bluuebunny/crossref_metadata_2025 huggingface dataset:
Single molecule dynamics in a virtual cell: a three-dimensional model that produces simulated fluorescence video-imaging data
Authors: Mashanov Gregory I.
Published: July 2014

The analysis of single molecule imaging experiments is complicated by the stochastic nature of single molecule events, by instrument noise and by the limited information which can be gathered about any individual molecule observed. Consequently, it is important to cross check experimental results using a model simulating single molecule dynamics (e.g. movements and binding events) in a virtual cell-like environment. The output of such a model should match the real data format allowing researchers to compare simulated results with the real experiments. The proposed model exploits the advantages of ‘object-oriented’ computing. First of all, the ability to create and manipulate a number of classes, each containing an arbitrary number of single molecule objects. These classes may include objects moving within the ‘cytoplasm’; objects moving at the ‘plasma membrane’; and static objects located inside the ‘body’. The objects of a given class can interact with each other and/or with the objects of other classes according to their physical and chemical properties. Each model run generates a sequence of images, each containing summed images of all fluorescent objects emitting light under given illumination conditions with realistic levels of noise and emission fluctuations. The model accurately reproduces reported single molecule experiments and predicts the outcome of future experiments.
Three-dimensional flow and lift characteristics of a hovering ruby-throated hummingbird
Authors: Song Jialei , Luo Haoxiang , Hedrick Tyson L.
Published: July 2014

A three-dimensional computational fluid dynamics simulation is performed for a ruby-throated hummingbird (
Archilochus colubris
) in hovering flight. Realistic wing kinematics are adopted in the numerical model by reconstructing the wing motion from high-speed imaging data of the bird. Lift history and the three-dimensional flow pattern around the wing in full stroke cycles are captured in the simulation. Significant asymmetry is observed for lift production within a stroke cycle. In particular, the downstroke generates about 2.5 times as much vertical force as the upstroke, a result that confirms the estimate based on the measurement of the circulation in a previous experimental study. Associated with lift production is the similar power imbalance between the two half strokes. Further analysis shows that in addition to the angle of attack, wing velocity and surface area, drag-based force and wing–wake interaction also contribute significantly to the lift asymmetry. Though the wing–wake interaction could be beneficial for lift enhancement, the isolated stroke simulation shows that this benefit is buried by other opposing effects, e.g. presence of downwash. The leading-edge vortex is stable during the downstroke but may shed during the upstroke. Finally, the full-body simulation result shows that the effects of wing–wing interaction and wing–body interaction are small.
Decoupling of plane waves in porous piezoelectric materials
Authors: Vashishth Anil K. , Gupta Vishakha
Published: July 2014

In this paper, the analytical and numerical studies of two-dimensional wave propagation in porous piezoelectric materials (PPMs) are carried out. The decoupling of waves, in such materials for various crystal classes, is studied analytically for different coordinate planes. It is found that, for wave propagation in a plane, the system is decoupled in some crystal classes, whereas it remains coupled in other crystal classes. It is established that the decoupled pure-shear wave, propagating in a PPM, can be stiffened or unstiffened with piezoelectric effects even if the PPM belongs to the same symmetry group but has a different crystal class. The skewing angles and mutual angles between the polarization directions of different waves are also computed numerically.
A novel hypothesis for the adaptive maintenance of environmental sex determination in a turtle
Authors: Spencer R.-J. , Janzen F. J.
Published: July 2014

Temperature-dependent sex determination (TSD) is widespread in reptiles, yet its adaptive significance and mechanisms for its maintenance remain obscure and controversial. Comparative analyses identify an ancient origin of TSD in turtles, crocodiles and tuatara, suggesting that this trait should be advantageous in order to persist. Based on this assumption, researchers primarily, and with minimal success, have employed a model to examine sex-specific variation in hatchling phenotypes and fitness generated by different incubation conditions. The unwavering focus on different incubation conditions may be misplaced at least in the many turtle species in which hatchlings overwinter in the natal nest. If overwintering temperatures differentially affect fitness of male and female hatchlings, TSD might be maintained adaptively by enabling embryos to develop as the sex best suited to those overwintering conditions. We test this novel hypothesis using the painted turtle (Chrysemys picta), a species with TSD in which eggs hatch in late summer and hatchlings remain within nests until the following spring. We used a split-clutch design to expose field-incubated hatchlings to warm and cool overwintering (autumn–winter–spring) regimes in the laboratory and measured metabolic rates, energy use, body size and mortality of male and female hatchlings. While overall mortality rates were low, males exposed to warmer overwintering regimes had significantly higher metabolic rates and used more residual yolk than females, whereas the reverse occurred in the cool temperature regime. Hatchlings from mixed-sex nests exhibited similar sex-specific trends and, crucially, they were less energy efficient and grew less than same-sex hatchlings that originated from single-sex clutches. Such sex- and incubation-specific physiological adaptation to winter temperatures may enhance fitness and even extend the northern range of many species that overwinter terrestrially.
Global variation in thermal tolerances and vulnerability of endotherms to climate change
Authors: Khaliq Imran , Hof Christian , Prinzinger Roland , Böhning-Gaese Katrin , Pfenninger Markus
Published: July 2014

The relationships among species' physiological capacities and the geographical variation of ambient climate are of key importance to understanding the distribution of life on the Earth. Furthermore, predictions of how species will respond to climate change will profit from the explicit consideration of their physiological tolerances. The climatic variability hypothesis, which predicts that climatic tolerances are broader in more variable climates, provides an analytical framework for studying these relationships between physiology and biogeography. However, direct empirical support for the hypothesis is mostly lacking for endotherms, and few studies have tried to integrate physiological data into assessments of species' climatic vulnerability at the global scale. Here, we test the climatic variability hypothesis for endotherms, with a comprehensive dataset on thermal tolerances derived from physiological experiments, and use these data to assess the vulnerability of species to projected climate change. We find the expected relationship between thermal tolerance and ambient climatic variability in birds, but not in mammals—a contrast possibly resulting from different adaptation strategies to ambient climate via behaviour, morphology or physiology. We show that currently most of the species are experiencing ambient temperatures well within their tolerance limits and that in the future many species may be able to tolerate projected temperature increases across significant proportions of their distributions. However, our findings also underline the high vulnerability of tropical regions to changes in temperature and other threats of anthropogenic global changes. Our study demonstrates that a better understanding of the interplay among species' physiology and the geography of climate change will advance assessments of species' vulnerability to climate change.
Closely Related NAC Transcription Factors of Tomato Differentially Regulate Stomatal Closure and Reopening during Pathogen Attack
Authors: Du Minmin , Zhai Qingzhe , Deng Lei , Li Shuyu , Li Hongshuang , Yan Liuhua , Huang Zhuo , Wang Bao , Jiang Hongling , Huang Tingting , Li Chang-Bao , Wei Jianing , Kang Le , Li Jingfu , Li Chuanyou
Published: July 2014

To restrict pathogen entry, plants close stomata as an integral part of innate immunity. To counteract this defense, Pseudomonas syringae pv tomato produces coronatine (COR), which mimics jasmonic acid (JA), to reopen stomata for bacterial entry. It is believed that abscisic acid (ABA) plays a central role in regulating bacteria-triggered stomatal closure and that stomatal reopening requires the JA/COR pathway, but the downstream signaling events remain unclear. We studied the stomatal immunity of tomato (Solanum lycopersicum) and report here the distinct roles of two homologous NAC (for NAM, ATAF1,2, and CUC2) transcription factors, JA2 (for jasmonic acid2) and JA2L (for JA2-like), in regulating pathogen-triggered stomatal movement. ABA activates JA2 expression, and genetic manipulation of JA2 revealed its positive role in ABA-mediated stomatal closure. We show that JA2 exerts this effect by regulating the expression of an ABA biosynthetic gene. By contrast, JA and COR activate JA2L expression, and genetic manipulation of JA2L revealed its positive role in JA/COR-mediated stomatal reopening. We show that JA2L executes this effect by regulating the expression of genes involved in the metabolism of salicylic acid. Thus, these closely related NAC proteins differentially regulate pathogen-induced stomatal closure and reopening through distinct mechanisms.
Multiple Bragg reflection by a thick mosaic crystal
Authors: Wuttke Joachim
Published: July 2014

Symmetric Bragg-case reflections from a thick, ideally imperfect, crystal slab are studied mostly by analytical means. The scattering transfer function of a thin mosaic layer is derived and brought into a form that allows for analytical approximations or easy quadrature. The Darwin–Hamilton equations are generalized, lifting the restriction of wavevectors to a two-dimensional scattering plane. A multireflection expansion shows that wavevector diffusion can be studied independently of the real-space coordinate. Combining analytical arguments and Monte Carlo simulations, multiple Bragg reflections are found to result in a minor correction of the reflected intensity, a moderate broadening of the reflected azimuth angle distribution, a considerable modification of the polar angle distribution, and a noticeable shift and distortion of rocking curves.
Octagonal symmetry in low-discrepancy β-manganese
Authors: Hornfeck Wolfgang , Kuhn Philipp
Published: July 2014

A low-discrepancy cubic variant of β-Mn is presented exhibiting local octagonal symmetry upon projection along any of the three mutually perpendicular 〈100〉 axes. Ideal structural parameters are derived to be x(8c) = (2-\sqrt{2})\big/16 and y(12d) = 1\big/(4 \sqrt{2}) for theP4132 enantiomorph. A comparison of the actual and ideal structure models of β-Mn is made in terms of the newly devised concept of geometrical discrepancy maps. Two-dimensional maps of both the geometrical star discrepancyD*and the minimal interatomic distancedminare calculated over the combined structural parameter range 0 \leq x(8c) \,\lt\, 1/8 and 1/8 \leq y(12d)\, \lt\, 1/4 of generalized β-Mn type structures, showing that the `octagonal' variant of β-Mn is almost optimal in terms of globally minimizingD*while at the same time globally maximizingdmin. Geometrical discrepancy maps combine predictive and discriminatory powers to appear useful within a wide range of structural chemistry studies.
Consultation about urinary and faecal incontinence in the year after childbirth: a cohort study
Authors: Brown S , Gartland D , Perlen S , McDonald E , MacArthur C
Published: July 2014

Objective

To investigate the extent to which primary‐care practitioners routinely inquire about postpartum urinary and faecal incontinence, and assess the proportion of women who disclose symptoms.

Design

Prospective pregnancy cohort study of nulliparous women.

Setting

Melbourne, Australia.

Sample

A total of 1507 nulliparous women recruited in early pregnancy.

Method

Women were recruited from six public maternity hospitals, with follow up at 3, 6, 9 and 12 months postpartum.

Main outcome measures

Standardised measures of urinary and bowel symptoms, and measures of health service use.

Results

In the first 12 months postpartum, the period prevalence of urinary incontinence was 47%, and of faecal incontinence was 17%. In all, 86% of women visited a primary health‐care practitioner at least once to discuss their own health in the first year after childbirth. However, only around a quarter were asked about urinary incontinence, and fewer than one in five women were asked about faecal incontinence. Discussion of symptoms with health professionals was most likely to occur in the first 3 months postpartum, and happened only rarely during the remainder of the first postnatal year. Over 70% of women reporting severe urinary incontinence and/or faecal incontinence had not discussed symptoms with a health professional.

Conclusion

The findings provide robust evidence that many women experiencing postpartum urinary and faecal incontinence—including women with moderate and severe symptoms—do not receive adequate primary‐care follow up in the first 12 months postpartum. Systems of maternal health surveillance need to include routine inquiry about urinary and faecal incontinence to overcome women's reluctance to seek help.
Illness‐course modulates suicidality‐related prefrontal gray matter reduction in women with bipolar disorder
Authors: Lijffijt M. , Rourke E. D. , Swann A. C. , Zunta‐Soares G. B. , Soares J. C.
Published: July 2014

Objective

Explore interrelationships between suicide attempt history (Objective 1) or suicide attempt severity (Objective 2) with prefrontal cortex gray matter (PFCGM) volume and illness‐course in patients with bipolar disorder (BD).

Method

Ninety‐three women with BD‐I or ‐II diagnosis (51 with and 42 without suicide attempt history) underwent structural MRI and filled out questionnaires. Measured were GM volumes of 11 PFC regions, BD illness‐course, and attempt history and severity. Effects were examined with repeated measures GLM or logit analyses.

Results

Objective 1: Attempt history was associated with increased trait impulsivity and aggression, and higher prevalence of BD‐I, past drug use disorder, and past psychiatric hospitalization. PFCGM volume was lower in patients with than without attempt history in those with past psychiatric hospitalization. PFCGM volume was higher in patients with than without attempt history in those without hospitalization. Higher trait aggression predicted attempt history. Objective 2: Increased frontal pole volume and younger age at first hospitalization predicted many suicide attempts.

Conclusion

Attempt history in patients with BD related to PFCGM volume reduction or increase. Volume modulation by psychiatric hospitalization could reflect effects of illness‐course or care. Attempt severity was not related to volume reduction. Research on suicidality–brain relationships should include illness‐course and attempt severity measures.
Changing China, Changing Africa: Future Contours of an Emerging Relationship
Authors: Davies Martyn , Draper Peter , Edinger Hannah
Published: July 2014

Current China–Africa relations have been statically framed: China invests in the continent and exports resources extracted by its state‐owned enterprises and fuelled by aid flows, while simultaneously undercutting African industry through cheap exports. We frame this debate, then explore how the framework could adjust in response to changing economic realities in China, centered on the “rebalancing” of the growth model toward domestic consumption. We argue that a new wave of private sector‐led, low‐cost manufacturers may find its way to selected African shores, in the process transforming those economies and the way in which China interacts with them, both for the better.
China's Foreign Aid at a Transitional Stage
Authors: Kitano Naohiro
Published: July 2014

By estimating China's foreign aid as a proxy for China's bilateral Official Development Assistance and by analyzing its implementation structure and policy, this paper sheds some light on China's foreign aid activities, which have been at a transitional stage. Based on our estimates, the level of foreign aid in terms of net disbursement has increased sharply since 2004, reaching around US$7.1 billion in 2013. Some measures to strengthen the implementation structure to deal with this expansion have been introduced by the central government; however, this transition process needs more time. To facilitate this process, China is attempting to absorb knowhow on development assistance from multilateral institutions and Organisation for Economic Cooperation and Development's Development Assistance Committee countries that are eager to share their knowledge, with the expectation that China will eventually play a major role in international development.
Predictors of Successful Cardioversion with Vernakalant in Patients with Recent‐Onset Atrial Fibrillation
Authors: Mochalina Natalia , Juhlin Tord , Öhlin Bertil , Carlson Jonas , Holmqvist Fredrik , Platonov Pyotr G.
Published: July 2014

Background

Vernakalant is a novel atrial‐selective antiarrhythmic drug able to convert recent‐onset atrial fibrillation (AF) with reportedly low proarrhythmic risk. Successful cardioversion predictors are largely unknown. We sought to evaluate clinical and electrocardiographic predictors of cardioversion of recent‐onset AF with vernakalant.

Methods

Consecutive patients with AF ≤48 hours admitted for cardioversion with vernakalant (n = 113, median age 62 years, 69 male) were included. Sinus rhythm (SR) within 90 minutes after infusion start was considered to be successful cardioversion. Predictive values of demographics, concomitant therapy, comorbidities, and electrocardiographic parameters were assessed. Atrial fibrillatory rate (AFR), exponential decay, and mean fibrillatory wave amplitude were measured from surface ECG using QRST cancellation and time‐frequency analysis.

Results

Cardioversion was achieved in 66% of patients. Conversion rate was higher in women than in men (80% vs 58%, P = 0.02) while none of other clinical characteristics, including index AF episode duration, could predict SR restoration. Female gender was predictive of vernakalant's effect in logistic regression analysis (OR = 2.82 95%CI 1.18–6.76, P = 0.020). There was no difference in AFR (350 ± 60 vs 348 ± 62 fibrillations per minute [fpm], P = 0.893), mean fibrillatory wave amplitude (86 ± 33 vs 88 ± 67 μV, P = 0.852), or exponential decay (1.30 ± 0.42 vs 1.35 ± 0.42, P = 0.376) between responders and nonresponders.

Conclusions

Female gender is associated with a higher rate of SR restoration using intravenous (i.v.) vernakalant for recent‐onset AF. ECG‐derived indices of AF organization, which previous studies associated with effect of rhythm control interventions, did not predict vernakalant's effect.
Robot‐assisted oesophageal and gastric surgery for benign disease: antireflux operations and Heller's myotomy
Authors: Falkenback Dan , Lehane Christopher W. , Lord Reginald V. N.
Published: July 2014

Background

Robot‐assisted general surgery operations are being performed more frequently. This review investigates whether robotic assistance results in significant advantages or disadvantages for the operative treatment of gastro‐oesophageal reflux disease and achalasia.

Methods

The electronic databases (Medline, Embase, PubMed) were searched for original English language publications for antireflux surgery and Heller's myotomy between January 1990 and December 2013.

Results

Thirty‐three publications included antireflux operations and 20 included Heller's myotomy. The publications indicate that the safety and effectiveness of robotic surgery is similar to that of conventional minimally invasive surgery for both operations. The six randomized trials of robot‐assisted versus laparoscopic antireflux surgery showed no significant advantages but significantly higher costs for the robotic method. Gastric perforation during non‐redo robotic fundoplication occurred in four trials.

Conclusions

No consistent advantage for robot‐assisted antireflux surgery has been demonstrated, and there is an increased cost with current robotic technology. A reported advantage for robotic in reducing the perforation rate during Heller's myotomy for achalasia remains unproven. Gastric perforation during robotic fundoplication may be due to the lack of haptic feedback combined with the superhuman strength of the robot.
A Compliant, Banded Outflow Cannula for Decreased Afterload Sensitivity of Rotary Right Ventricular Assist Devices
Authors: Gregory Shaun D. , Schummy Emma , Pearcy Mark , Pauls Jo P. , Tansley Geoff , Fraser John F. , Timms Daniel
Published: July 2014

Biventricular support with dual rotary ventricular assist devices (VADs) has been implemented clinically with restriction of the right VAD (RVAD) outflow cannula to artificially increase afterload and, therefore, operate within recommended design speed ranges. However, the low preload and high afterload sensitivity of these devices increase the susceptibility of suction events. Active control systems are prone to sensor drift or inaccurate inferred (sensor‐less) data, therefore an alternative solution may be of benefit. This study presents the in vitro evaluation of a compliant outflow cannula designed to passively decrease the afterload sensitivity of rotary RVADs and minimize left‐sided suction events. A one‐way fluid‐structure interaction model was initially used to produce a design with suitable flow dynamics and radial deformation. The resultant geometry was cast with different initial cross‐sectional restrictions and concentrations of a softening diluent before evaluation in a mock circulation loop. Pulmonary vascular resistance (PVR) was increased from 50 dyne s/cm5 until left‐sided suction events occurred with each compliant cannula and a rigid, 4.5 mm diameter outflow cannula for comparison. Early suction events (PVR ∼ 300 dyne s/cm5) were observed with the rigid outflow cannula. Addition of the compliant section with an initial 3 mm diameter restriction and 10% diluent expanded the outflow restriction as PVR increased, thus increasing RVAD flow rate and preventing left‐sided suction events at PVR levels beyond 1000 dyne s/cm5. Therefore, the compliant, restricted outflow cannula provided a passive control system to assist in the prevention of suction events with rotary biventricular support while maintaining pump speeds within normal ranges of operation.
Randomised clinical study: comparison of acceptability, patient tolerance, cardiac stress and endoscopic views in transnasal and transoral endoscopy under local anaesthetic
Authors: Alexandridis E. , Inglis S. , McAvoy N. C. , Falconer E. , Graham C. , Hayes P. C. , Plevris J. N.
Published: July 2014

Background

Transnasal endoscopy (TNE) with ultrathin endoscopes has been advocated as an attractive alternative, for diagnostic upper endoscopy.

Aim

To assess tolerability, acceptability and quality of TNE, in comparison with standard upper endoscopy (SOGD, standard oesophago‐gastro‐duodenoscopy) under local anaesthetic.

Methods

We prospectively recruited 157 patients (83 females/74 males) mean age 57 years. The Fujinon EG530N (5.9 mm) and EG530WR (9.4 mm) endoscopes were used. The endoscopist and all patients completed detailed questionnaires regarding tolerability, acceptance and quality of endoscopy using standard visual analogue scales (VAS). Oxygen saturation (SaO2), heart rate (HR) and systolic blood pressure (SBP) were recorded. Quality of biopsies was evaluated.

Results

Analysis included 161 procedures (TNE:79, SOGD:82) with duodenal intubation achieved in all patients. VAS scores for patient comfort were significantly better in the TNE group (7.3 vs. 5.3 respectively, P < 0.001). Twenty patients with previous experience of standard endoscopy were randomised to TNE and 19 of them (95.5%) preferred the TNE. Gagging was significantly less in the TNE group (0.12 vs. 3.41 respectively, P < 0.001). Cardiovascular stress was significantly less in the TNE group irrespective of the degree of gagging or comfort. TNE biopsies were smaller, but adequate for definitive diagnosis, similarly to standard endoscopy.

Conclusions

Transnasal endoscopy is superior to SOGD in terms of comfort and patient acceptance with significantly less cardiovascular stress. TNE can routinely be used as alternative to SOGD under local anaesthetic, for diagnosis and should be preferentially offered in cardiorespiratory compromised patients.
Mapping continuous forest type variation by means of correlating remotely sensed metrics to canopy N:P ratio in a boreal mixedwood forest
Authors: Gökkaya Kemal , Thomas Valerie , Noland Thomas , McCaughey Harry , Morrison Ian , Treitz Paul
Published: July 2014

Questions

Can the ratio of nitrogen to phosphorus (N:P ratio) be predicted at canopy level using imaging spectroscopy (IS) and light detection and ranging (LiDAR) remote sensing data? How do temporal variation and difference in spatial resolution of these data sources affect prediction accuracy of the canopy N:P ratio?

Location

Boreal mixedwood forest, northern Ontario, Canada.

Methods

Canopy N:P ratio was estimated using spectral indices calculated from IS data at two spatial resolutions, airborne and space‐borne, across two summers. The relationship between the canopy N:P ratio and forest structure was investigated through analysis of LiDAR data. The impact of temporal variation on canopy N:P ratio and the different spatial resolution of IS data on prediction accuracy for canopy N:P was addressed. Maps of canopy N:P ratio generated from airborne and space‐borne IS data were generated.

Results

Airborne and space‐borne IS data explained 70% and 69% of the variation in canopy N:P, ratio, with predictions errors of 5.0% and 7.2%, respectively, in two consecutive years. Predictions differed significantly with changes in spatial resolution. Predictive models obtained from LiDAR data explained 54% and 67% of the variation in canopy N:P ratio, with prediction errors of 6.1% and 7.5%, respectively, for the 2 yrs.

Conclusions

The results show that canopy N:P ratio can be predicted with remote sensing data based on the relationship between canopy N:P ratio and crown closure at this site. The spatial variation due to the mixed deciduous and coniferous forest type is the underlying mechanism that generates the observed spatial pattern in canopy N:P ratio in this ecosystem, and the canopy N:P ratio map displays this variation.
Pre‐dose plasma concentration monitoring of mycophenolate mofetil in patients with autoimmune diseases
Authors: Streicher Caroline , Djabarouti Sarah , Xuereb Fabien , Lazaro Estibaliz , Legeron Rachel , Bouchet Stéphane , Greib Carine , Breilh Dominique , Pellegrin Jean‐Luc , Viallard Jean‐François
Published: July 2014

Aim

To date, neither the benefit of mycophenolic acid (MPA) therapeutic drug monitoring (TDM), the prodrug of mycophenolate mofetil (MMF), nor the optimal monitoring technique have been established in autoimmune diseases. This study was undertaken to confirm, in a cohort of new patients, the plasma MPA thresholds previously published in patients with systemic lupus erythematosus (SLE) or vasculitis.

Methods

MPA areas under the concentration–time curves between 0 and 12 h, 12 h trough concentrations and pre‐dose concentrations (C0) were determined for 23 patients with SLE and 21 with systemic vasculitis. The relationship between patients' pharmacokinetic (PK) variables and their clinical outcomes during follow‐up were analyzed.

Results

In both autoimmune diseases, at PK assessment, median MPA C0 for patients with uncontrolled disease was significantly lower than that of patients with stable disease or in remission, 1.6 mg l–1 (IQR 0.9–2.1 mg l–1) vs. 2.95 mg l–1 (IQR 1.38–3.73 mg l–1) for SLE (P = 0.048) and 1.55 mg l–1 (IQR 0.98–2.18 mg l–1) vs. 3 mg l–1 (IQR 2.2–4.4 mg l–1) for vasculitis (P = 0.016). According to our receiver operating characteristics curve analysis, a C0 threshold of 2.5–3 mg l–1 was best able to discriminate a flare (SLE: 88% sensitivity, 80% specificity; vasculitis: 100% sensitivity, 90% specificity). Patients with C0 ≥ 2.5–3 mg l–1 at inclusion had better clinical outcomes during the 12 months following PK assessment.

Conclusion

Provided that the benefit of TDM in patients with autoimmune diseases could be confirmed by randomized, controlled trials, it might be based on the C0 measured approximately 12 h post‐dose.
Early and Sustained Activation of Autophagy in Degenerating Axons after Spinal Cord Injury
Authors: Ribas Vinicius Toledo , Schnepf Bianca , Challagundla Malleswari , Koch Jan Christoph , Bähr Mathias , Lingor Paul
Published: July 2014

Axonal degeneration is one of the initial steps in many neurological disorders and has been associated with increased autophagic activity. Although there are increasing data on the regulation of autophagy proteins in the neuronal soma after spinal cord injury (SCI), their characterization in the axon is scarce. Here, we examined the regulation of autophagy during axonal degeneration in a rat model of SCI following a lesion at Th 8. We analyzed the morphological and ultrastructural changes in injured axons by immunohistochemical evaluation of autophagy‐related proteins and electron microscopy at different time points following SCI. The expression of ULK1, Atg7 and Atg5 in damaged axons was rapidly upregulated within hours after SCI. The number of axonal LC3‐positive autophagosomes was also rapidly increased after SCI and remained at an increased level for up to 6 weeks. Ultrastructural analysis showed early signs of axonal degeneration and increased autophagy. In conclusion, we show that autophagy is increased early and for a sustained period in degenerating axons after SCI and that it might be an important executive step involved in axonal degeneration. Therefore, autophagy may represent a promising target for future therapeutic interventions in the treatment of axonal degeneration in traumatic central nervous system disorders.
TRPC6 regulates cell cycle progression by modulating membrane potential in bone marrow stromal cells
Authors: Ichikawa Jun , Inoue Ryuji
Published: July 2014

Background and Purpose

Ca2+ influx is important for cell cycle progression, but the mechanisms involved seem to vary. We investigated the potential roles of transient receptor potential (TRP) channels and store‐operated Ca2+ entry (SOCE)‐related molecules STIM (stromal interaction molecule)/Orai in the cell cycle progression of rat bone marrow stromal cells (BMSCs), a reliable therapeutic resource for regenerative medicine.

Experimental Approach

PCR and immunoblot analyses were used to examine mRNA and protein levels, fluorescence imaging and patch clamping for Ca2+ influx and membrane potential measurements, and flow cytometry for cell cycle analysis.

Key Results

Cell cycle synchronization of BMSCs revealed S phase‐specific enhancement of TRPC1, STIM and Orai mRNA and protein expression. In contrast, TRPC6 expression decreased in the S phase and increased in the G1 phase. Resting membrane potential (RMP) of BMSCs was most negative and positive in the S and G1 phases, respectively, and was accompanied by an enhancement and attenuation of SOCE respectively. Chemically depolarizing/hyperpolarizing the membrane erased these differences in SOCE magnitude during the cell cycle. siRNA knockdown of TRPC6 produced a negative shift in RMP, increased SOCE and caused redistribution of BMSCs with increased populations in the S and G2/M phases and accumulation of cyclins A2 and B1. A low concentration of Gd3+ (1 μM) suppressed BMSC proliferation at its concentration to inhibit SOC channels relatively specifically.

Conclusions and Implications

TRPC6, by changing the membrane potential, plays a pivotal role in controlling the SOCE magnitude, which is critical for cell cycle progression of BMSCs. This finding provides a new therapeutic strategy for regulating BMSC proliferation.
Nicotinic acetylcholine receptors control acetylcholine and noradrenaline release in the rodent habenulo‐interpeduncular complex
Authors: Beiranvand F , Zlabinger C , Orr‐Urtreger A , Ristl R , Huck S , Scholze P
Published: July 2014

Background and purpose

Nicotinic acetylcholine receptors (nACh receptors) play a central role in the habenulo‐interpeduncular system. We studied nicotine‐induced release of NA and ACh in the habenula and interpeduncular nucleus (IPN).

Experimental approach

The habenula and IPN were loaded with [3H]‐choline or [3H]‐NA and placed in superfusion chambers. [3H]‐ACh release was also stimulated using nicotinic agonists, electrical pulses and elevated [KCl]o in hippocampal and cortical slices from rats, wild‐type mice and mice lacking α5, α7, β2, or β4 nACh receptor subunits. Finally, we analysed nACh receptor subtypes in the IPN using immunoprecipitation.

Key results

Nicotine induced release of [3H]‐ACh in the IPN of rats and mice. This release was calcium‐dependent but not blocked by tetrodotoxin (TTX); moreover, [3H]‐ACh release was abolished in β4‐knockout mice but was unaffected in β2‐ and α5‐knockout mice. In contrast, nicotine‐induced release of [3H]‐NA in the IPN and habenula was blocked by TTX and reduced in both β2‐knockout and β4‐knockout mice, and dose–response curves were right‐shifted in α5‐knockout mice. Although electrical stimuli triggered the release of both transmitters, [3H]‐ACh release required more pulses delivered at a higher frequency.

Conclusions and implications

Our results confirm previous findings that β4‐containing nACh receptors are critical for [3H]‐ACh release in the mouse IPN. Experiments using α5‐knockout mice also revealed that unlike in the hippocampus, nicotine‐induced [3H]‐NA release in the habenulo‐interpeduncular system is altered in this knockout model. As α5‐containing nACh receptors play a key role in nicotine intake, our results add NA to the list of transmitters involved in this mechanism.
Prediagnostic serum levels of inflammatory biomarkers are correlated with future development of lung and esophageal cancer
Authors: Keeley Brieze R. , Islami Farhad , Pourshams Akram , Poustchi Hossein , Pak Jamie S. , Brennan Paul , Khademi Hooman , Genden Eric M. , Abnet Christian C. , Dawsey Sanford M. , Boffetta Paolo , Malekzadeh Reza , Sikora Andrew G.
Published: July 2014

This study tests the hypothesis that prediagnostic serum levels of 20 cancer‐associated inflammatory biomarkers correlate directly with future development of head and neck, esophageal, and lung cancers in a high‐risk prospective cohort. This is a nested case–control pilot study of subjects enrolled in the Golestan Cohort Study, an ongoing epidemiologic project assessing cancer trends in Golestan, Iran. We measured a panel of 20 21cytokines, chemokines, and inflammatory molecules using Luminex technology in serum samples collected 2 or more years before cancer diagnosis in 78 aerodigestive cancer cases and 81 controls. Data was analyzed using Wilcoxon rank sum test, odds ratios, receiver operating characteristic areas of discrimination, and multivariate analysis. Biomarkers were profoundly and globally elevated in future esophageal and lung cancer patients compared to controls. Odds ratios were significant for association between several biomarkers and future development of esophageal cancer, including interleukin‐1Rα (IL‐1Ra; 35.9), interferon α2 (IFN‐a2; 34.0), fibroblast growth factor‐2 (FGF‐2; 17.4), and granulocyte/macrophage colony‐stimulating factor (GM‐CSF; 17.4). The same pattern was observed among future lung cancer cases for G‐CSF (27.7), GM‐CSF (13.3), and tumor necrosis factor‐α (TNF‐a; 8.6). By contrast, the majority of biomarkers studied showed no significant correlation with future head and neck cancer development. This study provides the first direct evidence that multiple inflammatory biomarkers are coordinately elevated in future lung and esophageal cancer patients 2 or more years before cancer diagnosis.
Microscopic colitis: a review
Authors: Farrukh A. , Mayberry J. F.
Published: July 2014

Aim

In recent years, microscopic colitis has been increasingly diagnosed. This review was carried out to evaluate demographic factors for microscopic colitis and to perform a systematic assessment of available treatment options.

Method

Relevant publications up to December 2013 were identified following searches of PubMed and Google Scholar using the key words ‘microscopic colitis’, ‘collagenous colitis’ and ‘lymphocytic colitis’. Two‐hundred and forty‐eight articles were identified.

Results

The term microscopic colitis includes lymphocytic colitis and collagenous colitis. Both have common clinical symptoms but are well defined histopathologically. The clinical course is usually benign, but serious complications, including death, may occur. A peak incidence from 60 to 70 years of age with a female preponderance is observed. Although most cases are idiopathic, associations with autoimmune disorders, such as coeliac disease and hypothyroidism, as well as with exposure to nonsteroidal anti‐inflammatory drugs and proton‐pump inhibitors, have been observed. The incidence and prevalence of microscopic colitis is rising and good‐quality epidemiological research is needed. Treatment is currently largely based on anecdotal evidence and on results from limited clinical trials of budesonide. Long‐term follow‐up of these patients is not well established.

Conclusion

The review synthesizes work on the definition of microscopic colitis and the relationship between collagenous and lymphocytic colitis. It reviews the international epidemiology and work on aetiology. In addition, it critically considers the efficacy of a range of treatments.
Incidence and risk factors for colorectal neoplasia in patients with oral squamous cell carcinoma
Authors: Kishikawa H. , Sato K. , Yamauchi T. , Katakura A. , Shibahara T. , Takano N. , Nishida J.
Published: July 2014

Aim

Colorectal adenoma and cancer are not regarded as being associated with primary oral cancer. The aim of this study was to determine whether screening colonoscopy should be performed for patients with oral cancer in addition to the upper gastrointestinal endoscopic screening that is now routinely performed.

Method

Between 2007 and 2013, 162 patients with oral squamous cell carcinoma were enrolled at Tokyo Dental College, Ichikawa General Hospital, and 136 individuals were assigned to colonoscopic surveillance. Advanced neoplasia was defined as an adenoma ≥ 10 mm, adenoma with villous histology or high‐grade dysplasia regardless of size and invasive cancer. Associations between advanced neoplasia and clinical factors, including age, sex, body mass index, physical activity, smoking, alcohol consumption and oral cancer site and staging were determined.

Results

Advanced neoplasia, including five invasive cancers, was identified in 32 (23.5%) patients. An age‐ and sex‐adjusted multivariate analysis revealed that smoking (Brinkmann index > 400; OR = 3.24, 95% CI = 1.28–8.18), alcohol consumption (lifetime pure ethanol consumption > 600 l; OR = 2.84, 95% CI = 1.18–6.79) and a diagnosis of cancer of the floor of the mouth (OR = 7.97, 95% CI = 2.49–25.46) were independent risk factors for advanced colorectal neoplasia.

Conclusion

The prevalence of advanced colorectal neoplasia is unexpectedly high in patients with oral cancer. It should be recognized as a second primary tumour of oral cancer. Screening of oral cancer patients by colonoscopy should be routine practice, particularly among smokers and patients with a high intake of alcohol and cancer of the floor of the mouth.
Multiorgan transplantation from a deceased donor with intravascular diffuse large B‐cell lymphoma: transmission of the disease and results of treatment
Authors: Dziewanowski Krzysztof , Drozd Radosław , Parczewski Miłosz , Klinke Małgorzata
Published: July 2014

This report presents the transplantation of two kidneys and the liver from a deceased donor with suspected autoimmune encephalomeningitis (ADEM). Due to an atypical post‐transplantation clinical course, the transplanted kidneys were biopsied and this disclosed diffuse large B‐cell (DLBC) lymphoma of the intravascular type in each kidney. The same malignancy was found in the postmortem donor brain examination. The renal allografts from the two recipients were removed: despite every effort, one patient died, while chemotherapy was successful in the second. No malignancy was observed in the liver transplant recipient, who received prophylactic chemotherapy. These cases highlight the occasional failure of organ donor disease screening and the consequent unforeseen complications.
Species contribute differently to the taxonomic, functional, and phylogenetic alpha and beta diversity of freshwater fish communities
Authors: Pool Thomas K. , Grenouillet Gaël , Villéger Sébastien
Published: July 2014

Aim

We examined the current biogeographical patterns of native fish communities throughout France, using a multifaceted taxonomic, functional and phylogenetic diversity approach. We then identified the contribution of individual species to each facet of watershed's native fish diversity.

Location

Continental France.

Methods

The taxonomic, functional and phylogenetic diversity of the fish communities were quantified at the watershed‐scale (i.e. alpha diversity approach), and congruencies between diversity facets were assessed. Variation between watersheds was then quantified (i.e. beta diversity approach) using Jaccard's dissimilarity index for all three facets of diversity, and congruencies were assessed. We subsequently determined the relationship between alpha and beta diversity for each diversity facet. Lastly, the mean relative contribution of each species to watershed's alpha taxonomic, functional and phylogenetic diversity was quantified. The conservation status of each species was considered to determine if threatened and endangered species contributed more significantly to watershed alpha diversity than common species.

Results

Across all watersheds, taxonomic, functional and phylogenetic diversity facets were found to be highly congruent using both the alpha and beta diversity approaches. In contrast, the relationship between the watersheds' alpha and beta diversity was primarily negative; watersheds with decreased beta diversity tended to have increased alpha diversity for all three facets. Individual species also rarely contributed prominently to more than one diversity facet, with conservation status insignificantly influencing species relative contributions.

Main conclusions

We found that native fish diversity ‘hotspots’ exist in France; exhibited in our results by areas of high, overlapping taxonomic, functional and phylogenetic diversity. Consequently, conservation planning approaches supported by species‐based metrics may concurrently target areas of increased ecological and evolutionary importance at the watershed‐scale. Interestingly, a diverse mosaic of species accounted for the different facets of diversity, suggesting that future reductions in species richness could have differential effects on each watershed's diversity facets.
Careful clinical observation continues to improve understanding of the phenotype in individuals with tuberous sclerosis complex
Authors: Jansen Anna C
Published: July 2014

This commentary is on the original article by Boronat et al. on pages
1207–1211 of this issue.
On the reproductive success of early‐generation hatchery fish in the wild
Authors: Christie Mark R. , Ford Michael J. , Blouin Michael S.
Published: July 2014

Large numbers of hatchery salmon spawn in wild populations each year. Hatchery fish with multiple generations of hatchery ancestry often have heritably lower reproductive success than wild fish and may reduce the fitness of an entire population. Whether this reduced fitness also occurs for hatchery fish created with local‐ and predominantly wild‐origin parents remains controversial. Here, we review recent studies on the reproductive success of such ‘early‐generation’ hatchery fish that spawn in the wild. Combining 51 estimates from six studies on four salmon species, we found that (i) early‐generation hatchery fish averaged only half the reproductive success of their wild‐origin counterparts when spawning in the wild, (ii) the reduction in reproductive success was more severe for males than for females, and (iii) all species showed reduced fitness due to hatchery rearing. We review commonalities among studies that point to possible mechanisms (e.g., environmental versus genetic effects). Furthermore, we illustrate that sample sizes typical of these studies result in low statistical power to detect fitness differences unless the differences are substantial. This review demonstrates that reduced fitness of early‐generation hatchery fish may be a general phenomenon. Future research should focus on determining the causes of those fitness reductions and whether they lead to long‐term reductions in the fitness of wild populations.
Merkel cell carcinoma: is this a true carcinoma?
Authors: Jankowski Marek , Kopinski Piotr , Schwartz Robert , Czajkowski Rafal
Published: July 2014

Recent years have brought an enhanced understanding of Merkel cell carcinoma (MCC) biology, especially with regard to the Merkel cell polyoma virus as a causative agent. Differences between Merkel cell polyomavirus‐positive and Merkel cell polyomavirus‐negativeMCCin morphology,,gene expression, miRNAprofiles and prognosis have been reported. Origin ofMCCis controversial. Presence of neurosecretory granules has suggested that these carcinomas originate from one of the neurocrest derivatives, most probably Merkel cells; the name Merkel cell carcinoma is now widely accepted. Expression ofPGP9.5, chromogranin A and several neuropeptides, initially regarded as specific markers for neural and neuroendocrine cells, has recently been shown in a subset of lymphomas.MCCcommonly expresses terminal deoxynucleotidyl transferase andPAX5. Their co‐expression under physiologic circumstances is restricted to pro/pre‐B cells and pre‐B cells. These findings lead to the hypothesis by zur Hausen et al. thatMCCoriginates from early B cells. This review was intended to critically appraise zur Hausen's hypothesis and discuss the possibility thatMCCis a heterogenous entity with distinct subtypes.
Trichoderma reesei XYN VI – a novel appendage‐dependent eukaryotic glucuronoxylan hydrolase
Authors: Biely Peter , Puchart Vladimír , Stringer Mary Ann , Mørkeberg Krogh Kristian B.R.
Published: July 2014

Expression of a Trichoderma reesei gene coding for a putative GH30 xylanase in Aspergillus oryzae led to isolation and purification of a novel xylanase exhibiting catalytic properties different from those of the previously characterized GH30 xylanase XYN IV of T. reesei. The novel enzyme, named XYN VI, exhibited catalytic properties similar to appendage‐dependent GH30 glucuronoxylanases previously recognized only in bacteria. XYN VI showed high specific activity only on xylans or xylooligosaccharides containing 4‐O‐methyl‐d‐glucuronic acid or d‐glucuronic acid side substituents. The cleavage of the main chain takes place primarily at the second glycosidic linkage from the branch towards the reducing end of the polysaccharides or aldouronic acids. These catalytic properties resemble bacterial GH30 glucuronoxylanases, although the recognition of the uronic acid side chains by XYN VI is apparently based on interaction of the substrate with other amino acids. Moreover, in contrast to bacterial enzymes, XYN VI is also capable of slower but significant cleavage of unsubstituted parts of xylan and acidic xylooligosaccharides. The data point to a great catalytic diversity of xylanases produced by the most extensively studied cellulolytic fungus.