bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional responses of multitaxa communities to disturbance and stress gradients in a restored floodplain
Authors: Fournier Bertrand , Gillet François , Le Bayon Renée‐Claire , Mitchell Edward A. D. , Moretti Marco
Published: July 2015

Trait‐based approaches can reveal the mechanisms through which disturbances or stress impact communities, allowing comparisons of the role of different mechanisms in shaping communities among taxonomic groups. Such information can lead to higher comparability, transferability and predictability of the outcome of restoration projects. However, multitaxa trait‐based approaches were rarely used in the context of ecosystem restoration.

We investigated the responses to environmental gradients of seven taxa (vascular plants, staphylinid and carabid beetles, spiders, isopods, diplopods and earthworms) in a restored floodplain using a species traits approach. We assessed the impact of flood disturbances and soil hydric stress on the functional diversity (FD) and community‐weighted mean (CWM) response of traits for each taxon.

Ordination of hydrological variables revealed two main gradients. The first was related to the spatiotemporal dynamics of flood disturbances and the second to the average changes in soil hydric conditions.

The analysis of CWM revealed that larger, poorly mobile species with narrow ecological tolerances were filtered by regular floods and/or changes in soil hydric conditions.

Functional diversity patterns differed between the two gradients: decreasing with increasing flood disturbance, but increasing along the soil hydric stress gradient. This suggests that the mechanisms shaping community composition differ between the two gradients with environmental filtering being dominant with increasing flood disturbances and competition decreasing with more soil hydric stress.

Synthesis and applications. Our study shows that the impact of restored flood disturbances and soil hydric stress on plant and invertebrate functional diversity and community‐weighted mean can be positive, negative or more complex depending on the taxonomic group and environmental gradient considered. The patterns can to some extent be explained by the specific characteristics of each group. Larger, poorly mobile species with narrow ecological tolerances were particularly vulnerable to changes in disturbance and stress regime following floodplain restoration. These species may therefore be lost in the initial phases of restoration projects, but other more characteristic species of dynamic floodplains will be favoured. Understanding the consequences of these contrasted responses for biodiversity conservation and ecosystem functioning constitutes the next challenge for ecosystem restoration.
A two‐domain protein triggers heat shock pathway and necrosis pathway both in model plant and nematode
Authors: Ruan Lifang , Wang Huihui , Cai Ge , Peng Donghai , Zhou Hua , Zheng Jinshui , Zhu Lei , Wang Xixi , Yu Haoquan , Li Seng , Geng Ce , Sun Ming
Published: July 2015

The entomopathogen Bacillus thuringiensis is equipped with multiple virulent factors. The genome sequence of B. thuringiensis YBT1520 revealed the presence of a two‐domain protein named Nel which is composed of a necrosis‐inducing phytophthora protein 1‐like domain found in phytopathogens and a ricin B‐like lectin domain. The merging of two distantly related domains is relatively rare. Nel induced necrosis and pathogen‐triggered immunity (PTI) on model plants. The Nel also exhibited inhibition activity to nematode. Microscopic observation showed that the toxicity of Nel to nematodes targets the intestine. Quantitative proteomics revealed that Nel stimulated the host defence. The Nel thus possesses dual roles, as both toxin and elicitor. Remarkably, the Nel protein triggered a similar response, induction of the heat shock pathway and the necrosis pathway, in both model plants and nematodes. The unusual ability of Nel to function across kingdom suggests a highly conserved mechanism in eukaryotes that predates the divergence of plants and animal. It is also speculated that the two‐domain protein is the result of horizontal gene transfer (HGT) between phytopathogens and entomopathogens. Our results provide an example that HGT occurs between members of different species or even genera with lower frequency are particularly important for evolution of new bacterial pathogen lineages with new virulence. Bacillus thuringiensis occupies the same ecological niches, plant and soil, as phytopathogens, providing the opportunity for gene exchange.
Metallome of Pseudomonas aeruginosa: a role for siderophores
Authors: Cunrath Olivier , Geoffroy Valérie A. , Schalk Isabelle J.
Published: July 2015

In this paper, we describe the total metal composition (metallome) of Pseudomonas aeruginosa. Inductively coupled plasma atomic emission spectroscopy analyses showed that P. aeruginosa cells concentrate each metal of the metallome from the extracellular media with different efficiencies. Growth in nutrient‐restricted media did not substantially affect the overall profile of the metallome; however, the uptake of some metals was strongly stimulated, showing the high potential of some metal acquisition pathways to adapt to changing growth conditions. We also investigated the role of the two major siderophores produced by P. aeruginosa, pyoverdine and pyochelin, in iron uptake and more generally in metallome homeostasis. In addition to their role in iron acquisition, siderophore production also significantly prevented the accumulation of toxic metals in P. aeruginosa cells, thus preserving the equilibrium of the metallome in a polluted environment.
Intensive multi‐family therapy for adolescent anorexia nervosa: an open study of 30 families
Authors: Salaminiou Eva , Campbell Mari , Simic Mima , Kuipers Elizabeth , Eisler Ivan
Published: July 2015

The article reports on an innovative treatment for adolescent anorexia nervosa (AN) – intensive multi‐family therapy – in terms of symptoms, patients’ and parental psychological functioning and treatment acceptability. In all, thirty patients and their families took part in the study and were assessed at baseline, 3 and 6 months. At 6 months two‐thirds had gained sufficient weight to be in the normal weight range with significant improvements in AN cognition, mood and self‐esteem. Only two of the thirty families discontinued treatment early and both patients and parents scored high on treatment satisfaction, though parents scored significantly higher than patients. These results compare favourably with outcome data from larger more rigorous evaluations of single family therapy for adolescent AN currently considered to be the treatment of choice. While larger, randomized studies are needed, the results are promising and suggest that multi‐family therapy may be a useful additional treatment approach for this group of young people.

Practitioner points

Multi‐family therapy may provide an effective intervention for adolescent anorexia nervosa and compares well with other, more rigorously evaluated interventions.

Multi‐family therapy is highly successful in engaging families in treatment leading to minimal dropout rates.

Satisfaction with multi‐family therapy is high for both adolescents and parents.
Parent‐therapist alliance and parent attachment‐promoting behaviour in attachment‐based family therapy for suicidal and depressed adolescents
Authors: Feder Menachem M. , Diamond Gary M.
Published: July 2015

This study examines whether the strength of the parent‐therapist alliance, measured during the task of alliance building with parents alone, predicted the extent of parents’ attachment‐promoting behaviour in the subsequent conjoint parent‐adolescent attachment task in the context of attachment‐based family therapy (ABFT). Nineteen suicidal and depressed adolescents and their parents received 12 weeks of ABFT. The parent‐therapist alliance and parents’ attachment‐promoting behaviour were each measured observationally by two separate and independent groups of raters. The findings show that the strength of the parent‐therapist alliance predicted parents’ subsequent attachment‐promoting behaviour. However, parents’ attachment‐promoting behaviour did not predict the post‐treatment outcomes. Clinical and methodological implications are discussed.

Practitioner Points

Good parent-therapist alliances are linked to parents being empathic, curious and non‐defensive during emotional conversations with their suicidal and depressed adolescents.

Parental attachment‐promoting behaviour, including attunement, empathy, and active listening, may not always be sufficient curative factors.

Once the parent‐adolescent attachment relationship improves, parents may support their adolescent as they cope with school and peer conflict.
Family therapists’ adult attachment styles and the therapeutic alliance
Authors: Yusof Yusmarhaini , Carpenter John
Published: July 2015

Therapists’ adult attachment style may affect their ability to form effective therapeutic alliances. An analysis of semi‐structured interviews with eleven family therapists explored the relationship between their adult attachment styles, as assessed using a self‐report measure, and their perceptions of the therapeutic alliance. A framework analysis was employed, using four dimensions of the therapeutic alliance: engagement in the therapeutic process, emotional connection to the therapist, safety within the therapeutic system and shared sense of purpose within the family. Responses were compared between therapists with secure and insecure attachment styles according to different dimensions of the therapeutic alliance. There were no substantial differences in therapists’ accounts of their approach to engagement and creating a sense of safety; however they differed in their approaches to managing clients’ hostility. Secure and insecure therapists differed in one of the dimensions of therapeutic alliance; emotional connections to family members. Training and supervision could incorporate an understanding of attachment style. Suggestions are made for future research based on this exploratory study.

Practitioner Points

The ability to co‐create a secure base may be related to the therapist's adult attachment style.

Therapists with insecure attachment styles appear to have difficulty in managing clients’ hostility and close emotional connections.

Trainees may benefit from understanding their own adult attachment styles and resolving outstanding family‐of‐origin issues.

Clinical supervision could reflect on the interaction between the therapist's and family attachment styles.
Seselelame: feelings in the body: working alongside systemic ideas
Authors: Jude Julia
Published: July 2015

This article explores the way I use my cultural heritage as a tool to expand upon and develop skills in working with families, and how I then experience my position as a systemic therapist, interweaving systemic ideas and the intimacies of my own cultural heritage I examine the differences and similarities between systemic knowledge and practice, and African oral traditional ideas. Reclaiming my cultural heritage is the focus of this article and I explore the useful contribution it can make in the systemic field. Practical examples are given to illustrate the applicability of the ideas.

Practitioner points

African oral traditions (seselelame) characterize a dialogical feeling in the body that complements systemic family therapy and practice.

In seselelame human knowing is as valuable as western theories of knowledge.

Seselelame offers an appreciation of lived moments and encourages awareness of self (human knowing) as a means of sense‐making.

Seselelame practice reinforces the idea that the senses are natural resources.
Commercial Lobbying in Australia: Exploring the Australian Lobby Register
Authors: Halpin Darren , Warhurst John
Published: July 2015

Politicians and policy makers routinely engage with lobbyists and see them as crucial agents in the political process. But how much do we really know about the Australian lobby system? Although there are a range of reviews of lobby regulation schemes and discussions about the work of lobbyists, a comprehensive contemporary picture of the commercial lobbying system in Australia is missing. Using data from the ‘federal lobby register’, this article sets out to map the commercial lobbying scene at the national level. Using this as a backdrop, the article goes on to discuss what questions this raises and how we might develop a deeper understanding of the commercial lobbying system in Australia.
Voter Engagement, Electoral Inequality and First‐Time Compulsory Voting
Authors: Birch Sarah , Lodge Guy
Published: July 2015

This paper reviews the problem of declining turnout and proposes as a solution a system whereby each elector would be legally obliged to vote in the first election for which they were eligible. Popular attitudes toward first‐time compulsory voting are measured and probed by means of UK data. The main findings of the paper are that first‐time compulsory voting is a politically and administratively feasible proposal that appears tentatively to command popular support and has the potential to help address a number of the problems associated with declining turnout, and in particular low rates of electoral participation among younger citizens.
‘Keeping the Story Alive’: Is Ethnic and Racial Dilution Inevitable for Multiracial People and their Children?
Authors: Song Miri , Gutierrez Caitlin O'Neill
Published: July 2015

This paper explores how multiracial parents with White partners articulate narratives of ethnic and racial ‘dilution’ and cultural loss in relation to the socialization of their children. In our broader study of how multiracial parents raise their children, we found that parents commonly spoke of concerns around dilution and generational change in relation to four key themes: the loss of cultural knowledge and diminishing practices that connected parents and their children to a minority ancestry; the embodiment of White-appearing children and the implications of this for family relationships; the use of biological or genetic discourses in relation to reduced blood quantum; and concerns amongst Black/White participants about whitening and the loss of racial consciousness. Parental understandings of dilution varied greatly; some expressed sadness at ‘inevitable’ loss; others were more philosophical about generational change; and others still proactively countered loss through strategies to connect their children to their minority heritages. We show that despite growing awareness of the social constructedness of race and an emergent cosmopolitanism among these parents, discourses of genetics, cultural lineage, and the ‘naturalness’ of race continue to hold sway amongst many multiracial parents.
Downloading plug‐ins for nationalism and cosmopolitanism
Authors: Tabak Edin
Published: July 2015

A crucial factor in differentiation between existing approaches to nationalism and cosmopolitanism is the positioning of these approaches within a continuum between particularism and universalism, based on their understanding of space and time. However, this also poses a major difficulty in studying practices of nationalism and cosmopolitanism: Reducing these practices to a position within the particularism/universalism continuum establishes different forms of nationalism and cosmopolitanism as ‘order of things’, through which any practice is projected as an approximation or a distortion of this ideal ‘order’. Such a projection tells more about the researchers' own theoretical commitments than the participants' practices. This article utilizes some conceptual tools fromActor‐NetworkTheory in an effort to establish a sketch for an alternative projection to study practices of nationalism and cosmopolitanism, which will give the participants an opportunity to perform their own time and space, instead of reducing them to placeholders of an already determined position, a priori identified by researchers.
Revisiting resource selection probability functions and single‐visit methods: clarification and extensions
Authors: Sólymos Péter , Lele Subhash R.
Published: July 2015

Models accounting for imperfect detection are important. Single‐visit (SV) methods have been proposed as an alternative to multiple‐visit methods to relax the assumption of closed population. Knape & Korner‐Nievergelt (Methods in Ecology and Evolution, 2015) showed that under certain models of probability of detection,SVmethods are statistically non‐identifiable leading to biased population estimates.

There is a close relationship between estimation of the resource selection probability function (RSPF) using weighted distributions andSVmethods for occupancy and abundance estimation. We explain the precise mathematical conditions needed forRSPFestimation as stated in Lele & Keim (Ecology, 87, 2006, 3021). The identical conditions that remained unstated in our papers onSVmethodology are needed forSVmethodology to work. We show that the class of admissible models is quite broad and does not excessively restrict the application of theRSPFor theSVmethodology.

To complement the work by Knape and Korner‐Nievergelt, we study the performance of multiple‐visit methods under the scaled logistic detection function and a much wider set of situations. In general, under the scaled logistic detection function, multiple‐visit methods also lead to biased estimates.

As a solution to this problem, we extend theSVmethodology to a class of models that allows use of scaled probability function. We propose a multinomial extension ofSVmethodology that can be used to check whether the detection function satisfies theRSPFcondition or not. Furthermore, we show that if the scaling factor depends on covariates, then it can also be estimated.

We argue that the instances where theRSPFcondition is not satisfied are rare in practice. Hence, we disagree with the implication in Knape & Korner‐Nievergelt (Methods in Ecology and Evolution, 2015) that the need forRSPFcondition makesSVmethodology irrelevant in practice.
Regional brain volumes, diffusivity, and metabolite changes after electroconvulsive therapy for severe depression
Authors: Jorgensen A. , Magnusson P. , Hanson L. G. , Kirkegaard T. , Benveniste H. , Lee H. , Svarer C. , Mikkelsen J. D. , Fink‐Jensen A. , Knudsen G. M. , Paulson O. B. , Bolwig T. G. , Jorgensen M. B.
Published: July 2015

Objective

To investigate the role of hippocampal plasticity in the antidepressant effect of electroconvulsive therapy (ECT).

Method

We used magnetic resonance (MR) imaging including diffusion tensor imaging (DTI) and proton MR spectroscopy (1H‐MRS) to investigate hippocampal volume, diffusivity, and metabolite changes in 19 patients receiving ECT for severe depression. Other regions of interest included the amygdala, dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex, and hypothalamus. Patients received a 3T MR scan before ECT (TP1), 1 week (TP2), and 4 weeks (TP3) after ECT.

Results

Hippocampal and amygdala volume increased significantly at TP2 and continued to be increased at TP3. DLPFC exhibited a transient volume reduction at TP2. DTI revealed a reduced anisotropy and diffusivity of the hippocampus at TP2. We found no significant post‐ECT changes in brain metabolite concentrations, and we were unable to identify a spectral signature at ≈1.30 ppm previously suggested to reflect neurogenesis induced by ECT. None of the brain imaging measures correlated to the clinical response.

Conclusion

Our findings show that ECT causes a remodeling of brain structures involved in affective regulation, but due to their lack of correlation with the antidepressant effect, this remodeling does not appear to be directly underlying the antidepressant action of ECT.
A human needs approach to revealing nature's benefits for visitors to the coast
Authors: Willis Cheryl
Published: July 2015

The positive influence on psychological well‐being of interactions in nature appears to be particularly important in understanding the profound connections that people have with natural environments. Such influences have been recorded as being associated with increases in self‐esteem, feelings of rejuvenation and renewal as well as stress reduction. To a large extent, these understandings have been garnered through laboratory experiments to elicit preferences for different environments, frequently comparing contrasting scenes such as urban and rural. This paper aims to describe and evaluate a methodology for assessing and measuring, in‐situ, how interactions at the coast contribute to a range of dimensions associated with psychological well‐being. It describes the development and the empirical testing of this methodology, which is based on the premise that certain human needs can be satisfied through interactions in nature that positively influence psychological well‐being. Specifically, indicators of human needs were incorporated into a survey using a Likert scale to capture the extent to which needs were satisfied in two case‐study locations along the Jurassic Coast, Dorset. Based on the results of this study, it is concluded that this approach has merit as a methodology for determining the multiple ways in which psychological well‐being is influenced as a result of a specific visit to a unique setting and one that can be replicated for use in different environmental location.
Improved informed consent documents for biomedical research do not increase patients’ understanding but reduce enrolment: a study in real settings
Authors: Paris Adeline , Deygas Béatrice , Cornu Catherine , Thalamas Claire , Maison Patrick , Duale Christian , Kane Maty , Hodaj Enkelejda , Cracowski Jean‐Luc
Published: July 2015

Aims

The aim was to evaluate the comprehension of participants of an improved informed consent document (ICD).

Method

This was a randomized controlled French multicentre study performed in real conditions. Participants were adult patients undergoing screening for enrolment in biomedical research studies, who agreed to answer a validated questionnaire evaluating objective and subjective comprehension scored from 0 (no comprehension) to 100 (excellent comprehension). Patients were provided either the original ICD or an ICD modified in terms of structure and readability. The primary end point was the score of objective comprehension. The secondary end‐points were the enrolment rate in the clinical study and patient characteristics associated with the score of objective comprehension.

Results

Four hundred and eighty‐one patients were included, 241 patients in the original ICD group and 240 patients in the modified ICD group. There was no difference between the two groups for the score of objective comprehension (original ICD 72.7 (95% CI 71.3, 74.1) vs. modified ICD 72.5 (95% CI 71.0, 74.0); P = 0.81). However, the rate of enrolment in the clinical study was lower in the group who received the modified ICD (64.4% (95% CI 58.3, 70.5)) than for the original ICD (73.0% (95% CI 67.4, 78.7)) (P = 0.042). Only female gender and high educational level were associated with a better objective comprehension.

Conclusions

Improving ICDs had no effect on participants’ understanding, whereas the rate of enrolment was lower in this group. In attempts at improving potential participants’ understanding of clinical research information, efforts and future trials should focus on other ways to improve comprehension.
EMBO Workshop al fin del mundo: a meeting on membrane trafficking and its implication for polarity and diseases
Authors: Marzolo María‐Paz , Faundez Victor , Galli Thierry
Published: July 2015

The EMBO worskhop at the “end of the world’” (al fin del mundo), a meeting on membrane trafficking and its implication for polarity and diseases, took place in the Chilean Patagonia surrounded by the landscapes once witnessed by Charles Darwin. The meeting showcased some of the best membrane trafficking science with an emphasis in neuroscience and disease models. Speakers from Europe, USA, South America and the graduate students behind it; embarked on an enthusiastic and eclectic dialog where a wide range of cell types, model genetic systems, and diseases where discussed. This meeting demonstrated the power of trafficking concepts to integrate diverse biology and to formulate mechanisms of normal and disease cells.
The novel cardiac myosin activator omecamtiv mecarbil increases the calcium sensitivity of force production in isolated cardiomyocytes and skeletal muscle fibres of the rat
Authors: Nagy L , Kovács Á , Bódi B , Pásztor E T , Fülöp G Á , Tóth A , Édes I , Papp Z
Published: July 2015

Background and Purpose

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator drug for inotropic support in systolic heart failure. Here we have assessed the concentration‐dependent mechanical effects of OM in permeabilized cardiomyocyte‐sized preparations and single skeletal muscle fibres of Wistar‐Kyoto rats under isometric conditions.

Experimental Approaches

Ca2+‐dependent active force production (Factive), its Ca2+ sensitivity (pCa50), the kinetic characteristics of Ca2+‐regulated activation and relaxation, and Ca2+‐independent passive force (Fpassive) were monitored in Triton X‐100‐skinned preparations with and without OM (3nM‐10 μM).

Key Results

In permeabilized cardiomyocytes, OM increased the Ca2+ sensitivity of force production (ΔpCa50: 0.11 or 0.34 at 0.1 or 1 μM respectively). The concentration–response relationship of the Ca2+ sensitization was bell‐shaped, with maximal effects at 0.3–1 μM OM (EC50: 0.08 ± 0.01 μM). The kinetics of force development and relaxation slowed progressively with increasing OM concentration. Moreover, OM increased Fpassive in the cardiomyocytes with an apparent EC50 value of 0.26 ± 0.11 μM. OM‐evoked effects in the diaphragm muscle fibres with intrinsically slow kinetics were largely similar to those in cardiomyocytes, while they were less apparent in muscle fibres with fast kinetics.

Conclusions and Implications

OM acted as a Ca2+‐sensitizing agent with a downstream mechanism of action in both cardiomyocytes and diaphragm muscle fibres. The mechanism of action of OM is connected to slowed activation–relaxation kinetics and at higher OM concentrations increased Fpassive production.
Neutrophil elastase induces inflammation and pain in mouse knee joints via activation of proteinase‐activated receptor‐2
Authors: Muley Milind M , Reid Allison R , Botz Bálint , Bölcskei Kata , Helyes Zsuzsanna , McDougall Jason J
Published: July 2015

Background and Purpose

Neutrophil elastase plays a crucial role in arthritis. Here, its potential in triggering joint inflammation and pain was assessed, and whether these effects were mediated by proteinase‐activated receptor‐2 (PAR2).

Experimental Approach

Neutrophil elastase (5 μg) was injected into the knee joints of mice and changes in blood perfusion, leukocyte kinetics and paw withdrawal threshold were assessed. Similar experiments were performed in animals pretreated with the neutrophil elastase inhibitor sivelestat, the PAR2 antagonist GB83, the p44/42 MAPK inhibitor U0126 and in PAR2 receptor knockout (KO) mice. Neutrophil elastase activity was also evaluated in arthritic joints by fluorescent imaging and sivelestat was assessed for anti‐inflammatory and analgesic properties.

Key Results

Intra‐articular injection of neutrophil elastase caused an increase in blood perfusion, leukocyte kinetics and a decrease in paw withdrawal threshold. Sivelestat treatment suppressed this effect. The PAR2 antagonist GB83 reversed neutrophil elastase‐induced synovitis and pain and these responses were also attenuated in PAR2 KO mice. The MAPK inhibitor U0126 also blocked neutrophil elastase‐induced inflammation and pain. Active neutrophil elastase was increased in acutely inflamed knees as shown by an activatable fluorescent probe. Sivelestat appeared to reduce neutrophil elastase activity, but had only a moderate anti‐inflammatory effect in this model.

Conclusions and Implications

Neutrophil elastase induced acute inflammation and pain in knee joints of mice. These changes are PAR2‐dependent and appear to involve activation of a p44/42 MAPK pathway. Blocking neutrophil elastase, PAR2 and p44/42 MAPK activity can reduce inflammation and pain, suggesting their utility as therapeutic targets.

Linked Articles

This article is part of a themed section on Inflammation: maladies, models, mechanisms and molecules. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2016.173.issue-4
The novel PAR2 ligand C391 blocks multiple PAR2 signalling pathways in vitro and in vivo
Authors: Boitano Scott , Hoffman Justin , Flynn Andrea N , Asiedu Marina N , Tillu Dipti V , Zhang Zhenyu , Sherwood Cara L , Rivas Candy M , DeFea Kathryn A , Vagner Josef , Price Theodore J
Published: July 2015

Background and Purpose

Proteinase‐activated receptor‐2 (PAR2) is a GPCR linked to diverse pathologies, including acute and chronic pain. PAR2 is one of the four PARs that are activated by proteolytic cleavage of the extracellular amino terminus, resulting in an exposed, tethered peptide agonist. Several peptide and peptidomimetic agonists, with high potency and efficacy, have been developed to probe the functions of PAR2, in vitro and in vivo. However, few similarly potent and effective antagonists have been described.

Experimental Approach

We modified the peptidomimetic PAR2 agonist, 2‐furoyl‐LIGRLO‐NH2, to create a novel PAR2 peptidomimetic ligand, C391. C391 was evaluated for PAR2 agonist/antagonist activity to PAR2 across Gq signalling pathways using the naturally expressing PAR2 cell line 16HBE14o‐. For antagonist studies, a highly potent and specific peptidomimetic agonist (2‐aminothiazo‐4‐yl‐LIGRL‐NH2) and proteinase agonist (trypsin) were used to activate PAR2. C391 was also evaluated in vivo for reduction of thermal hyperalgesia, mediated by mast cell degranulation, in mice.

Key Results

C391 is a potent and specific peptidomimetic antagonist, blocking multiple signalling pathways (Gq‐dependent Ca2+, MAPK) induced following peptidomimetic or proteinase activation of human PAR2. In a PAR2‐dependent behavioural assay in mice, C391 dose‐dependently (75 μg maximum effect) blocked the thermal hyperalgesia, mediated by mast cell degranulation.

Conclusions and Implications

C391 is the first low MW antagonist to block both PAR2 Ca2+ and MAPK signalling pathways activated by peptidomimetics and/or proteinase activation. C391 represents a new molecular structure for PAR2 antagonism and can serve as a basis for further development for this important therapeutic target.
Enantioselective inhibition of d‐serine transport by (S)‐ketamine
Authors: Singh Nagendra S , Bernier Michel , Camandola Simonetta , Khadeer Mohammed A , Moaddel Ruin , Mattson Mark P , Wainer Irving W
Published: July 2015

Background and Purpose

Patients with major depressive disorder receiving racemic ketamine, (R,S)‐ketamine, experience transient increases in Clinician‐Administered Dissociative States Scale scores and a coincident drop in plasma d‐serine levels. The results suggest that (R,S)‐ketamine produces an immediate, concentration‐dependent pharmacological effect on d‐serine plasma concentrations. One potential source of this effect is (R,S)‐ketamine‐induced inhibition of the transporter ASCT2, which regulates intracellular d‐serine concentrations. In this study, we tested this hypothesis by examining the effect of (S)‐ and (R)‐ketamine on ASCT2‐mediated transport of d‐serine in PC‐12 and 1321N1 cells and primary neuronal cells in culture.

Experimental Approach

Intracellular and extracellular d‐serine levels were determined using capillary electrophoresis–laser‐induced fluorescence and liquid chromatography–mass spectrometry respectively. Expression of ASCT2, Asc‐1 and serine racemase was determined utilizing Western blotting.

Key Results

(S)‐Ketamine produced a concentration‐dependent increase in intracellular d‐serine and reduced extracellular d‐serine accumulation. In contrast, (R)‐ketamine decreased both intracellular and extracellular d‐serine levels. The ASCT2 inhibitor, benzyl‐d‐serine (BDS), and ASCT2 gene knockdown mimicked the action of (S)‐ketamine on d‐serine in PC‐12 cells, while the Asc‐1 agonist d‐isoleucine reduced intracellular d‐serine and increased extracellular d‐serine accumulation. This response to d‐isoleucine was not affected by BDS or (S)‐ketamine. Primary cultures of rat neuronal cells expressed ASCT2 and were responsive to (S)‐ketamine and BDS. (S)‐ and (R)‐ketamine increased the expression of monomeric serine racemase in all the cells studied, with (S)‐ketamine having the greatest effect.

Conclusions and Implications

(S)‐Ketamine decreased cellular export of d‐serine via selective inhibition of ASCT2, and this could represent a possible source of dissociative effects observed with (R,S)‐ketamine.
Ibopamine challenge testing differentiates glaucoma suspect, stable glaucoma and progressive glaucoma cases
Authors: Landers John , Ullrich Katja , Craig Jamie E
Published: July 2015

Background

An ibopamine challenge is a novel technique for assessing glaucoma using ibopamine, a topical drug which temporarily increases aqueous production. We aimed to determine whether change in intraocular pressure (IOP) and/or optic cup volume (OCV) during the test differentiated between glaucoma patients at different stages of disease; namely, glaucoma suspects (GS), glaucoma patients who are stable (SG) and glaucoma patients who have demonstrated rapid progression (PG).

Design

Non‐randomized clinical trial evaluating a diagnostic test.

Participants

Sixty‐one patients were recruited through glaucoma clinics at the Flinders Medical Centre (24 GS, 24 SG and 13 PG).

Methods

Patients underwent IOP measurement and OCV assessment using optical coherence tomography. Two drops of ibopamine 2% solution were instilled into the study eye of each patient. After 45 min, IOP and OCV were reassessed. Changes from baseline were compared between groups.

Main Outcome Measure

Change in IOP and OCV after ibopamine challenge.

Results

Following the ibopamine challenge, IOP increased by 1.8 mmHg for GS patients, 4.5 mmHg for SG patients (P = 0.003) and 8.1 mmHg for PG patients (P < 0.0001). OCV increased by 0.2% for GS patients, 0.6% for SG patients and 5.5% for PG patients. This was not significantly different between GS patients and SG patients; however, it was significantly different between GS patients and PG patients (P < 0.0001), and between SG and PG patients (P = 0.001).

Conclusion

GS patients may be differentiated from those with SG or PG by their IOP response, and SG may be differentiated from PG patients by their change in OCV following an ibopamine challenge.
Biallelic HERC1 mutations in a syndromic form of overgrowth and intellectual disability
Authors: Ortega‐Recalde O. , Beltrán O.I. , Gálvez J.M. , Palma‐Montero A. , Restrepo C.M. , Mateus H.E. , Laissue P.
Published: July 2015

We report two Colombian siblings affected by overgrowth, intellectual disability and facial dysmorphism. Exome (via NGS) and Sanger sequencing revealed that biallelic sequence variants in a novel gene (HERC1) might be related to the disease pathogenesis. These results provide useful data for future genotype–phenotype correlations and for a molecular diagnosis of overgrowth.
Robust Cardiac Function Assessment in 4D PC‐MRI Data of the Aorta and Pulmonary Artery
Authors: Köhler Benjamin , Preim Uta , Grothoff Matthias , Gutberlet Matthias , Fischbach Katharina , Preim Bernhard
Published: July 2015

Four‐dimensional phase‐contrast magnetic resonance imaging (4D PC‐MRI) allows the non‐invasive acquisition of time‐resolved, 3D blood flow information. Stroke volumes (SVs) and regurgitation fractions (RFs) are two of the main measures to assess the cardiac function and severity of valvular pathologies. The flow rates in forward and backward direction through a plane above the aortic or pulmonary valve are required for their quantification. Unfortunately, the calculations are highly sensitive towards the plane's angulation since orthogonally passing flow is considered. This often leads to physiologically implausible results. In this work, a robust quantification method is introduced to overcome this problem. Collaborating radiologists and cardiologists were carefully observed while estimating SVs and RFs in various healthy volunteer and patient 4D PC‐MRI data sets with conventional quantification methods, that is, using a single plane above the valve that is freely movable along the centerline. By default it is aligned perpendicular to the vessel's centerline, but free angulation (rotation) is possible. This facilitated the automation of their approach which, in turn, allows to derive statistical information about the plane angulation sensitivity. Moreover, the experts expect a continuous decrease of the blood flow volume along the vessel course. Conventional methods are often unable to produce this behaviour. Thus, we present a procedure to fit a monotonous function that ensures such physiologically plausible results. In addition, this technique was adapted for the usage in branching vessels such as the pulmonary artery. The performed informal evaluation shows the capability of our method to support diagnosis; a parameter evaluation confirms the robustness. Vortex flow was identified as one of the main causes for quantification uncertainties.
Differential expression of LOXL4 in normal and tumour tissue samples of laryngeal squamous cell carcinoma
Authors: Yilmaz M. , Suer I. , Karatas O.F. , Cansiz H. , Ozen M.
Published: July 2015

Objective

Head and neck cancer is the sixth most common cancer in worldwide with an increasing incidence rate in recent years. LOXL4 is expressed in several tissues, and its expression has been shown to display a significant correlation with local lymph node metastasis. In this study, we aimed to explore the LOXL4 expression level in metastatic and non‐metastatic LSCC tissues and to determine its prognostic significance.

Study design

Basic science research study.

Setting

University hospital.

Participants

A total of 40 patients were included in the study.

Main outcome measure

LOXL4 expression status in metastatic, non‐metastatic LSCC and normal tissue samples was investigated by quantitative reverse‐transcription PCR.

Results

We demonstrated that LOXL4 was significantly overexpressed in LSCC tumour tissue samples in comparison with the corresponding normal tissues (P < 0.001); however, no significant relationship has been found between LOXL4 expression and either the metastatic potential or the T classification of the specimens.

Conclusions

Although expression of LOXL4 is not statistically associated with neck metastases, we showed that LOXL4 expression significantly increased in laryngeal cancer.
A review of the safety and efficacy data for insulin glargine 300 units/ml, a new formulation of insulin glargine
Authors: Dailey G. , Lavernia F.
Published: July 2015

Insulin glargine 100 units/ml (Gla‐100) has become a standard of care in diabetes treatment over the past decade, providing 24‐h basal insulin coverage after once‐daily subcutaneous injection for many people with diabetes, with a well‐established efficacy and safety profile. New insulin glargine 300 units/ml (Gla‐300) is a basal insulin that provides the same number of units as Gla‐100 in a third of the volume. Compared with Gla‐100, Gla‐300 has shown more constant and prolonged pharmacokinetic (PK)/pharmacodynamic (PD) profiles. This review summarizes the findings from the EDITION series of clinical trials that investigated Gla‐300 in individuals with type 1 and type 2 diabetes mellitus. Overall, Gla‐300 has been shown to achieve similar glycaemic control with less, or similar, nocturnal hypoglycaemia compared with Gla‐100, and a trend towards lower hypoglycaemia at any time of day. The EDITION series of clinical trials also provides some evidence for less weight gain with Gla‐300 than with Gla‐100. In addition, the PK/PD profiles of Gla‐300 may allow more flexibility in the timing of doses, improving convenience; thus, Gla‐300 could offer several positive features for individuals with diabetes requiring basal insulin therapy.
Political Regimes and Currency Crises
Authors: Steinberg David A. , Koesel Karrie J. , Thompson Nicolas W.
Published: July 2015

This paper examines the relationship between political regime type and currency crises. Some theories suggest that democratic regimes, owing to their greater political transparency and larger number of veto players, should have a lower risk of currency crisis than dictatorships. Alternative arguments emphasize the advantages of political insulation and rulers with long time horizons, and imply that crises should be most likely in democracies and least common in monarchic dictatorships. We evaluate these competing arguments across four types of political regimes using a time‐series cross‐sectional dataset that covers 178 countries between 1973 and 2009. Our findings suggest that the risk of currency crisis is substantially lower in monarchies than in democracies and other types of dictatorship. Further analyses indicate that the adoption of prudent financial policies largely account for this robust negative association between monarchies and the probability of currency crises. This suggests that political regimes strongly influence financial stability, and perverse political incentives help explain why currency crises are so common.
Altitudinal distribution limits of aquatic macroinvertebrates: an experimental test in a tropical alpine stream
Authors: MADSEN PHILIP B. , MORABOWEN ANDRÉS , ANDINO PATRICIO , ESPINOSA RODRIGO , CAUVY‐FRAUNIÉ SOPHIE , DANGLES OLIVIER , JACOBSEN DEAN
Published: July 2015

1. Temperature and oxygen are recognised as the main drivers of altitudinal limits of species distributions. However, the two factors are linked, and both decrease with altitude, why their effects are difficult to disentangle.

2. This was experimentally addressed using aquatic macroinvertebrates; larvae ofAndesiops(Ephemeroptera),Claudioperla, (Plecoptera),Scirtes(Coleoptera) andAnomalocosmoecus(Trichoptera), and the amphipodHyalellain anEcuadorian glacier‐fed stream (4100–4500 m a.s.l.). The following were performed: (i) quantitative benthic sampling at three sites to determine altitudinal patterns in population densities, (ii) transplants of the five taxa upstream of their natural altitudinal limit to test the short‐term (14 days) effect on survival, and (iii)in situexperiments of locomotory activity as a proxy for animal response to relatively small differences in temperature (5 °C vs. 10 °C) and oxygen saturation (55% vs. 62%).

3. The transplant experiment reduced survival to a varying degree among taxa, butClaudioperlasurvived well at a site where it did not naturally occur. In thein situexperiment,ScirtesandHyalelladecreased their activity at lower oxygen saturation, whereasAndesiopsandAnomalocosmoecusdid so at a low temperature. The decrease in activity from a high to a low temperature and oxygen for the five taxa was significantly correlated with their mortality in the transplant experiment.

4. Together the present experiments indicate that even relatively small differences in temperature and oxygen may produce effects explaining ecological patterns, and depending on the taxon, either water temperature or oxygen saturation, without clear interacting effects, are important drivers of altitudinal limits.
Psychiatric and behavioral adverse events in randomized clinical studies of the noncompetitive AMPA receptor antagonist perampanel
Authors: Ettinger Alan B. , LoPresti Antonia , Yang Haichen , Williams Betsy , Zhou Sharon , Fain Randi , Laurenza Antonio
Published: July 2015

Objective

Perampanel, a selective, noncompetitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) glutamate receptor antagonist, is indicated for adjunctive treatment of partial seizures in patients ≥12 years based on three phase III clinical studies. The perampanel U.S. Prescribing Information includes a boxed warning for serious psychiatric and behavioral adverse reactions. To provide context for this warning, detail on psychiatric and behavioral safety data from perampanel clinical studies is presented.

Methods

An analysis of pooled safety data from three phase III studies in patients with partial seizures is presented. Data from phase I and phase II studies in patients with and without epilepsy were also analyzed. Psychiatric and behavioral treatment‐emergent adverse events (TEAEs) were evaluated according to Medical Dictionary for Regulatory Activities (MedDRA) terms, using “narrow” and “narrow‐and‐broad” standardized MedDRA queries (SMQs) for TEAEs suggestive of hostility/aggression.

Results

From the three phase III partial‐seizure studies, the overall rate of psychiatric TEAEs was higher in the 8 mg (17.2%) and 12 mg (22.4%) perampanel groups versus placebo (12.4%). In the “narrow” SMQ, hostility/aggression TEAEs were observed in 2.8% for 8 mg and 6.3% for 12 mg perampanel groups, versus 0.7% of placebo patients. “Narrow‐and‐broad” SMQs for hostility/aggression TEAE rates were 12.3% for 8 mg and 20.4% for 12 mg perampanel groups, versus 5.7% for placebo; rates for events resulting in discontinuation were perampanel = 1.6% versus placebo = 0.7%. For events reported as serious AEs (SAEs), rates were perampanel = 0.7% versus placebo = 0.2%. In nonepilepsy patients, psychiatric TEAEs were similar between patients receiving perampanel and placebo. In phase I subjects/volunteers, all psychiatric TEAEs were mild or moderate. These analyses suggest that psychiatric adverse effects are associated with use of perampanel.

Significance

Patients and caregivers should be counseled regarding the potential risk of psychiatric and behavioral events with perampanel in patients with partial seizures; patients should be monitored for these events during treatment, especially during titration and at higher doses.
Using neutral, selected, and hitchhiker loci to assess connectivity of marine populations in the genomic era
Authors: Gagnaire Pierre‐Alexandre , Broquet Thomas , Aurelle Didier , Viard Frédérique , Souissi Ahmed , Bonhomme François , Arnaud‐Haond Sophie , Bierne Nicolas
Published: July 2015

Estimating the rate of exchange of individuals among populations is a central concern to evolutionary ecology and its applications to conservation and management. For instance, the efficiency of protected areas in sustaining locally endangered populations and ecosystems depends on reserve network connectivity. The population genetics theory offers a powerful framework for estimating dispersal distances and migration rates from molecular data. In the marine realm, however, decades of molecular studies have met limited success in inferring genetic connectivity, due to the frequent lack of spatial genetic structure in species exhibiting high fecundity and dispersal capabilities. This is especially true within biogeographic regions bounded by well‐known hotspots of genetic differentiation. Here, we provide an overview of the current methods for estimating genetic connectivity using molecular markers and propose several directions for improving existing approaches using large population genomic datasets. We highlight several issues that limit the effectiveness of methods based on neutral markers when there is virtually no genetic differentiation among samples. We then focus on alternative methods based on markers influenced by selection. Although some of these methodologies are still underexplored, our aim was to stimulate new research to test how broadly they are applicable to nonmodel marine species. We argue that the increased ability to apply the concepts of cline analyses will improve dispersal inferences across physical and ecological barriers that reduce connectivity locally. We finally present how neutral markers hitchhiking with selected loci can also provide information about connectivity patterns within apparently well‐mixed biogeographic regions. We contend that one of the most promising applications of population genomics is the use of outlier loci to delineate relevant conservation units and related eco‐geographic features across which connectivity can be measured.