underpinning the protection of bears against metabolic challenges and provide insight into the design of soluble analogs of human amylin.
A Novel Process for CO2 Capture by Using Sodium Metaborate, Part II: Carbonation Reaction and Kinetic Studies
Authors: Kibar Murat Efgan , Akin Ayşe Nilgün 
Published: December 2016

ABSTRACTIn Part II of this two‐part series of papers, optimization of carbonation reaction with sodium metaborate and kinetics of the reaction are studied and compared to the structural properties, which were reported in Part I. This paper presents a comprehensive study on the optimization of reaction conditions and determination of reaction parameters of sodium metaborate (NaBO2) and carbon dioxide (CO2). Both hydrated and dehydrated forms of NaBO2 have high sorption capacities of CO2 up to 400°C. Decomposition of the products starts beyond 400°C and completes at 600°C. The shrinking core model is used to explain the kinetics of the noncatalytic heterogeneous reaction. The reaction progresses in two stages: one is surface reaction controlled and the other is diffusion controlled. The apparent activation energy and preexponential factor for reaction‐controlled and diffusion‐controlled regions are calculated as 11.8 kJ/mol and 3.5 × 106 cm2/min and 18.2 kJ/mol and 6.5 × 10−5 cm2/min, respectively.
Direct Observation of Alternating Stretch‐Coil and Coil‐Stretch Transitions of Semiflexible Polymers in Microstructured Flow
Authors: Strelnikova Natalja , Göllner Michael , Pfohl Thomas 
Published: December 2016

Analyzing the behavior of semiflexible polymers experiencing hydrodynamic forces is an important step toward a better understanding of polymer dynamics in microfluidic applications as well as in living cells. In particular, studying conformational changes of fluorescently labeled, semiflexible actin filaments in flow fields of spatially varying flow strength will significantly contribute to this goal. The experimental situation is realized in flows through structured microchannels with alternating high‐ and low‐velocity segments. While entering the wider channel segments, the semiflexible filaments undergo a buckling transition under compression whereas they are stretched with a suppression of thermal fluctuations in the extensional regime when reentering the narrow segments. The nature of these nonequilibrium and nonstationary conformational transitions is characterized by analyzing the evolution of the end‐to‐end distances, center‐of‐mass velocities, and bending energies along the passage of the filaments through the channels.
image
A SLC39A8 variant causes manganese deficiency, and glycosylation and mitochondrial disorders
Authors: Riley Lisa G. , Cowley Mark J. , Gayevskiy Velimir , Roscioli Tony , Thorburn David R. , Prelog Kristina , Bahlo Melanie , Sue Carolyn M. , Balasubramaniam Shanti , Christodoulou John 
Published: December 2016

SummarySLC39A8 variants have recently been reported to cause a type II congenital disorder of glycosylation (CDG) in patients with intellectual disability and cerebellar atrophy. Here we report a novel SLC39A8 variant in siblings with features of Leigh‐like mitochondrial disease. Two sisters born to consanguineous Lebanese parents had profound developmental delay, dystonia, seizures and failure to thrive. Brain MRI of both siblings identified bilateral basal ganglia hyperintensities on T2‐weighted imaging and cerebral atrophy. CSF lactate was elevated in patient 1 and normal in patient 2. Respiratory chain enzymology was only performed on patient 1 and revealed complex IV and II + III activity was low in liver, with elevated complex I activity. Complex IV activity was borderline low in patient 1 muscle and pyruvate dehydrogenase activity was reduced. Whole genome sequencing identified a homozygous Chr4(GRCh37):g.103236869C>G; c.338G>C; p.(Cys113Ser) variant in SLC39A8, located in one of eight regions identified by homozygosity mapping. SLC39A8 encodes a manganese and zinc transporter which localises to the cell and mitochondrial membranes. Patient 2 blood and urine manganese levels were undetectably low. Transferrin electrophoresis of patient 2 serum revealed a type II CDG defect. Oral supplementation with galactose and uridine led to improvement of the transferrin isoform pattern within 14 days of treatment initiation. Oral manganese has only recently been added to the treatment. These results suggest SLC39A8 deficiency can cause both a type II CDG and Leigh‐like syndrome, possibly via reduced activity of the manganese‐dependent enzymes β‐galactosyltransferase and mitochondrial manganese superoxide dismutase.
Epac activation inhibits IL-6-induced cardiac myocyte dysfunction
Authors: Jin Huiling , Fujita Takayuki , Jin Meihua , Kurotani Reiko , Hidaka Yuko , Cai Wenqian , Suita Kenji , Prajapati Rajesh , Liang Chen , Ohnuki Yoshiki , Mototani Yasumasa , Umemura Masanari , Yokoyama Utako , Sato Motohiko , Okumura Satoshi , Ishikawa Yoshihiro 
Published: December 2016

Abstract
Pro-inflammatory cytokines are released in septic shock and impair cardiac function via the Jak-STAT pathway. It is well known that sympathetic and thus catecholamine signaling is activated thereafter to compensate for cardiac dysfunction. The mechanism of such compensation by catecholamine signaling has been traditionally understood to be cyclic AMP-dependent protein kinase (PKA)-mediated enforcement of cardiac contractility. We hypothesized that the exchange protein activated by cAMP (Epac), a newly identified target of cAMP signaling that functions independently of PKA, also plays a key role in this mechanism. In cultured cardiac myocytes, activation of Epac attenuated the inhibitory effect of interleukin-6 on the increase of intracellular Ca2+ concentration and contractility in response to isoproterenol, most likely through inhibition of the Jak-STAT pathway via SOCS3, with subsequent changes in inducible nitric oxide synthase expression. These findings suggest a new role of catecholamine signaling in compensating for cardiac dysfunction in heart failure. Epac and its downstream pathway may be a novel target for treating cardiac dysfunction in endotoxemia.
Exenatide Add-on to Continuous Subcutaneous Insulin Infusion Therapy Reduces Bolus Insulin Doses in Patients with Type 2 Diabetes: A Randomized, Controlled, Open-Label Trial
Authors: Li Feng-fei , Jiang Lanlan , Fu Liyuan , Zhu Hong-hong , Zhou Peihua , Zhang Danfeng , Su Xiao-fei , Wu Jin-dan , Ye Lei , Ma Jian-hua 
Published: December 2016

Abstract
Introduction
The objective of this study was to investigate the effect of adding exenatide to continuous subcutaneous insulin infusion (CSII) therapy on the precise insulin doses required by type 2 diabetic patients to maintain glycemic control.

Methods
This was a single-center, randomized, controlled, open-label trial. Uncontrolled T2D patients were recruited between March 2010 and November 2011 at Nanjing First Hospital, China. Subjects were randomly assigned (1:1) to either an exenatide add-on to CSII group or a CSII therapy only (i.e., control) group (n = 18, respectively) for 5 weeks. Patients were subjected to 3 days of continuous glucose monitoring (CGM) during the screening period and after therapy. The precise insulin doses, the times taken by the patients to achieve euglycemic control, and the mean amplitude of glycemic excursion (MAGE) at the endpoint were compared between the two groups. The primary endpoint was precise insulin dose differences between groups from baseline to the endpoint.

Results
A total of 36 subjects were admitted as inpatients. Patients in the exenatide add-on therapy group needed less insulin titration time to achieve glycemic control (3.67 ± 1.33 vs. 4.78 ± 1.00 days, P = 0.028) and significantly lower bolus insulin doses than the control group at the endpoint (total bolus, 0.13 ± 0.03 vs. 0.17 ± 0.04 U/kg, P = 0.02, breakfast bolus, 0.05 ± 0.01 vs. 0.06 ± 0.01 U/kg, P = 0.01, lunch bolus, 0.04 ± 0.01 vs. 0.06 ± 0.01 U/kg, P = 0.01, dinner bolus, 0.04 ± 0.01 vs. 0.05 ± 0.01 U/kg, P = 0.01, respectively). Moreover, the CGM data showed that patients in the exenatide add-on therapy group exhibited a significant reduction in MAGE as compared to the control group (2.96 ± 1.14 vs. 4.21 ± 1.39 mmol/L, P = 0.012).

Conclusion
Our data suggest that adding exenatide therapy to CSII therapy leads to an improvement in glycemic excursions and the use of smaller bolus insulin doses.

Trial Registration
Chinese Clinical Trial Registry identifier, ChiCTR-PPR-15007045.
A consilience framework: Revealing hidden features of the independent contractor
Authors: McKeown Tui 
Published: December 2016

AbstractThis paper presents the results of a consilience framework developed and tested to reconcile the varying definitions, methodologies and purposes of the data collected on independent contracting within Australia. The result is a multilayered profile of the self-employed contractor which draws together official labour market statistics, taxation office liabilities and marketing-based consumer data sources. The framework sees independent contractors emerge as a dynamic, entrepreneurial and complex group who defy many of the age, gender and industry stereotypes that law and policy makers confine them to. While these initial results are limited to Australia, the challenge independent contractors present to established systems of legal, social and government regulation are embedded within the wider contexts of self-employment and small business. These contexts are universal and the sooner these challenges are answered, the sooner the opportunities they also present can be realised.
Suicidal ideation and subsequent completed suicide in both psychiatric and non-psychiatric populations: a meta-analysis
Authors: Hubers A. A. M. , Moaddine S. , Peersmann S. H. M. , Stijnen T. , van Duijn E. , van der Mast R. C. , Dekkers O. M. , Giltay E. J. 
Published: December 2016

Aims.Several authors claimed that expression of suicidal ideation is one of the most important predictors of completed suicide. However, the strength of the association between suicidal ideation and subsequent completed suicide has not been firmly established in different populations. Furthermore, the absolute suicide risk after expression of suicidal ideation is unknown. In this meta-analysis, we examined whether the expression of suicidal ideation predicted subsequent completed suicide in various populations, including both psychiatric and non-psychiatric populations.Methods.A meta-analysis of cohort and case–control studies that assessed suicidal ideation as determinant for completed suicide in adults. Two independent reviewers screened 5726 articles for eligibility and extracted data of the 81 included studies. Pooled risk ratios were estimated in a random effects model stratified for different populations. Meta-regression analysis was used to determine suicide risk during the first year of follow-up.Results.The risk for completed suicide was clearly higher in people who had expressed suicidal ideation compared with people who had not, with substantial variation between the different populations: risk ratio ranging from 2.35 (95% confidence interval (CI) 1.43–3.87) in affective disorder populations to 8.00 (95% CI 5.46–11.7) in non-psychiatric populations. In contrast, the suicide risk after expression of suicidal ideation in the first year of follow-up was higher in psychiatric patients (risk 1.40%, 95% CI 0.74–2.64) than in non-psychiatric participants (risk 0.23%, 95% CI 0.10–0.54). Past suicide attempt-adjusted risk ratios were not pooled due to large underreporting.Conclusions.Assessment of suicidal ideation is of priority in psychiatric patients. Expression of suicidal ideation in psychiatric patients should prompt secondary prevention strategies to reduce their substantial increased risk of suicide.
The non-canonical mitochondrial inner membrane presequence translocase of trypanosomatids contains two essential rhomboid-like proteins
Authors: Harsman Anke , Oeljeklaus Silke , Wenger Christoph , Huot Jonathan L. , Warscheid Bettina , Schneider André 
Published: December 2016

AbstractMitochondrial protein import is essential for all eukaryotes. Here we show that the early diverging eukaryote Trypanosoma brucei has a non-canonical inner membrane (IM) protein translocation machinery. Besides TbTim17, the single member of the Tim17/22/23 family in trypanosomes, the presequence translocase contains nine subunits that co-purify in reciprocal immunoprecipitations and with a presequence-containing substrate that is trapped in the translocation channel. Two of the newly discovered subunits are rhomboid-like proteins, which are essential for growth and mitochondrial protein import. Rhomboid-like proteins were proposed to form the protein translocation pore of the ER-associated degradation system, suggesting that they may contribute to pore formation in the presequence translocase of T. brucei. Pulldown of import-arrested mitochondrial carrier protein shows that the carrier translocase shares eight subunits with the presequence translocase. This indicates that T. brucei may have a single IM translocase that with compositional variations mediates import of presequence-containing and carrier proteins.
Greenland subglacial drainage evolution regulated by weakly connected regions of the bed
Authors: Hoffman Matthew J. , Andrews Lauren C. , Price Stephen F. , Catania Ginny A. , Neumann Thomas A. , Lüthi Martin P. , Gulley Jason , Ryser Claudia , Hawley Robert L. , Morriss Blaine 
Published: December 2016

AbstractPenetration of surface meltwater to the bed of the Greenland Ice Sheet each summer causes an initial increase in ice speed due to elevated basal water pressure, followed by slowdown in late summer that continues into fall and winter. While this seasonal pattern is commonly explained by an evolution of the subglacial drainage system from an inefficient distributed to efficient channelized configuration, mounting evidence indicates that subglacial channels are unable to explain important aspects of hydrodynamic coupling in late summer and fall. Here we use numerical models of subglacial drainage and ice flow to show that limited, gradual leakage of water and lowering of water pressure in weakly connected regions of the bed can explain the dominant features in late and post melt season ice dynamics. These results suggest that a third weakly connected drainage component should be included in the conceptual model of subglacial hydrology.
The spliceosome U2 snRNP factors promote genome stability through distinct mechanisms; transcription of repair factors and R-loop processing
Authors: Tanikawa M , Sanjiv K , Helleday T , Herr P , Mortusewicz O 
Published: December 2016

AbstractRecent whole-exome sequencing of malignancies have detected recurrent somatic mutations in U2 small nuclear ribonucleoprotein complex (snRNP) components of the spliceosome. These factors have also been identified as novel players in the DNA-damage response (DDR) in several genome-wide screens and proteomic analysis. Although accumulating evidence implies that the spliceosome has an important role in genome stability and is an emerging hallmark of cancer, its precise role in DNA repair still remains elusive. Here we identify two distinct mechanisms of how spliceosome U2 snRNP factors contribute to genome stability. We show that the spliceosome maintains protein levels of essential repair factors, thus contributing to homologous recombination repair. In addition, real-time laser microirradiation analysis identified rapid recruitment of the U2 snRNP factor SNRPA1 to DNA-damage sites. Functional analysis of SNRPA1 revealed a more immediate and direct role in preventing R-loop-induced DNA damage. Our present study implies a complex interrelation between transcription, mRNA splicing and the DDR. Cells require rapid spatio-temporal coordination of these chromatin transactions to cope with various forms of genotoxic stress.