bluuebunny/crossref_metadata_2025 huggingface dataset:
Successful experience of rituximab therapy for systemic sclerosis‐associated interstitial lung disease with concomitant systemic lupus erythematosus
Authors: Sumida Hayakazu , Asano Yoshihide , Tamaki Zenshiro , Aozasa Naohiko , Taniguchi Takashi , Takahashi Takehiro , Toyama Tetsuo , Ichimura Yohei , Noda Shinji , Akamata Kaname , Miyazaki Miki , Kuwano Yoshihiro , Yanaba Koichi , Sato Shinichi
Published: May 2014

Previous studies have demonstrated that B cells play critical roles in autoimmune disorders including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). However, the effectiveness of rituximab (RTX), a chimeric anti‐CD20 antibody, for SSc‐associated interstitial lung disease (ILD) or SLE disease activity remains controversial. We herein report an SSc patient with severely progressed ILD and concomitant SLE treated by two cycles of RTX at baseline and half a year later. This treatment improved ILD and SLE activities, along with reduction of dermal sclerosis and serum anti‐topoisomerase I antibody levels. In addition, our detailed time‐course data indicate that half a year may be appropriate as an interval between each cycle of RTX therapy aimed at SSc‐associated ILD or SLE. Overall, the current report could pave the way to establish RTX as a disease‐modifying drug for patients with SSc and/or SLE showing resistance to other already approved medications.
Comparative genome analysis of Pseudomonas knackmussii B13, the first bacterium known to degrade chloroaromatic compounds
Authors: Miyazaki Ryo , Bertelli Claire , Benaglio Paola , Canton Jonas , De Coi Nicoló , Gharib Walid H. , Gjoksi Bebeka , Goesmann Alexander , Greub Gilbert , Harshman Keith , Linke Burkhard , Mikulic Josip , Mueller Linda , Nicolas Damien , Robinson‐Rechavi Marc , Rivolta Carlo , Roggo Clémence , Roy Shantanu , Sentchilo Vladimir , Siebenthal Alexandra Von , Falquet Laurent , van der Meer Jan Roelof
Published: May 2014

Pseudomonas knackmussii B13 was the first strain to be isolated in 1974 that could degrade chlorinated aromatic hydrocarbons. This discovery was the prologue for subsequent characterization of numerous bacterial metabolic pathways, for genetic and biochemical studies, and which spurred ideas for pollutant bioremediation. In this study, we determined the complete genome sequence of B13 using next generation sequencing technologies and optical mapping. Genome annotation indicated that B13 has a variety of metabolic pathways for degrading monoaromatic hydrocarbons including chlorobenzoate, aminophenol, anthranilate and hydroxyquinol, but not polyaromatic compounds. Comparative genome analysis revealed that B13 is closest to Pseudomonas denitrificans and Pseudomonas aeruginosa. The B13 genome contains at least eight genomic islands [prophages and integrative conjugative elements (ICEs)], which were absent in closely related pseudomonads. We confirm that two ICEs are identical copies of the 103 kb self‐transmissible element ICEclc that carries the genes for chlorocatechol metabolism. Comparison of ICEclc showed that it is composed of a variable and a ‘core’ region, which is very conserved among proteobacterial genomes, suggesting a widely distributed family of so far uncharacterized ICE. Resequencing of two spontaneous B13 mutants revealed a number of single nucleotide substitutions, as well as excision of a large 220 kb region and a prophage that drastically change the host metabolic capacity and survivability.
How Macroprudential Financial Regulation Can save Neoliberalism
Authors: Casey Terrence
Published: May 2014

Research Highlights and Abstract

This article

Examines the global financial crisis through the larger lens of the optimal models of growth for the Anglo-American political economies. Offers a concise yet thorough synthesis of two major explanations—the debt-driven growth hypothesis and the financial instability hypothesis—of the global financial crisis. Analyzes substantial empirical evidence for both hypotheses, calling into question the utility of the widely cited debt-driven growth hypothesis. Offers a novel interpretation of how the financial instability hypothesis can in fact be interpreted as showing the potential for stabilizing the neoliberal model of growth through macroprudential financial regulation. Outlines the major elements and institutions of macroprudential regulation and examines both the potential and pitfalls of this approach.

For many, the 2008 global financial crisis (GFC) signaled the end of neoliberalism. This article argues that the crash was less the exhaustion of the free market model as a problem of excessive credit. Focusing on Anglo-American economies, this article explores two competing hypotheses—debt-driven growth and financial instability. The rationale and empirical evidence for both are reviewed, showing that the financial instability hypothesis, with its emphasis on financial (credit) cycles, offers the more compelling explanation. The main flaw of the neoliberal growth model is a tendency for excessive credit growth, producing crashes that wipe out gains in the real economy. The solution is macroprudential financial regulations—broad controls on financial markets to smooth the credit cycle. Implementing macroprudential financial controls could ‘save’ neoliberalism by securing its more robust output while limiting the disruptive financial shocks that serve to undercut that dynamism.
A quantitative study of empty referential subjects in Old English prose and poetry
Authors: Rusten Kristian A.
Published: May 2014

This paper presents a corpus‐based, quantitative investigation of the non‐expression of referential pronominal subjects in a wide selection of Old English prose and poetic texts. The paper demonstrates that ‘empty’ referential subjects are significantly more frequent in Old English poetry as opposed to the prose. This result may contribute to explaining the widely differing assessments found in the literature concerning the grammaticality of empty subjects in Old English. It is also shown for both genres that the occurrence of such subjects correlates with the date of composition and, to a weaker degree, with the translation‐status of the analysed texts. These results weaken Walkden's (2012) dialect‐split hypothesis somewhat, since the asymmetry between West Saxon and Anglian/Anglian‐influenced texts discussed by Walkden may at least partially be explained by the genre, period and translation‐status of the texts. The paper also shows that the differences in frequency between prose and poetry cannot be explained by morphosyntactic factors such as clause type and person/number features, since the empty subjects form similar patterns of distribution across these variables in both genres. It is also argued that verbal agreement cannot explain the occurrence of empty referential subjects in Old English prose or poetry.
Analysis of Trace Metals and Perfluorinated Compounds in 43 Representative Tea Products from South China
Authors: Zheng Hai , Li Jian‐Long , Li Hai‐Hang , Hu Guo‐Cheng , Li Hua‐Shou
Published: May 2014

Six trace metals (Cd, Pb, Cr, Cu, Zn, and Mn) and 2 perfluorinated compounds (PFCs), perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), were analyzed in 43 representative tea products (including 18 green, 12 Oolong, and 13 black teas) from 7 main tea production provinces in China, using the atomic absorption spectrophotometer for trace metals analysis and HPLC‐MS/MS for PFOS and PFOA analysis. The average contents of the 3 essential metals Mn, Cu, and Zn ions in the tea samples were 629.74, 17.75, and 37.38 mg/kg, whereas 3 toxic metals Cd, Cr, and Pb were 0.65, 1.02, and 1.92 mg/kg, respectively. The contents of heavy metals in the 3 types of tea were in the order of black tea > Oolong tea > green tea. Both PFOS and PFOA contents were low and PFOA content was higher than PFOS in the tea samples. The highest concentration of PFOA was 0.25 ng/g dry weight found in a Hunan green tea. The Principal component analysis was performed with the trace metals and PFCs to analyze the relationships of these indices. The results showed that black teas had higher trace metals and PFCs than green and Oolong teas, and the teas from Hunan and Zhejiang provinces had higher Pb and Cr than others.
Optimal auction design in two‐sided markets
Authors: Gomes Renato
Published: May 2014

A key feature of online markets for advertising (e.g., sponsored links) is that clicking rates depend on the searchers' expectations that the platform selects relevant advertisers. This article studies auction design by a platform that maximizes profits in the long run, where clicking rates are mechanism dependent. In line with the practice of the major search engines, the revenue‐maximizing mechanism is a scoring auction that combines the willingness to pay and the relevance to searchers of advertisers. By trading off rent extraction and clicking volume, this mechanism works as a cross‐subsidization device between searchers and advertisers.
Discrete games with flexible information structures: an application to local grocery markets
Authors: Grieco Paul L. E.
Published: May 2014

Game‐theoretic models are frequently employed to study strategic interaction between agents. Empirical research has focused on estimating payoff functions while maintaining strong assumptions regarding the information structure of the game. I show how to relax informational assumptions to enhance the credibility of empirical analysis in discrete games. I apply the method to data on the entry and exit patterns of grocery stores. The model provides useful bounds on equilibrium outcomes. In addition, the empirical analysis indicates that more restrictive informational assumptions can generate qualitatively misleading counterfactual outcomes.
Domain knowledge, ability, and the principal's authority relations
Authors: Levy Nadav
Published: May 2014

I consider how different managerial traits affect the authority relation between a principal and his agent. An increase in the principal's domain knowledge—which enhances his capability to verify the agent's recommendations—leads to an increase in the proportion of the agent's recommendations that are approved, an increase in the agent's initiative, and is unambiguously beneficial to the principal and to the agent. In contrast, an increase in the principal's general ability to explore additional alternatives on his own leads to the principal making a larger proportion of the decisions. This discourages the agent's initiative and can adversely affect the principal.
Tackling the Challenges of Postcrisis Reconstruction in Africa: Lessons from the Field
Authors: Kakonge John O.
Published: May 2014

As more and more of its countries emerge from periods of crisis, the issue of postcrisis reconstruction in Africa is gaining increasing prominence on the international agenda. The passage from crisis to stability and progress is a time‐consuming and potentially open‐ended process. During my career, I worked in two postcrisis African countries – Rwanda and Liberia – and I was also concerned indirectly with conflict situations in other countries. In this article I set out some personal reflections on what I consider to be the key challenges facing governments and civil society in their efforts to deal with the effects and scars of crisis and civil disruption.

In my view, seven factors have a direct bearing on the pace of rebuilding and recovery.
The influence of firm financial position and industry characteristics on capital structure adjustment
Authors: Smith David J. , Chen Jianguo , Anderson Hamish D.
Published: May 2014

We extend Byoun's (2008) modelling of the relationship between deficits and surpluses and adjustment speed, to demonstrate how industry characteristics identified by Kayo and Kimura (2011), including industry concentration, industry munificence and industry dynamism, impact on speed of adjustment. Using New Zealand firms as a case study, we find significant evidence that, as well as firm financial position, industry characteristics also impact on adjustment speed. The firm financial position results are the most robust, and we recommend further research to confirm the nature of the relationship between industry characteristics and the speed at which firms adjust towards target capital structures.
Interventions to reduce tourniquet‐related ischaemic damage in orthopaedic surgery: a qualitative systematic review of randomised trials
Authors: Halladin N. L. , Zahle F. V. , Rosenberg J. , Gögenur I.
Published: May 2014

Ischaemia of the extremity from the use of a tourniquet and the subsequent reperfusion contribute to the release of reactive oxygen species. This release may result in injury to remote organs. We performed a qualitative systematic review exploring the interventions used to prevent tourniquet‐related oxidative damage in adults undergoing orthopaedic surgery, and the possible relationship between biochemical oxidative stress markers and postoperative clinical outcomes. Seventeen randomised controlled studies were included in the qualitative synthesis. Most trials were of low methodological quality and only two studies reported postoperative clinical outcomes. Nine studies tested anaesthetics (propofol, dexmedetomidine, ketamine, and spinal anaesthesia); four studies tested antioxidants (N‐acetyl‐cysteine, vitamin C, and mannitol); and four studies tested ischaemic pre‐conditioning. Fifteen studies showed a significant reduction in biochemical oxidative stress markers. We conclude that propofol and ischaemic pre‐conditioning, in particular, appear to show some benefit at reducing oxidative stress following operations under tourniquet; the correlation between a reduction in oxidative stress and postoperative clinical outcomes should be further investigated in the future.
Evaluation of changes in tidal volume during mask ventilation following administration of neuromuscular blocking drugs
Authors: Sachdeva R. , Kannan T. R. , Mendonca C. , Patteril M.
Published: May 2014

The practice of checking the ability to mask ventilate before administering neuromuscular blocking drugs remains controversial. We prospectively evaluated the changes in the expired tidal volume during pressure‐controlled ventilation (two‐handed mask ventilation technique) as a surrogate marker to assess the ease of mask ventilation following administration of rocuronium. After informed consent, 125 patients were anaesthetised using a standard induction technique consisting of fentanyl, propofol and rocuronium, with anaesthesia then maintained with isoflurane in oxygen. The mean (SD) expired tidal volume before administration of rocuronium increased by 61 (13) ml at 2 min following onset of neuromuscular block (p < 0.001). This supports the concept that neuromuscular blockade induced by rocuronium facilitates mask ventilation.
Comparative efficacy and safety of the Ambu® AuraOnce™ laryngeal mask airway during general anaesthesia in adults: a systematic review and meta‐analysis
Authors: Baidya D. K. , Chandralekha  , Darlong V. , Pandey R. , Maitra S. , Khanna P.
Published: May 2014

Previous comparisons between the Ambu® AuraOnce™ and other laryngeal mask airways have revealed different results across various clinical studies. We aimed to perform a systematic review with meta‐analysis on the efficacy and safety of the AuraOnce compared with other laryngeal mask airways for airway maintenance in adults undergoing general anaesthesia. Our search of PubMed, PubMed Central, Scopus and the Central Register of Clinical Trials of the Cochrane Collaboration yielded nine randomised controlled trials eligible for inclusion. Comparator laryngeal mask airways were the LMA Unique™ (four trials), the LMA Classic® (five trials) and the Portex® Soft Seal® (three trials). The AuraOnce provided an oropharyngeal leak pressure higher than the LMA Unique (304 participants, mean (95% CI) difference 3.1 (1.6–4.7) cmH2O, p < 0.0001) and equivalent to the LMA Classic. The Soft Seal provided a higher leak pressure than the AuraOnce (229 participants, mean (95% CI) difference 3.5 (0.4–6.7) cmH2O, p = 0.03). Insertion was significantly faster with the AuraOnce than the LMA Unique (304 participants, mean (95% CI) difference 5.4 (2.1–8.71) s, p = 0.001) and Soft Seal (229 participants, mean (95% CI) difference 9.5 (3.0–15.9) s, p = 0.004), but similar to the LMA Classic. The first‐insertion success rate of the AuraOnce was equivalent to the LMA Unique, LMA Classic and Soft Seal. We found a higher likelihood of bloodstaining on the cuff with the Soft Seal and a higher incidence of sore throat with the LMA Classic. We conclude that the AuraOnce is an effective alternative to the LMA Classic and LMA Unique, and easier to insert than all three other devices studied.
Circulating anti‐retinal antibodies in response to anti‐angiogenic therapy in exudative age‐related macular degeneration
Authors: Kubicka‐Trząska Agnieszka , Wilańska Joanna , Romanowska‐Dixon Bożena , Sanak Marek
Published: May 2014

Purpose

To determine changes in anti‐retinal antibodies (ARAs) during anti‐VEGF therapy in patients with exudative age‐related macular degeneration (AMD) and to assess the correlations between ARAs and disease activity.

Methods

The study comprised 98 patients treated with intravitreal bevacizumab. The ophthalmic examination included best corrected visual acuity (BCVA), slit lamp biomicroscopy, fundoscopy, fluorescein angiography (FA), and optical coherence tomography (OCT). Serum ARAs levels were assessed by indirect immunofluorescence (IIF) on normal monkey retina substrate. These studies were repeated at 4 week intervals within 8 months of a follow‐up. The sera of 50 sex‐ and age‐matched healthy subjects were used as controls.

Results

At baseline examination, 94 (95.5%) of the 98 patients were positive for ARAs. The ARAs titres were significantly higher (p = 0.0000) than in controls. A positive correlation was found between titres of ARAs and the diameter of choroidal neovascularization (CNV) as measured by FA (p = 0.0000), and central retinal thickness (CRT) assessed by OCT (p = 0.0000). A positive correlation was also found between the diameter of CNV, CRT and the complexity of circulating ARAs. Following treatment all patients demonstrated significant decrease in ARAs levels as well as improvement of BCVA, reduction of subretinal fluid on OCT and decreased leakage on FA.

Conclusion

Changes in serum ARAs levels occurred in parallel with clinical outcomes of anti‐VEGF therapy. Treatment reduced serum levels of ARAs, with the greatest reduction occurring during the ‘loading’ phase. This study demonstrated that ARAs may act as a serum biomarker of the efficacy of anti‐VEGF therapy.
Antihypertensive agents acting on the renin–angiotensin system and the risk of sepsis
Authors: Dial Sandra , Nessim Sharon J. , Kezouh Abbas , Benisty Jacques , Suissa Samy
Published: May 2014

Aims

In response to safety concerns from two large randomized controlled trials, we investigated whether the use of telmisartan, an angiotensin receptor blocker (ARB), ARBs as a class and angiotensin‐converting enzyme inhibitors (ACEIs) increase the risk of sepsis, sepsis‐associated mortality and renal failure in hypertensive patients.

Methods

We performed a nested case–control study from a retrospective cohort of adults with hypertension from the UK General Practice Research Database diagnosed between 1 January 2000 and 30 June 2009. All subjects hospitalized with sepsis during follow‐up were matched for age, sex, practice and duration of follow‐up with 10 control subjects. Exposure was defined as current use of antihypertensive drugs.

Results

From the cohort of 550 436 hypertensive patients, 1965 were hospitalized with sepsis during follow‐up (rate 6.9 per 10 000 per year), of whom 824 died and 346 developed acute renal failure within 30 days. Compared with use of β‐blockers, calcium‐channel blockers or diuretics, use of ARBs, including telmisartan, was not associated with an elevated risk of sepsis (relative risk 1.09; 95% confidence interval 0.83–1.43); but use ACEIs was (relative risk 1.65; 95% confidence interval 1.42–1.93). Users of ARBs, β‐blockers, calcium‐channel blockers or diuretics, but not users of ACEIs, had lower rates of hospitalization for sepsis compared with untreated hypertensive patients. Findings were similar for sepsis‐related 30 day mortality and renal failure.

Conclusions

Hypertensive patients treated with ARBs, including telmisartan, do not appear to be at increased risk of sepsis or sepsis‐related 30 day mortality or renal failure. On the contrary, users of ACEIs may have an increased risk.
Alpha‐thalassemia intellectual disability: variable phenotypic expression among males with a recurrent nonsense mutation – c.109C>T (p.R37X)
Authors: Basehore M.J. , Michaelson‐Cohen R. , Levy‐Lahad E. , Sismani C. , Bird L.M. , Friez M.J. , Walsh T. , Abidi F. , Holloway L. , Skinner C. , McGee S. , Alexandrou A. , Syrrou M. , Patsalis P.C. , Raymond G. , Wang T. , Schwartz C.E. , King M.‐C. , Stevenson R.E.
Published: May 2014

Alpha‐thalassemia intellectual disability, one of the recognizable X‐linked disability syndromes, is characterized by short stature, microcephaly, distinctive facies, hypotonic appearance, cardiac and genital anomalies, and marked skewing of X‐inactivation in female carriers. With the advent of next generation sequencing, mutations have been identified that result in less severe phenotypes lacking one or more of these phenotypic manifestations. Here we report five unrelated kindreds in which a c.109C>T (p.R37X) mutation segregates with a variable but overall milder phenotype. The distinctive facial appearance of alpha‐thalassemia intellectual disability was present in only one of the 18 affected males evaluated beyond the age of puberty, although suggestive facial appearance was present in several during infancy or early childhood. Although the responsible genetic alteration is a nonsense mutation in exon 2 of ATRX, the phenotype appears to be partially rescued by the production of alternative transcripts and/or other molecular mechanisms.
The intra‐operative incidence of Fallopian canal dehiscence during surgery for cholesteatoma: a prospective case–control study and review of the literature
Authors: Trinidade A. , Yung M.W.
Published: May 2014

Objective

To investigate Fallopian canal dehiscence (FCD) during cholesteatoma surgery.

Study design

Prospective case–control study.

Patients

Four hundred and one patients with cholesteatoma and 172 with otosclerosis.

Interventions

Therapeutic.

Setting

District general hospital.

Main outcome measures

(i) Intra‐operative incidence of FCD during (a) surgery for cholesteatoma versus a homogeneous control group (patients with otosclerosis); (b) revision surgery for cholesteatoma as compared to primary surgery. (ii) Intra‐operative incidence of a fistula if FCD is present.

Results

Data were prospectively collected and analysed using chi‐square tests. FCD was found in 19% of cases versus 5.2% of controls. Intra‐operative incidence of (i) FCD during cholesteatoma surgery versus otosclerosis surgery was statistically very highly significant (P < 0.0001, OR = 5.43); (ii) FCD during revision versus primary cholesteatoma surgery was not statistically significant (P = 0.83); and (iii) encountering a fistula in the presence of FCD during cholesteatoma surgery was statistically very highly significant (P < 0.0001, OR = 6.71).

Conclusions

A surgeon is more likely to encounter FCD during cholesteatoma surgery than in stapes surgery. If during cholesteatoma surgery FCD is found, then a fistula is also more likely to be present, mainly of the semicircular canal. The incidence of FCD is not increased in revision surgery. These findings are very relevant for any otologist undertaking cholesteatoma surgery.
Frequent Stock Repurchases, False Signaling, and Corporate Governance: Evidence from Korea
Authors: Han Seung Hun , Lee Bong‐Soo , Song Minji
Published: May 2014

Manuscript Type

Empirical

Research Question/Issue

We examine the relation between stock repurchases and their potential false signaling of undervaluation using unique Korean data.

Research Findings/Insights

We find that the firms that repurchase stocks frequently are less undervalued and have lower post‐announcement operating performance than firms that repurchase stocks infrequently. We further find that agency cost and industry‐adjusted Tobin's Q of frequent repurchase firms negatively affect abnormal returns from the repurchase announcement. Corporate governance, especially ownership structure and board independence, affects the probability of frequent signaling.

Theoretical/Academic Implications

Our results suggest that the main motivation for frequent stock repurchases is likely to be false signaling, and that corporate governance can mitigate false signaling caused by agency cost.

Practitioner/Policy Implications

Frequent stock repurchases are not necessarily motivated by firm undervaluation. Rather, the degree of agency problems and managers' abuse of information asymmetry tend to increase the frequency of stock repurchases. Therefore, frequent stock repurchases are associated with false signaling by managers; this false signaling can be lowered through better corporate governance. This finding supports the monitoring effect of corporate governance systems.
Support for the stability of the Alberta Infant Motor Scale after ‘back‐to‐sleep’
Authors: Vargus‐Adams Jilda
Published: May 2014

This commentary is on the original article by Darrah et al. on pages 877–881 of this issue.
Variations in the quality and sustainability of long‐term glycaemic control with continuous subcutaneous insulin infusion
Authors: Nixon R. , Folwell R. , Pickup J. C.
Published: May 2014

Aims

To investigate the pattern of changes in HbA1c in people with Type 1 diabetes managed by long‐term Continuous subcutaneous insulin infusion.

Methods

We studied HbA1c changes using computerized clinic records in 35 adult people with Type 1 diabetes and an elevated HbA1c (≥ 64 mmol/mol, 8.0%) on multiple daily insulin injections, who were then switched to continuous subcutaneous insulin infusion for at least 5 years.

Results

We identified three subgroups with similar baseline HbA1c but different long‐term responses to pump therapy: group A—those with improvement followed by deterioration (57%); group B—those with improvement that was sustained throughout the 5 years (31%); and group C—those where HbA1c did not change significantly from baseline (12%). The patients in group C had a higher BMI: 31.0 ± 5.2 vs. 25.9 ± 3.3 vs. 25.2 ± 3.1 kg/m2 (group C vs. group A and group B; P = 0.02).

Conclusions

Improved glycaemic control with continuous subcutaneous insulin infusion was maintained over 5 years by 88% of people with Type 1 diabetes in this study, but there were variations in the long‐term efficacy, with some people improving and worsening, others maintaining strict control and a few subcutaneous insulin infusion ‘non‐responders’.
Mesenchymal stem cell therapies: the quest for fine‐tuning
Authors: Goodrich Angelina Daisy , Hematti Peiman
Published: May 2014

Mesenchymal stem cells (MSCs) have a vastly unharnessed therapeutic potential with close to 400 studies currently registered on clinicaltrials.gov for evaluation of their clinical promises. While many of these investigations are for immune‐mediated disorders, there is no established consensus on how to optimize the immunomodulatory properties of MSCs. Factors that could be used to predict efficacy of MSC therapies include donor heterogeneity, recipient environment and drug interactions. Incorporating pertinent quality control parameters to maximize the clinical potential of MSCs through good manufacturing practice (GMP) production of clinical grade cells could lead to the realization of greater therapeutic success.
Influenza A viral nucleoprotein interacts with cytoskeleton scaffolding protein α‐actinin‐4 for viral replication
Authors: Sharma Shipra , Mayank Adarsh K. , Nailwal Himani , Tripathi Shashank , Patel Jenish R. , Bowzard John B. , Gaur Pratibha , Donis Ruben O. , Katz Jacqueline M. , Cox Nancy J. , Lal Renu B. , Farooqi Humaira , Sambhara Suryaprakash , Lal Sunil K.
Published: May 2014

Influenza A virus (IAV), similar to other viruses, exploits the machinery of human host cells for its survival and replication. We identified α‐actinin‐4, a host cytoskeletal protein, as an interacting partner of IAV nucleoprotein (NP). We confirmed this interaction using co‐immunoprecipitation studies, first in a coupled in vitro transcription‐translation assay and then in cells either transiently co‐expressing the two proteins or infected with whole IAV. Importantly, the NP–actinin‐4 interaction was observed in several IAV subtypes, including the 2009 H1N1 pandemic virus. Moreover, immunofluorescence studies revealed that both NP and actinin‐4 co‐localized largely around the nucleus and also in the cytoplasmic region of virus‐infected A549 cells. Silencing of actinin‐4 expression resulted in not only a significant decrease in NP, M2 and NS1 viral protein expression, but also a reduction of both NP mRNA and viral RNA levels, as well as viral titers, 24 h post‐infection with IAV, suggesting that actinin‐4 was critical for viral replication. Furthermore, actinin‐4 depletion reduced the amount of NP localized in the nucleus. Treatment of infected cells with wortmannin, a known inhibitor of actinin‐4, led to a decrease in NP mRNA levels and also caused the nuclear retention of NP, further strengthening our previous observations. Taken together, the results of the present study indicate that actinin‐4, a novel interacting partner of IAV NP, plays a crucial role in viral replication and this interaction may participate in nuclear localization of NP and/or viral ribonucleoproteins.

Structured digital abstract

•NP physically interacts with actinin-4 by anti bait coimmunoprecipitation (1, 2)•NP and actnin-4 colocalize by fluorescence microscopy (View interaction)•NP physically interacts with actinin-4 by anti bait coimmunoprecipitation (View interaction)•NP binds to actinin-4 by anti tag coimmunoprecipitation (1, 2)•NP physically interacts with actinin-4 by anti bait coimmunoprecipitation (View interaction)•NP physically interacts with actinin-4 by anti tag coimmunoprecipitation (View interaction)•NP physically interacts with actinin-4 by anti bait coimmunoprecipitation (View interaction) •NP physically interacts with actinin-4 by anti bait coimmunoprecipitation (View interaction) •NP physically interacts with actinin-4 by two hybrid (1, 2) •NP physically interacts with actinin-4 by anti bait coimmunoprecipitation (View interaction)
The hydrophobic contacts between the center of the βI domain and the α1/α7 helices are crucial for the low‐affinity state of integrin α4β7
Authors: Liu Jie , Fu Ting , Peng Bo , Sun Hao , Chu HuiYing , Li GuoHui , Chen JianFeng
Published: May 2014

Integrin α4β7 mediates both rolling and firm adhesion of lymphocytes by modulating its affinity to the ligand: mucosal addressin cell adhesion molecule‐1 (MAdCAM‐1). Integrin activation is associated with allosteric reshaping in the β subunit I (βI) domain. A prominently conformational change comprises displacement of the α1 and α7 helices in the βI domain, suggesting that the location of these helices is important for the change in integrin affinity. In the present study, we report that the hydrophobic contacts between the center of the β7I domain and the α1/α7 helices play critical roles in keeping α4β7 in a low‐affinity state. Using molecular dynamics simulation, we identified nine hydrophobic residues that might be involved in the critical hydrophobic contacts maintaining integrin in a low‐affinity state. Integrin β7I domain exhibited a lower binding free energy for ligand after disrupting these hydrophobic contacts by substituting the hydrophobic residues with Ala. Moreover, these α4β7 mutants not only showed high‐affinity binding to soluble MAdCAM‐1, but also demonstrated firm cell adhesion to immobilized MAdCAM‐1 in shear flow and enhanced the strength of the α4β7–MAdCAM‐1 interaction. Disruption of the hydrophobic contacts also induced the active conformation of α4β7. Thus, the findings obtained in the present study reveal an important structural basis for the low‐affinity state of integrin.
The electrostatic interactions of relaxin‐3 with receptor RXFP4 and the influence of its B‐chain C‐terminal conformation
Authors: Wang Xin‐Yi , Guo Yu‐Qi , Zhang Wei‐Jie , Shao Xiao‐Xia , Liu Ya‐Li , Xu Zeng‐Guang , Guo Zhan‐Yun
Published: May 2014

Relaxin‐3 (also known as insulin‐like peptide 7) is an insulin/relaxin‐superfamily peptide hormone that can bind and activate three relaxin‐family peptide receptors: RXFP3, RXFP4, and RXFP1. Recently, we identified key electrostatic interactions between relaxin‐3 and its cognate receptor RXFP3 by using a charge‐exchange mutagenesis approach. In the present study, the electrostatic interactions between relaxin‐3 and RXFP4 were investigated with the same approach. Mutagenesis of the negatively charged extracellular residues of human RXFP4 identified a conserved EXXXD(100–104) motif that is essential for RXFP4 activation by relaxin‐3. Mutagenesis of the conserved positively charged Arg residues of relaxin‐3 demonstrated that B12Arg, B16Arg and B26Arg were all involved in the binding and activation of RXFP4, especially B26Arg. The activity complementation between the mutant ligands and the mutant receptors suggested two probable electrostatic interaction pairs: Glu100 of RXFP4 versus B26Arg of relaxin‐3, and Asp104 of RXFP4 versus both B12Arg and B16Arg of relaxin‐3. For interaction with the essential EXXXD motifs of both RXFP3 and RXFP4, a folding‐back conformation of the relaxin‐3 B‐chain C‐terminus seems to be critical, because it brings B26Arg sufficiently close to B12Arg and B16Arg. To test this hypothesis, we replaced the conserved B23Gly‐B24Gly dipeptide of relaxin‐3 with an Ala‐Ser dipeptide that occupied the corresponding position of insulin‐like peptide 5 and resulted in an extended helical conformation. The mutant relaxin‐3 showed a significant decrease in receptor‐activation potency towards both RXFP3 and RXFP4, suggesting that a folding‐back conformation of the B‐chain C‐terminus was important for relaxin‐3 to efficiently interact with the EXXXD motifs of both receptors.

Structured digital abstract

RXFP4 and relaxin-3 physically interact by competition binding (1, 2, 3, 4, 5, 6, 7, 8, 9)
Flow regulation by dams affects ecosystem metabolism in Mediterranean rivers
Authors: Aristi Ibon , Arroita Maite , Larrañaga Aitor , Ponsatí Lydia , Sabater Sergi , von Schiller Daniel , Elosegi Arturo , Acuña Vicenç
Published: May 2014

Large dams regulate river hydrology and influence water chemistry, sediment dynamics, channel form and biotic communities. These effects may translate into important changes in river ecosystem processes, especially in rivers naturally subject to strong seasonality, such as those under Mediterranean climate.

The effects of flow regulation on ecosystem metabolism [i.e. gross primary production (GPP) and ecosystem respiration (ER)] were analysed by means of open‐stream measurements. Organic matter accrual and metabolism were measured in reaches upstream and downstream from large reservoirs in three tributaries of the Ebro River (NE Iberian Peninsula) during three sampling campaigns.

Dams reduced downstream hydrological variability, dampened floods and increased the duration of interflood periods. Benthic organic matter increased twofold and chlorophyll‐a eightfold. GPP increased by 59% on average, whereas ER increased by 75%.

In general, flow regulation intensified the capacity of downstream river reaches to store and process materials and energy, therefore increasing the amount of organic carbon processed and altering the whole flux of materials and energy along the river continuum.
Enkephalin knockout male mice are resistant to chronic mild stress
Authors: Melo I. , Drews E. , Zimmer A. , Bilkei‐Gorzo A.
Published: May 2014

Enhanced stress reactivity or sensitivity to chronic stress increases the susceptibility to mood pathologies such as major depression. The opioid peptide enkephalin is an important modulator of the stress response. Previous studies using preproenkephalin knockout (PENK KO) mice showed that these animals exhibit abnormal stress reactivity and show increased anxiety behavior in acute stress situations. However, the consequence of enkephalin deficiency in the reactivity to chronic stress conditions is not known. In this study, we therefore submitted wild‐type (WT) and PENK KO male mice to chronic stress conditions, using the chronic mild stress (CMS) protocol. Subsequently, we studied the CMS effects on the behavioral and hormonal level and also performed gene expression analyses. In WT animals, CMS increased the expression of the enkephalin gene in the paraventricular nucleus (PVN) of the hypothalamus and elevated the corticosterone levels. In addition, WT mice exhibited enhanced anxiety in the zero‐maze test and depression‐related behaviors in the sucrose preference and forced swim tests. Surprisingly, in PENK KO mice, we did not detect anxiety and depression‐related behavioral changes after the CMS procedure, and even measured a decreased hormonal stress response. These results indicate that PENK KO mice are resistant to the CMS effects, suggesting that enkephalin enhances the reactivity to chronic stress.
Physiological, biochemical, and genome‐wide transcriptional analysis reveals that elevated CO2 mitigates the impact of combined heat wave and drought stress in Arabidopsis thaliana at multiple organizational levels
Authors: Zinta Gaurav , AbdElgawad Hamada , Domagalska Malgorzata A. , Vergauwen Lucia , Knapen Dries , Nijs Ivan , Janssens Ivan A. , Beemster Gerrit T.S. , Asard Han
Published: May 2014

Climate changes increasingly threaten plant growth and productivity. Such changes are complex and involve multiple environmental factors, including rising CO2 levels and climate extreme events. As the molecular and physiological mechanisms underlying plant responses to realistic future climate extreme conditions are still poorly understood, a multiple organizational level analysis (i.e. eco‐physiological, biochemical, and transcriptional) was performed, using Arabidopsis exposed to incremental heat wave and water deficit under ambient and elevated CO2. The climate extreme resulted in biomass reduction, photosynthesis inhibition, and considerable increases in stress parameters. Photosynthesis was a major target as demonstrated at the physiological and transcriptional levels. In contrast, the climate extreme treatment induced a protective effect on oxidative membrane damage, most likely as a result of strongly increased lipophilic antioxidants and membrane‐protecting enzymes. Elevated CO2 significantly mitigated the negative impact of a combined heat and drought, as apparent in biomass reduction, photosynthesis inhibition, chlorophyll fluorescence decline, H2O2 production, and protein oxidation. Analysis of enzymatic and molecular antioxidants revealed that the stress‐mitigating CO2 effect operates through up‐regulation of antioxidant defense metabolism, as well as by reduced photorespiration resulting in lowered oxidative pressure. Therefore, exposure to future climate extreme episodes will negatively impact plant growth and production, but elevated CO2 is likely to mitigate this effect.
Recombinant factorIX: discrepancies between one‐stage clotting and chromogenic assays
Authors: Wilmot H. V. , Hogwood J. , Gray E.
Published: May 2014

New and modified recombinant factor IX (rFIX) products are in development and accurate potency estimation is important to ensure the consistency of production and efficacy of these therapeutics. Collaborative study data obtained during the replacement of the 3rd International Standard (IS) for FIX concentrate suggested that there was a discrepancy between potency estimates forrFIXusing clotting and chromogenic methods, when therFIXcandidate was measured against the plasma‐derived FIX (pdFIX) IS. This study explores potential chromogenic and one‐stage clotting method discrepancies in more detail. Five batches each ofrFIXand pdFIX were assayed against the 4th IS FIX concentrate (a pdFIX) by activated partial thromboplastin time (APTT) one‐stage clotting assay and specific functional chromogenic assay. The potency ofrFIXby chromogenic assay was consistently around 70% of the one‐stage clotting potency (average 78 and 108 IU mL−1respectively). These differences were not observed with pdFIX, which had similar potencies (average 96 IU mL−1) by each assay method. In addition, different APTT reagents yielded different potency estimates forrFIXwhen assayed against the pdFIX IS, with a variation of up to 23%. In all cases, the differences were largely resolved when arFIXreference was used as the standard. This study highlights some of the challenges associated with assay ofrFIXproducts in the laboratory and that careful consideration needs to be given to the choice of reference material used. This is especially important with the imminent arrival of new and modifiedrFIXproducts.
An efficient system for secretory production of fibrinogen using a hepatocellular carcinoma cell line
Authors: Matsumoto Michinori , Matsuura Tomokazu , Aoki Katsuhiko , Maehashi Haruka , Iwamoto Takeo , Ohkawa Kiyoshi , Yoshida Kiyotsugu , Yanaga Katsuhiko , Takada Koji
Published: May 2014

Aim

Despite an increasing demand, blood products are not always safe because most are derived from blood donations. One possible solution is the development and commercialization of recombinant fibrinogen, but this process remains poorly developed. This study aimed to develop an effective production system for producing risk‐free fibrinogen using human hepatocellular cell lines and serum‐free media.

Methods

Three human liver cancer cell lines (HepG2, FLC‐4 and FLC‐7) were cultivated in a serum‐supplemented medium or two serum‐free media (ASF104N and IS‐RPMI) to compare their fibrinogen secretion abilities. Fibrinogen subunit gene expression was estimated by quantitative polymerase chain reaction. Massive fibrinogen production was induced using a 5‐mL radial flow bioreactor (RFB) while monitoring glucose metabolism. Subsequently, fibrinogen's biochemical characteristics derived from these cells were analyzed.

Results

FLC‐7 cell culture combined with IS‐RPMI resulted in significantly better fibrinogen production (21.6 μg/107 cells per day). ASF104N had more positive effects on cell growth compared with IS‐RPMI, whereas fibrinogen production was more efficient with IS‐RPMI than with ASF104N. Changing the medium from ASF104N to IS‐RPMI led to significantly increased fibrinogen gene expression and glucose consumption. In the RFB culture, the fibrinogen secretion rate of FLC‐7 cells reached 0.73 μg/mL per day during a 42‐day cultivation period. The subunit composition and clot formation activity of FLC‐7 cell‐derived fibrinogen corresponded to those of plasma fibrinogen.

Conclusion

The FLC‐7 cell culture system is suitable for large‐scale fibrinogen preparation production.
The ‘Golden Age of Historiography’: Records and Writers in the Reign of Henry II
Authors: Hosler John D.
Published: May 2014

The study of the reign of King Henry II of England (1154‐1189) has been vibrant since the 19th century. As sources for his reign have been discovered, edited and printed, a host of scholars have attempted to assess his impact upon medieval diplomacy, law, politics, and warfare. The array of narrative texts, record documents, and financial records, however, is dizzying in both number and size and can be confusing for non‐specialists. Sorting through the sources by type, as well as situating them within a historiographical context, is a necessary first step towards a fuller understanding of the modern scholarship.
The Ottoman Economy, c.1300‐c.1585
Authors: Fleet Kate
Published: May 2014

This article examines the Ottoman economy from the rise of the state in around 1300 to the major debasement of c.1585. After a brief assessment of the problems of sources and an overview of the economy, it investigates the nature of the Ottoman economy, considering the model proposed by Mehmet Genç based on provisionalism, traditionalism and fiscalism, and arguing that what characterised the early Ottoman economy was decentralisation, regional diversity and the pragmatic application of control.
Salivary duct carcinoma and the concept of early carcinoma ex pleomorphic adenoma
Authors: Griffith Christopher C , Thompson Lester D R , Assaad Adel , Purgina Bibianna M , Lai Chi , Bauman Julie E , Weinreb Ilan , Seethala Raja R , Chiosea Simion I
Published: May 2014

Aims

The data on the histological type of carcinomatous component and the extent of extracapsular invasion for salivary carcinomas ex pleomorphic adenoma (PA) are conflicting. We aimed to determine the prognostic value of extracapsular invasion in salivary duct carcinomas (SDC) ex PA.

Methods and results

A total of 117 patients with SDC were identified retrospectively; 44 cases involving major salivary glands had pre‐existing PA (44 of 117, 37%). The morphological spectrum of SDC ex PA was characterized. The primary endpoint was overall survival (OS). Most SDC ex PA were widely invasive at presentation (27 of 44; 61%). Five patients with intracapsular SDC ex PA experienced no disease progression. The assessment of extracapsular invasion was precluded in eight cases (e.g. positive margins of resection). The rate of lymph node involvement was similar in cases with extracapsular invasion of ≤2 mm (two of three) and >7 mm (22 of 26). Only pT correlated with OS [116 months, 95% confidence interval (CI) 22–210 months for pT1 versus 20 months (95% CI 6–34) for pT4; P = 0.013].

Conclusions

Intracapsular SDC ex PA are potentially indolent. SDC ex PA with extracapsular invasion of ≤2 mm are rare, and appear to be clinically aggressive. Several histological parameters preclude assessment of extracapsular invasion.
Raman Micro‐Spectroscopy of Polytype and Structural Changes in 6H‐Silicon Carbide due to Machining
Authors: Groth Benjamin , Haber Richard , Mann Adrian
Published: May 2014

SiC is an important structural ceramic with many polytypes that differ by the stacking of their crystal planes. Machining mechanically deforms the structure giving stacking faults and different polytypes. This can lead to inferior performance and an increased risk of failure. Raman micro‐spectroscopy with different wavelengths, in confocal and normal settings, was used to quantify machining damage. Changes in the ratio of characteristic peaks, peak intensities versus peak positions, and additional Raman peaks were found. These are due to statistical increases in stacking faults and new phases (4H and 3C). The damage is found to extend several micrometer subsurfaces.