bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic instability 30 years later: complexities in microtubule growth and catastrophe
Authors: Brouhard Gary J.
Published: March 2015

Microtubules are not like other polymers. Whereas polymers such as F-actin will grow continuously as long as the subunit concentration is high enough, a steadily growing microtubule can suddenly shrink even when there is ample αβ-tubulin around. This remarkable behavior was discovered in 1984 when Tim Mitchison and Marc Kirschner deduced that microtubules switch from growth to shrinkage when they lose their GTP caps. Here, I review the canonical explanation of dynamic instability that was fleshed out in the years after its discovery. Many aspects of this explanation have been recently subverted, particularly those related to how GTP-tubulin forms polymers and why GTP hydrolysis disrupts them. I describe these developments and speculate on how our explanation of dynamic instability can be changed to accommodate them.
Stock assessment of eels in the Baltic: reconciling survey estimates to achieve quantitative analysis
Authors: Westerberg Håkan , Wickström Håkan
Published: March 2015

The data from two scientific surveys, where eel is part of the catch, have been studied to assess trends in recruitment and escapement to and from the Baltic. Abundance of juvenile eel was monitored in the Sound, between Sweden and Denmark, from 1992 to 2002. The total natural recruitment of new eels was estimated under the assumption that the number of juvenile eels observed in the surveys represented an accumulation of eels migrating into the Baltic. To assess the total recruitment, the stocking by imported glass eels, or transplanted juveniles from outside the Baltic, was added. Fish larvae monitoring at a nuclear power plant in the Kattegat gave an index of glass eel abundance which was well correlated with glass eel monitoring in the Sound. This was used to extrapolate the recruitment time-series to the full period from 1981 to the present. The main conclusions from the analysis were: (i) the recruitment to the Baltic region, including the contribution from stocking, has declined by 95% between 1981 and 2012. (ii) The stocking of glass eel and bootlace eel has been of the same order of magnitude as natural recruitment, averaging 25–30% of the total supply of glass eel to the Baltic, with a decreasing trend with time. (iii) The total landings in the Baltic countries have ranged from 5 to 15% of the estimated survival without anthropogenic mortality. This proportion has been stable and independent of a large decrease in potential escapement.
The Rpd3/Hda1 family of histone deacetylases regulates azole resistance in Candida albicans
Authors: Li Xiaofang , Cai Qing , Mei Huan , Zhou Xiaowei , Shen Yongnian , Li Dongmei , Liu Weida
Published: March 2015

Objectives

The histone deacetylase (HDAC) has recently been linked to the morphogenesis and virulence of yeast. However, the effects of HDAC on antifungal susceptibility are not well understood. We sought to characterize the action of histone deacetylation on azole resistance in Candida albicans and its possible mechanism of action.

Methods

A total of 40 C. albicans strains were studied. Azole susceptibility with or without trichostatin A (TSA) was determined according to the CLSI microdilution method. The null mutants of HDA1 and RPD3 (genes targeted by TSA) were also investigated using drop-plate assays and a rapid acquisition of adaptation to the azole test. Transcriptional levels of HDAC genes and efflux genes were quantified using RT–PCR for both the basal and fluconazole-induced conditions.

Results

The inhibition of HDACs by TSA (0.25 mg/L) markedly reduced the trailing growth and the growth of most C. albicans strains. Trailing growth for C. albicans strains was decreased from 2-fold to 256-fold at 48 h. The deletion of HDA1 or RPD3 increased the susceptibility to azoles compared with the WT strain. The expression of HDA1 and RPD3 was up-regulated to different levels, and returned to the level of the susceptible parental strain when stable resistance had formed during the course of acquired fluconazole resistance both in vitro and in vivo. Efflux genes were poorly expressed in mutant strains compared with those of the WT strain.

Conclusions

Our results indicate the important role of the Rpd3/Hda1 family in the development of azole resistance in C. albicans. Histone deacetylation may govern the expression of genes related to the early stages of adaptation to azole stress, such as efflux pump genes.
The GHKL ATPase MORC1 Modulates Species-Specific Plant Immunity in Solanaceae
Authors: Manosalva Patricia , Manohar Murli , Kogel Karl-Heinz , Kang Hong-Gu , Klessig Daniel F.
Published: March 2015

The microrchidia (MORC) proteins, a subset of the GHKL ATPase superfamily, were recently described as components involved in transcriptional gene silencing and plant immunity in Arabidopsis. To assess the role of MORC1 during resistance to Phytophthora infestans in solanaceous species, we altered the expression of the corresponding MORC1 homologs in potato, tomato, and Nicotiana benthamiana. Basal resistance to P. infestans was compromised in StMORC1-silenced potato and enhanced in overexpressing lines, indicating that StMORC1 positively affects immunity. By contrast, silencing SlMORC1 expression in tomato or NbMORC1 expression in N. benthamiana enhanced basal resistance to this oomycete pathogen. In addition, silencing SlMORC1 further enhanced resistance conferred by two resistance genes in tomato. Transient expression of StMORC1 in N. benthamiana accelerated cell death induced by infestin1 (INF1), whereas SlMORC1 or NbMORC1 suppressed it. Domain-swapping and mutational analyses indicated that the C-terminal region dictates the species-specific effects of the solanaceous MORC1 proteins on INF1-induced cell death. This C-terminal region also was required for homodimerization and phosphorylation of recombinant StMORC1 and SlMORC1, and its transient expression induced spontaneous cell death in N. benthamiana. Thus, this C-terminal region likely plays important roles in both determining and modulating the biological activity of MORC1 proteins.
Transcutaneous Electrical Nerve Stimulation Increases Rectal Activity in Children
Authors: Moeller Joensson Iben , Hagstroem Soren , Siggaard Charlotte , Bower Wendy , Djurhuus Jens Christian , Krogh Klaus
Published: April 2015

Objectives:

Neurostimulation is increasingly used in treating bladder and bowel dysfunction, but its effect on rectal motility is obscure. The aim of the study was to evaluate the acute effect of transcutaneous electrical nerve stimulation (TENS) on rectal motility in children with overactive bladder (OAB).

Methods:

In this double‐blind placebo‐controlled study in 20 children with OAB (mean age 8.6 ± 1.8 years; 7 girls), 48‐hour urodynamic monitoring including rectal manometry was performed. After 24‐hours of baseline investigation without stimulation the children were randomised to either active TENS (n = 10) or placebo (n = 10). Surface electrodes were placed over the sacral bone. The exterior of active and placebo stimulators was identical. Starting in the morning, the children received either continuous TENS stimulation or placebo until bedtime. Rectal contractions were deﬁned as pressure runs exceeding 5 cm H2O and lasting ≥3 minutes.

Results:

At baseline there was no significant difference in proportion of time with rectal contractions in the 2 groups (TENS group median 31% [range 12%–66%] vs placebo group median 31% [range 10%–66%]; P = 0.75); however, on the day of stimulation there was more time with rectal contractions in the group receiving TENS (median 51% [range 25%–78%]) compared with placebo (median 32% [range 4%–68%]; P = 0.02). Also, there was an increase in time with rectal contractions in the TENS group (P = 0.007) but not in the placebo group (P = 0.39). The night after the TENS was disabled, rectal activity in both groups returned to baseline level.

Conclusions:

TENS acutely increases time with rectal contractions in children undergoing urodynamic investigation. The effect disappears when the stimulator is turned off.
Threonine Requirement of the Enterally Fed Term Infant in the First Month of Life
Authors: Hogewind‐Schoonenboom Jacomine E. , Huang Lisha , de Groof Femke , Zhu Li , Voortman Gardi J. , Schierbeek Henk , Vermes Andras , Chen Chao , Huang Ying , van Goudoever Johannes B.
Published: April 2015

Objective:

Threonine is one of the essential amino acids. Its major fate is incorporation into intestinal mucosal proteins and synthesis of secretory glycoproteins. Therefore, it has an important function in the neonatal gut barrier integrity. The objective was to quantify the threonine requirement in fully enterally fed term neonates by means of the indicator amino acid oxidation (IAAO) method, using L‐[1‐13C]phenylalanine as indicator.

Methods:

After a 24‐hour test diet adaptation, containing randomly assigned amounts of threonine (range 5–182 mg · kg−1 · day−1), the participating neonates received a primed continuous infusion of [13C]bicarbonate and L‐[1–13C]phenylalanine. At baseline and during the plateau phase of both infusions, breath samples were obtained for 13CO2. The fractional L‐[1‐13C]phenylalanine oxidation (F13CO2) was estimated and plotted against the threonine intakes. Biphasic linear regression crossover analysis was used to calculate the breakpoint of the F13CO2, representing the mean threonine requirement. Data are presented as mean ± SD.

Results:

Thirty‐two term neonates (gestational age 39 ± 1 weeks, birth weight 3.3 ± 0.3 kg, mean postnatal age 10 ± 4 days) were studied. The mean threonine requirement was estimated to be 68 mg · kg−1 · day−1 with an upper and lower 95% confidence interval of 104 and 32 mg · kg−1 · day−1, respectively (r2 = 0.37).

Conclusions:

The determined threonine requirement is extremely close to the existing requirement recommendations (~90% of the present World Health Organization requirement guidelines). Infant formula preparations presently on the market, however, contain up to twice as much threonine as recommended. The threonine intake in formula‐fed infants may therefore be reduced considerably.
Consciousness: here, there and everywhere?
Authors: Tononi Giulio , Koch Christof
Published: March 2015

The science of consciousness has made great strides by focusing on the behavioural and neuronal correlates of experience. However, while such correlates are important for progress to occur, they are not enough if we are to understand even basic facts, for example, why the cerebral cortex gives rise to consciousness but the cerebellum does not, though it has even more neurons and appears to be just as complicated. Moreover, correlates are of little help in many instances where we would like to know if consciousness is present: patients with a few remaining islands of functioning cortex, preterm infants, non-mammalian species and machines that are rapidly outperforming people at driving, recognizing faces and objects, and answering difficult questions. To address these issues, we need not only more data but also a theory of consciousness—one that says what experience is and what type of physical systems can have it. Integrated information theory (IIT) does so by starting from experience itself via five phenomenological axioms:intrinsic existence, composition, information, integrationandexclusion. From these it derives five postulates about the properties required of physical mechanisms to support consciousness. The theory provides a principled account of both the quantity and the quality of an individual experience (a quale), and a calculus to evaluate whether or not a particular physical system is conscious and of what. Moreover, IIT can explain a range of clinical and laboratory findings, makes a number of testable predictions and extrapolates to a number of problematic conditions. The theory holds that consciousness is a fundamental property possessed by physical systems having specific causal properties. It predicts that consciousness is graded, is common among biological organisms and can occur in some very simple systems. Conversely, it predicts that feed-forward networks, even complex ones, are not conscious, nor are aggregates such as groups of individuals or heaps of sand. Also, in sharp contrast to widespread functionalist beliefs, IIT implies that digital computers, even if their behaviour were to be functionally equivalent to ours, and even if they were to run faithful simulations of the human brain, would experience next to nothing.
Cerebral hierarchies: predictive processing, precision and the pulvinar
Authors: Kanai Ryota , Komura Yutaka , Shipp Stewart , Friston Karl
Published: March 2015

This paper considers neuronal architectures from a computational perspective and asks what aspects of neuroanatomy and neurophysiology can be disclosed by the nature of neuronal computations? In particular, we extend current formulations of the brain as an organ of inference—based upon hierarchical predictive coding—and consider how these inferences are orchestrated. In other words, what would the brain require to dynamically coordinate and contextualize its message passing to optimize its computational goals? The answer that emerges rests on the delicate (modulatory) gain control of neuronal populations that select and coordinate (prediction error) signals that ascend cortical hierarchies. This is important because it speaks to a hierarchical anatomy of extrinsic (between region) connections that form two distinct classes, namely a class of driving (first-order) connections that are concerned with encoding the content of neuronal representations and a class of modulatory (second-order) connections that establish context—in the form of the salience or
precision
ascribed to content. We explore the implications of this distinction from a formal perspective (using simulations of feature–ground segregation) and consider the neurobiological substrates of the ensuing precision-engineered dynamics, with a special focus on the pulvinar and attention.
Brain/MINDS: brain-mapping project in Japan
Authors: Okano Hideyuki , Miyawaki Atsushi , Kasai Kiyoto
Published: March 2015

There is an emerging interest in brain-mapping projects in countries across the world, including the USA, Europe, Australia and China. In 2014, Japan started a brain-mapping project called Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS). Brain/MINDS aims to map the structure and function of neuronal circuits to ultimately understand the vast complexity of the human brain, and takes advantage of a unique non-human primate animal model, the common marmoset (
Callithrix jacchus
). In Brain/MINDS, the RIKEN Brain Science Institute acts as a central institute. The objectives of Brain/MINDS can be categorized into the following three major subject areas: (i) structure and functional mapping of a non-human primate brain (the marmoset brain); (ii) development of innovative neurotechnologies for brain mapping; and (iii) human brain mapping; and clinical research. Brain/MINDS researchers are highly motivated to identify the neuronal circuits responsible for the phenotype of neurological and psychiatric disorders, and to understand the development of these devastating disorders through the integration of these three subject areas.
Demequina activiva sp. nov., isolated from a tidal flat
Authors: Park Sooyeon , Jung Yong-Taek , Won Sung-Min , Lee Jung-Sook , Yoon Jung-Hoon
Published: March 2015

A Gram-stain-positive, facultatively anaerobic, non-spore-forming, non-flagellated and rod-shaped or ovoid bacterial strain, designated BS-12MT, was isolated from a tidal flat sediment on the South Sea, South Korea. Strain BS-12MT grew optimally at 35 °C, at pH 7.0–8.0 and in the presence of 2.0 % (w/v) NaCl. The neighbour-joining phylogenetic tree based on 16S rRNA gene sequences revealed that strain BS-12MT fell within the cluster comprising the type strains of species of the genus Demequina, joining the type strain of Demequina aestuarii with which it shared the highest sequence similarity (98.6 %). It exhibited 16S rRNA gene sequence similarity of 96.1–97.9 % to the type strains of other species of the genus Demequina. The peptidoglycan type of strain BS-12MT was A4β based on l-Orn − l-Ser − d-Glu. Strain BS-12MT contained demethylmenaquinone-9(H4) as the major menaquinone and anteiso-C15:0 and C16:0 as the major fatty acids. The major polar lipids of strain BS-12MT were phosphatidylinositol and phosphatidylinositolmannoside. The DNA G+C content of strain BS-12MT was 70.7 mol% and its DNA–DNA relatedness values with the type strains of five phylogenetically related species of the genus Demequina were 15–34 %. Differential phenotypic properties, together with phylogenetic and genetic distinctiveness, revealed that strain BS-12MT is separate from other species of the genus Demequina. On the basis of the data presented, strain BS-12MT is considered to represent a novel species of the genus Demequina, for which the name Demequina activiva sp. nov. is proposed. The type strain is BS-12MT ( = KCTC 29674T = NBRC 110675T).
Shape up or ship out: migratory behaviour predicts morphology across spatial scale in a freshwater fish
Authors: Chapman Ben B. , Hulthén Kaj , Brönmark Christer , Nilsson P. Anders , Skov Christian , Hansson Lars‐Anders , Brodersen Jakob
Published: March 2015

Migration is a widespread phenomenon, with powerful ecological and evolutionary consequences. Morphological adaptations to reduce the energetic costs associated with migratory transport are commonly documented for migratory species. However, few studies have investigated whether variation in body morphology can be explained by variation in migratory strategy within a species.

We address this question in roachRutilus rutilus, a partially migratory freshwater fish that migrates from lakes into streams during winter. We both compare body shape between populations that differ in migratory opportunity (open vs. closed lakes), and between individuals from a single population that vary in migratory propensity (migrants and residents from a partially migratory population). Following hydrodynamic theory, we posit that migrants should have a more shallow body depth, to reduce the costs associated with migrating into streams with higher flow conditions than the lakes the residents occupy all year round.

We find evidence both across and within populations to support our prediction, with individuals from open lakes and migrants from the partially migratory population having a more slender, shallow‐bodied morphology than fish from closed lakes and all‐year residents.

Our data suggest that a shallow body morphology is beneficial to migratory individuals and our study is one of the first to link migratory strategy and intraspecific variation in body shape.
Ambiguity in the Operator's Sense
Authors: van Stralen Daved , Mercer Thomas A.
Published: March 2015

Ambiguity is a central problem for operators working in dynamic, high‐risk environments. Operators must decide on a course of action before knowing with certainty how the system will respond. Though ambiguity is expected, how it presents is unexpected. We reduce ambiguity when we can give meaning to information and events through use of context, responsiveness of the system, and when we can view events from a higher level. Preparation and training for routine operations helps identify potential ambiguities before events begin. The experienced operator engages the situation relying on real‐time experience to learn what works through action, thus further reducing ambiguity.
Scatterhoarding rodents favor higher predation risks for cache sites: The potential for predators to influence the seed dispersal process
Authors: STEELE Michael A. , ROMPRÉ Ghislain , STRATFORD Jeffrey A. , ZHANG Hongmao , SUCHOCKI Matthew , MARINO Shealyn
Published: March 2015

Scatterhoarding rodents often place caches in the open where pilferage rates are reduced, suggesting that they tradeoff higher risks of predation for more secure cache sites. We tested this hypothesis in two study systems by measuring predation risks inferred from measures of giving‐up densities (GUDs) at known cache sites and other sites for comparison. Rodent GUDs were measured with small trays containing 3 L of fine sand mixed with sunflower seeds. In the first experiment, we relied on a 2‐year seed dispersal study in a natural forest to identify caches of eastern gray squirrels (Sciurus carolinensis) and then measured GUDs at: (i) these caches; (ii) comparable points along logs and rocks where rodent activity was assumed highest; and (iii) a set of random points. We found that GUDs and, presumably, predation risks, were higher at both cache and random points than those with cover. At the second site, we measured GUDs of eastern gray squirrels in an open park system and found that GUDs were consistently lowest at the base of the tree compared to more open sites, where previous studies show caching by squirrels to be highest and pilferage rates by naïve competitors to be lowest. These results confirm that predation risks can influence scatterhoarding decisions but that they are also highly context dependent, and that the landscape of fear, now so well documented in the literature, could potentially shape the temporal and spatial patterns of seedling establishment and forest regeneration in systems where scatterhoarding is common.
Role of Rhizomys pruinosus as a natural animal host of Penicillium marneffei in Guangdong, China
Authors: Huang Xiaowen , He Guohua , Lu Sha , Liang Yuheng , Xi Liyan
Published: March 2015

Penicillium marneffei, a dimorphic fungus that can cause penicilliosis marneffei, is endemic in Southeast Asia. The only known hosts of P. marneffei are humans and bamboo rats. The aim of our study was to explore the distribution of P. marneffei in bamboo rats, their associated environment and non‐rat‐associated environments. Totally, 270 samples were collected in Guangdong province of China in 2012; the prevalence of P. marneffei was much higher in samples collected from surrounding areas of burrows (8.2%) than in the samples obtained from non‐rat‐associated sites (2%) or artificial farms of bamboo rats (0%). There was no difference in P. marneffei isolated rate from different areas of Guangdong province. The infection is prevalent in all rats, and this fungus could be frequently seen in the rats' lungs. This study confirms that bamboo rat is the ecological niche of P. marneffei and hypothesizes that bamboo rats become infected by inhaling aerosolized conidia originating from environmental sources, rather than by the fecal–oral route or transplacental crossing. According to the result of no detection of P. marneffei in the artificial farm, the activity of bamboo rats might be more relevant to the distribution and dissemination of P. marneffei in natural environment.
Disentangling mite predator‐prey relationships by multiplex PCR
Authors: Pérez‐Sayas Consuelo , Pina Tatiana , Gómez‐Martínez María A. , Camañes Gemma , Ibáñez‐Gual María V. , Jaques Josep A. , Hurtado Mónica A.
Published: March 2015

Gut content analysis using molecular techniques can help elucidate predator‐prey relationships in situations in which other methodologies are not feasible, such as in the case of trophic interactions between minute species such as mites. We designed species‐specific primers for a mite community occurring in Spanish citrus orchards comprising two herbivores, the Tetranychidae Tetranychus urticae and Panonychus citri, and six predatory mites belonging to the Phytoseiidae family; these predatory mites are considered to be these herbivores’ main biological control agents. These primers were successfully multiplexed in a single PCR to test the range of predators feeding on each of the two prey species. We estimated prey DNA detectability success over time (DS50), which depended on the predator‐prey combination and ranged from 0.2 to 18 h. These values were further used to weight prey detection in field samples to disentangle the predatory role played by the most abundant predators (i.e. Euseius stipulatus and Phytoseiulus persimilis). The corrected predation value for E. stipulatus was significantly higher than for P. persimilis. However, because this 1.5‐fold difference was less than that observed regarding their sevenfold difference in abundance, we conclude that P. persimilis is the most effective predator in the system; it preyed on tetranychids almost five times more frequently than E. stipulatus did. The present results demonstrate that molecular tools are appropriate to unravel predator‐prey interactions in tiny species such as mites, which include important agricultural pests and their predators.
Application of extended Biologische Bundesantalt, Bundessortenamt and Chemische Industrie scale for phenological studies in longan (Dimocarpus longan)
Authors: Shi S.Y. , Li W.C. , Zhang H.N. , Liu L.Q. , Shu B. , Liang Q.Z. , Xie J.H. , Wei Y.Z.
Published: March 2015

Extended Biologische Bundesantalt, Bundessortenamt and Chemische Industrie scale was applied to achieve precise and normative description of each growth stage of longan. The entire growth cycle of longan was divided into seven primary stages, namely, development of shoots, leaves and branches, formation of inflorescence, flowering, fruit development and maturity. These primary stages were further subdivided into 47 secondary stages. This study focused on the entire fruit development process of longan. The correlation between phenology, temperature and humidity was also discussed. Knowledge of these rules will provide guidance for the implementation of production management measures, including fertilisation, disease and pest control, branch control, flower induction, flower and fruit retention and application of growth regulator. The present findings will also help longan planters to adopt the most appropriate cultivation and management measures according to the climate conditions and growth status of the trees.
Awareness of forensic odontology among dentists in Australia: are they keeping forensically valuable dental records?
Authors: Al‐Azri AR , Harford J , James H
Published: March 2015

Background

Forensic odontologists provide an important service to the community by identifying unknown deceased people, allowing both legal outcomes and family closure. Non‐visual identification may be achieved by comparison of post‐mortem data with ante‐mortem dental records provided by oral health practitioners. Success is dependent largely on the accuracy and adequacy of data in the dental records.

Methods

An online self‐administered questionnaire evaluated Australian dentists’ knowledge and behaviours relevant to forensic odontology. Reported record keeping practices were assessed for detail, legibility, accessibility and retention. Behaviours were classified according to the frequency of response.

Results

Dentists reported overall reasonable awareness of the major applications of forensic odontology. Personal information and details of restorative treatment were recorded at high levels, while tooth anomalies, photography, additional patient details and denture marking were recorded inadequately. Legible tooth coding was reported at a high level, while other key legibility practices were recorded inadequately. Few of the behaviours related to retention or to maximize accessibility were recorded at a high level.

Conclusions

Australian dentists have high expectations of the forensic value of their dental records; however, many processes that would enhance the diagnostic, medico‐legal and forensic value of dental records are not routinely applied.
Evaluating the impact of rising fertilizer prices on crop yields
Authors: Brunelle T. , Dumas P. , Souty F. , Dorin B. , Nadaud F.
Published: March 2015

Because of tensions on fossil energy and phosphorus markets, the rise in fertilizer prices observed during the last decades may continue in the future, putting into question production pathways relying heavily on crop intensification. To evaluate how, in this context, economic choices may alter crop yields, we first construct different fertilizer price scenarios to 2050 based on an econometric relation with oil and gas prices. Other possible scenarios, such as the continuation of historical trends, are also considered. The resulting changes in fertilizer price range between +0.8% and +3.6% per year over the 2005–2050 period. These scenarios are tested in a global land‐use model incorporating an endogenous representation of the land–fertilizer substitution. We find that the supply‐side response to rising fertilizer prices could lower crop yields in 2050 from −6% to −13%, with a corresponding increase in global cropland area ranging between 100 and 240 Mha if the demand for food and nonfood products has to be met. The sensitivity of these results is tested with regard to assumptions on food consumption, change in potential yield and nutrient use efficiency.
Antidiabetic Agents and Endothelial Dysfunction – Beyond Glucose Control
Authors: Eriksson Linnéa , Nyström Thomas
Published: March 2015

Diabetes is rapidly increasing worldwide, and the number of patients suffering from diabetes is projected to rise by 50% over the next 25 years, then affecting almost 600 million adults. Type 2 diabetes comprises 90–95% of all people with diabetes, and they constitute a patient group that carries a high burden of cardiovascular disease. The relationship between hyperglycaemia and macrovascular complications is still uncertain, at least in terms of the possibility of reducing cardiovascular events solely by improving glycaemic control. This MiniReview has thus focused on the effect of common antidiabetic agents, with emphasis on glucagon‐like peptide‐1, on the endothelial cells of the vasculature. Patients with type 2 diabetes suffer a two to four times higher risk of myocardial infarction and stroke than healthy persons. In addition to this, patients with diabetes have an increased atherosclerotic burden. Endothelial dysfunction is thought to be an early and important predictor of atherosclerosis and cardiovascular disease, and in people with type 2 diabetes, endothelial dysfunction is a common finding. It is therefore of importance to consider whether drugs used within the clinical management of Type 2 diabetes mellitus (T2DM) exert direct and positive effects on the vasculature independent of their glucose‐lowering ability. This might serve to limit the adverse consequences of the macrovascular complications of T2DM, as dysfunction of endothelial cells is believed to contribute to a premature development of atherosclerosis.
Activation of the Prostaglandin E2 receptor EP2 prevents house dust mite‐induced airway hyperresponsiveness and inflammation by restraining mast cells’ activity
Authors: Serra‐Pages M. , Torres R. , Plaza J. , Herrerias A. , Costa‐Farré C. , Marco A. , Jiménez M. , Maurer M. , Picado C. , de Mora F.
Published: March 2015

Background

Prostaglandin E2 (PGE2) has been proposed to exert antiasthmatic effects in patients, to prevent antigen‐induced airway pathology in murine models, and to inhibit mast cells (MC) activity in vitro.

Objective

To assess in a murine model whether the protective effect of PGE2 may be a consequence of its ability to activate the E‐prostanoid (EP)2 receptor on airway MC.

Methods

Either BALB/c or C57BL/6 mice were exposed intranasally (i.n.) to house dust mite (HDM) aeroallergens. Both strains were given PGE2 locally (0.3 mg/kg), but only BALB/c mice were administered butaprost (EP2 agonist: 0.3 mg/kg), or AH6809 (EP2 antagonist; 2.5 mg/kg) combined with the MC stabilizer sodium cromoglycate (SCG: 25 mg/kg). Airway hyperresponsiveness (AHR) and inflammation, along with lung MC activity, were evaluated. In addition, butaprost's effect was assessed in MC‐mediated passive cutaneous anaphylaxis (PCA) in mice challenged with 2,4‐dinitrophenol (DNP).

Results

Selective EP2 agonism attenuated aeroallergen‐caused AHR and inflammation in HDM‐exposed BALB/c mice, and this correlated with a reduced lung MC activity. Accordingly, the blockade of endogenous PGE2 by means of AH6809 worsened airway responsiveness in sensitive BALB/c mice, and such worsening was reversed by SCG. The relevance of MC to PGE2‐EP2 driven protection was further highlighted in MC‐dependent PCA, where butaprost fully prevented MC‐induced ear swelling. Unlike in BALB/c mice, PGE2 did not protect the airways of HDM‐sensitized C57BL/6 animals, a strain in which we showed MC to be irrelevant to aeroallergen‐driven AHR and inflammation.

Conclusions & Clinical Relevance

The beneficial effect of both exogenous and endogenous PGE2 in aeroallergen‐sensitized mice may be attributable to the activation of the EP2 receptor, which in turn acts as a restrainer of airway MC activity. This opens a path towards the identification of therapeutic targets against asthma along the ‘EP2 ‐MC‐airway’ axis.
Therapeutic effects of growth hormone combined with low‐dose stanozolol on growth velocity and final height of girls with Turner syndrome
Authors: Xiong Hui , Chen Hong‐Shan , Du Min‐Lian , Li Yan‐Hong , Ma Hua‐Mei , Su Zhe , Chen Qiu‐Li
Published: March 2015

Objective

Turner syndrome (TS), which is characterized by short stature and gonadal dysfunction, is managed by pharmacotherapy. This study aimed to investigate the therapeutic effects of recombinant human growth hormone (rhGH) combined with low‐dose stanozolol on the growth and final adult height (FAH) of girls with Turner syndrome (TS).

Design

Prospective study.

Patients

A total of 44 girls with TS were treated with rhGH (47·6–52·4 μg/kg/day) and low‐dose stanozolol (20–35 μg/kg/day), starting at a mean age of 12·65 ± 1·99 year. The control group consisted of 22 girls with TS, who did not receive treatment.

Measurements

Subjects’ growth velocity (GV) was investigated. Height standard deviation score (HtSDS) was calculated relative to healthy Chinese girls (HtSDSNor) as well as untreated Chinese girls with TS (HtSDSTS). Post‐treatment follow‐up was performed until the subjects achieved FAH or near FAH.

Results

FAH was significantly higher in subjects receiving treatment compared to the untreated controls (151·42 vs 137·75 cm, P < 0·001). GV was significantly higher in the first to fourth years of treatment compared to baseline values (P < 0·001); it was significantly lower in the second to fourth years of treatment compared to the first year (P < 0·001).

Conclusions

In girls with TS, 9–12 years of age, rhGH combined with low‐dose stanozolol may effectively increase growth. At least a 2‐year course of this treatment may effectively improve FAH with proper delay of oestrogen‐induced development.
Comparative ex vivo study on humidifying function of three speaking valves with integrated heat and moisture exchanger for tracheotomised patients
Authors: van den Boer C. , Lansaat L. , Muller S.H. , van den Brekel M.W.M. , Hilgers F.J.M.
Published: March 2015

Objective

Assessment of humidifying function of tracheotomy speaking valves with integrated heat and moisture exchanger.

Design

Ex vivo measurement of water exchange and storage capacity of three tracheotomy speaking valves: Humidiphon Plus, Spiro and ProTrach DualCare (with two different heat and moisture exchangers: XtraMoist and Regular).

Setting

Comprehensive Cancer Centre.

Participant

Healthy volunteer.

Main outcome measures

Difference between end‐inspiratory and end‐expiratory weight as measure for water exchange capacity, weight after 10 min breathing as measure for water storage capacity, weighing at 1‐min intervals to assess residual water exchange potential in speaking mode and absolute humidity in mg/L as measure for environmental and respiratory humidity.

Results

None of the tracheotomy speaking valves provides humidification while in speaking mode. Only the ProTrach DualCare allows blocking the speaking valve and breathing through the heat and moisture exchanger during inhalation and exhalation (heat and moisture exchanger mode). This leads to an increase in inspiratory humidity of 2.5 mg (XtraMoist) and 1.6 mg (Regular). There was no measurable water storage in speaking mode in any of the three tracheotomy speaking valves. In breathing mode, water storage in the DualCare heat and moisture exchangers was 47 and 37 mg, respectively. The remaining humidifying potential in speaking mode after 10 min breathing in heat and moisture exchanger mode for XtraMoist was 38%, 15% and 10% at 1, 2 and 3 min, respectively. For Regular, this was 47%, 24% and 13%, respectively.

Conclusions

Tracheostoma valves with integrated heat and moisture exchanger have no humidification function in speaking mode. Only ProTrach DualCare, allowing blocking the speaking mode, in heat and moisture exchanger mode enables a significant increase in humidification. Regular switching between speaking and heat and moisture exchanger mode with this latter device prolongs the humidification in speaking mode.
Establishment and characterization of a novel VEGF‐producing HHV‐8‐unrelated PEL‐like lymphoma cell line, OGU1
Authors: Kawauchi Kiyotaka , Ogasawara Toshie , Aiba Motohiko , Fujibayashi Mariko , Sanaka Tsutomu , Sakura Hiroshi , Shibuya Masabumi
Published: April 2015

Primary effusion lymphoma (PEL) is a rare B‐cell lymphoma subtype that is characterized by lymphomatous effusion without the presence of masses, and it typically occurs in human immunodeficiency virus (HIV)‐infected individuals. Lymphoma cells are universally positive for human herpesvirus 8 (HHV‐8). Recently, a cavity‐based effusion lymphoma that is similar to PEL without HHV‐8 infection, called HHV‐8‐unrelated PEL‐like lymphoma, has been reported in non‐HIV‐infected individuals. However, the pathophysiology of this lymphoma is largely undefined. We established a novel B‐cell line OGU1 derived from a patient with HHV‐8‐unrelated PEL‐like lymphoma. Notably, OGU1 cells produced vascular endothelial growth factor (VEGF) and expressed VEGF receptor 1, whose inhibitors retarded cell growth. Because VEGF acts as a vascular permeability and growth factor, it could play a role, at least in part, in the pathogenesis of this unique lymphoma. Thus, the OGU1 cell line is useful for the investigation of HHV‐8‐unrelated PEL‐like lymphoma.
T‐cell chronic lymphocytic leukemia or small‐cell variant of T‐cell prolymphocytic leukemia: a historical perspective and search for consensus
Authors: Rashidi Armin , Fisher Stephen I.
Published: April 2015

There is a rich history behind the extinct entity ‘T‐cell chronic lymphocytic leukemia (T‐CLL)’ and the now‐established replacement, small‐cell variant of T‐cell prolymphocytic leukemia (T‐PLL‐sv). Herein, we review the history of the events, observations, and discussions that led to this replacement. We also provide a systematic analysis of all previously reported cases of T‐PLL‐sv as well as our four new additional cases. Despite the higher frequency of a normal karyotype and perhaps an overrepresented CD4−CD8− immunophenotype among these patients (compared to T‐PLL in general) as well as bland morphology (that makes them superficially appear more similar to B‐CLL), we argue that the current World Health Organization (WHO)‐based classification as T‐PLL‐sv is adequate and should continue for the time being. Morphologically, T‐PLL‐sv represents approximately one‐fifth of all T‐PLL cases. However, morphology alone does not determine the clinical course and should not be the basis for clinical decision making and prognostication. We propose a clonal evolution model in which mature T‐cell leukemias classified in the past as T‐CLL are perhaps T‐PLL diagnosed early in the course of the disease. Future research using next‐generation sequencing, comparative genomic hybridization, and molecular array studies, including serial analyses of individual cases over time, is needed to better identify this rarely diagnosed, inherently controversial form of T‐cell leukemia.
STAT3 the oncogene – still eluding therapy?
Authors: Wake Matthew S. , Watson Christine J.
Published: March 2015

The STAT family of transcription factors (signal transducers and activators of transcription) transduce signals from cytokine receptors to the nucleus, where STAT dimers bind to DNA and regulate transcription. STAT3 is the most ubiquitous of the STATs, being activated by a wide variety of cytokines and growth factors. STAT3 has many roles in physiological processes such as inflammatory signalling, aerobic glycolysis and immune suppression, and was also the first family member shown to be aberrantly activated in a wide range of both solid and liquid tumours. STAT3 promotes tumorigenesis by regulating the expression of various target genes, including cell‐cycle regulators, angiogenic factors and anti‐apoptosis genes. Paradoxically, in some circumstances, STAT3 signalling induces cell death. The best known example is the involuting mammary gland, where STAT3 is essential for induction of a lysosomal pathway of cell death. Nevertheless, direct silencing or inhibition of STAT3 diminishes tumour growth and survival in both animal and human studies. This suggests that abolishing STAT3 activity may be an effective cancer therapeutic strategy. However, despite this potential as a therapeutic target, and the extensive attempts by many laboratories and pharmaceutical companies to develop an effective STAT3 inhibitor for use in the clinic, no direct STAT3 inhibitor has been approved for clinical use. In this review, we focus on the role of STAT3 in tumorigenesis, and discuss its potential as a therapeutic target for cancer treatment.
Novel familial dilated cardiomyopathy mutation in MYL2 affects the structure and function of myosin regulatory light chain
Authors: Huang Wenrui , Liang Jingsheng , Yuan Chen‐Ching , Kazmierczak Katarzyna , Zhou Zhiqun , Morales Ana , McBride Kim L. , Fitzgerald‐Butt Sara M. , Hershberger Ray E. , Szczesna‐Cordary Danuta
Published: March 2015

Dilated cardiomyopathy (DCM) is a disease of the myocardium characterized by left ventricular dilatation and diminished contractile function. Here we describe a novel DCM mutation in the myosin regulatory light chain (RLC), in which aspartic acid at position 94 is replaced by alanine (D94A). The mutation was identified by exome sequencing of three adult first‐degree relatives who met formal criteria for idiopathic DCM. To obtain insight into the functional significance of this pathogenic MYL2 variant, we cloned and purified the human ventricular RLC wild‐type (WT) and D94A mutant proteins, and performed in vitro experiments using RLC‐mutant or WT‐reconstituted porcine cardiac preparations. The mutation induced a reduction in the α‐helical content of the RLC, and imposed intra‐molecular rearrangements. The phosphorylation of RLC by Ca2+/calmodulin‐activated myosin light chain kinase was not affected by D94A. The mutation was seen to impair binding of RLC to the myosin heavy chain, and its incorporation into RLC‐depleted porcine myosin. The actin‐activated ATPase activity of mutant‐reconstituted porcine cardiac myosin was significantly higher compared with ATPase of wild‐type. No changes in the myofibrillar ATPase–pCa relationship were observed in wild‐type‐ or D94A‐reconstituted preparations. Measurements of contractile force showed a slightly reduced maximal tension per cross‐section of muscle, with no change in the calcium sensitivity of force in D94A‐reconstituted skinned porcine papillary muscle strips compared with wild‐type. Our data indicate that subtle structural rearrangements in the RLC molecule, followed by its impaired interaction with the myosin heavy chain, may trigger functional abnormalities contributing to the DCM phenotype.
Effects of large river restoration on currently used bioindicators and alternative metrics
Authors: Dolédec Sylvain , Forcellini Maxence , Olivier Jean‐Michel , Roset Nicolas
Published: March 2015

Data‐rich restoration experiments offer opportunities to test the ability of bioassessment tools, such as those currently used to assess the ‘ecological status’ of waterbodies targeted by the European Water Framework Directive, to detect observed ecological changes.

Minimum flow increases in four regulated reaches of the French Rhône River modified the invertebrate and fish communities in a predictable way, as detailed in other articles of this Special Issue. We tested the ability of several fish and macroinvertebrate metrics currently used in bioassessment to detect these changes. In addition, we considered changes in metrics that are expected to respond specifically to flow increase. These metrics were related to the habitat requirements of species, the ecological specialisation of communities and the abundance of macroinvertebrate functional groups (seen as surrogates for ecosystem attributes).

For invertebrate communities, bioassessment metrics based on richness had equivocal responses to restoration and the Potamon‐Type Index demonstrated no or contradictory responses to restoration. The French biotic index was not sensitive to restoration and instead depicted spatial differences in biological quality. For fish communities, the French fish index was marginally sensitive in the reach with the largest minimum flow increase and some of its metrics were sensitive in other reaches.

Contrasting with commonly used bioassessment indices and metrics, several metrics related to habitat requirements appropriately indicated the observed changes in community structure. Large flow changes increased the proportion of fish and macroinvertebrate individuals with preferences for midstream habitats, fast currents, deep waters and/or coarse substrates. However, these changes did not translate into the expected increase in ecological specialisation. In addition, functional metrics indicated that restoration led to higher proportions of grazers and higher availability of suspended food for filtering collectors, suggesting a return to the ecological conditions of a large river.

The mixed and potentially contradictory responses of the different metrics confirm the difficulty of establishing benchmarks for ecological indicators in large‐regulated rivers and the need to design appropriate bioassessment metrics.
Indexing livelihood vulnerability to the effects of typhoons in indigenous communities in Taiwan
Authors: Lin Kuan‐Hui Elaine , Polsky Colin
Published: April 2015

The theoretical importance of understanding how livelihoods shape local vulnerability to the effects of climate change has received broad attention, but with relatively few attempts to produce and implement an analytical framework based on the theory. This study develops a livelihood vulnerability analytical framework, and applies it to the case of rural indigenous communities of Taiwan that are regularly exposed to typhoons and associated geological hazards. Measures of the factors influencing how typhoons impact these indigenous communities (sensitivities), and of the abilities of such communities to respond in anticipatory or reactive modes (adaptive capacities) are also included. The study is based on mixed qualitative and quantitative analysis, combining data from in‐person interviews and surveys from 2006 to 2009. Livelihood vulnerability narratives are developed accordingly, together with a spatially‐explicit livelihood vulnerability index to diagnose the dimensionality and the distribution of vulnerability across the area. Three patterns of livelihood vulnerability are found including least vulnerable communities in the remotest area with relatively abundant livelihood capitals to mitigate vulnerability, intermediate vulnerability communities which are doubly exposed to market and typhoon‐associated stresses, and the most vulnerable communities trapped in poverty and vulnerability loops. The patterns reveal strong spatial relationships of social development beginning with the Japanese colonial government (1895–1945) and continuing through the Kuomintang Chinese government (1945–present). This historical development shaped the original human‐environmental conditions in each community and the inequality continues to expand due to increased hazard risk and inappropriate policy interventions. This study highlights the need for future research to develop a continuous program for longitudinally tracking the dynamism of the three patterns of vulnerability.