bluuebunny/crossref_metadata_2025 huggingface dataset:
European health inequality through the ‘Great Recession’: social policy matters
Authors: van der Wel Kjetil A. , Saltkjel Therese , Chen Wen‐Hao , Dahl Espen , Halvorsen Knut
Published: March 2018

This paper investigates the association between the Great Recession and educational inequalities in self‐rated general health in 25 European countries. We investigate four different indicators related to economic recession: GDP; unemployment; austerity and a ‘crisis’ indicator signifying severe simultaneous drops in GDP and welfare generosity. We also assess the extent to which health inequality changes can be attributed to changes in the economic conditions and social capital in the European populations. The paper uses data from the European Social Survey (2002–2014). The analyses include both cross‐sectional and lagged associations using multilevel linear regression models with country fixed effects. This approach allows us to identify health inequality changes net of all time‐invariant differences between countries. GDP drops and increasing unemployment were associated with decreasing health inequalities. Austerity, however, was related to increasing health inequalities, an association that grew stronger with time. The strongest increase in health inequality was found for the more robust ‘crisis’ indicator. Changes in trust, social relationships and in the experience of economic hardship of the populations accounted for much of the increase in health inequality. The paper concludes that social policy has an important role in the development of health inequalities, particularly during times of economic crisis.
Role ambiguity and perceptions of unfair performance appraisals: mitigating roles of personal resources
Authors: De Clercq Dirk , Haq Inam Ul , Azeem Muhammad Umer
Published: March 2018

Drawing from conservation of resources theory and attribution theory, this study adds to human resource literature by investigating the relationship between role ambiguity and employees’ beliefs that their performance is unfairly evaluated by their organization, as well as the buffering roles of relevant personal resources. In particular, the presence of unclear role descriptions may spur perceptions of unfair performance appraisals, but this process should be mitigated by organization‐specific experience and Islamic work values. Data from Pakistani firms offer empirical support for these hypothesized effects. From a practical perspective, the findings indicate that human resource managers who fail to provide clear role descriptions to employees can mitigate accompanying concerns about the presence of unfair performance evaluations, to the extent that they encourage employees to leverage valuable personal resources.
momentuHMM: R package for generalized hidden Markov models of animal movement
Authors: McClintock Brett T. , Michelot Théo
Published: March 2018

Discrete‐time hidden Markov models (HMMs) have become an immensely popular tool for inferring latent animal behaviours from telemetry data. While movement HMMs typically rely solely on location data (e.g. step length and turning angle), auxiliary biotelemetry and environmental data are powerful and readily‐available resources for incorporating much more ecological and behavioural realism. However, complex movement or observation process models often necessitate custom and computationally demanding HMM model‐fitting techniques that are impractical for most practitioners, and there is a paucity of generalized user‐friendly software available for implementing multivariate HMMs of animal movement.

Here, we introduce an open‐source R package, momentuHMM, that addresses many of the deficiencies in existing HMM software. Features include: (1) data pre‐processing and visualization; (2) user‐specified probability distributions for an unlimited number of data streams and latent behaviour states; (3) biased and correlated random walk movement models, including dynamic “activity centres” associated with attractive or repulsive forces; (4) user‐specified design matrices and constraints for covariate modelling of parameters using formulas familiar to most R users; (5) multiple imputation methods that account for measurement error and temporally irregular or missing data; (6) seamless integration of spatio‐temporal covariate raster data; (7) cosinor and spline models for cyclical and other complicated patterns; (8) model checking and selection; and (9) simulation.

After providing an overview of the main features of the package, we demonstrate some of the capabilities of momentuHMM using real‐world examples. These include models for cyclical movement patterns of African elephants, foraging trips of northern fur seals, loggerhead turtle movements relative to ocean surface currents, and grey seal movements among three activity centres.

momentuHMM considerably extends the capabilities of existing HMM software while accounting for common challenges associated with telemetry data. It therefore facilitates more realistic hypothesis‐driven animal movement analyses that have hitherto been largely inaccessible to non‐statisticians. While motivated by telemetry data, the package can be used for analysing any type of data that is amenable to HMMs. Practitioners interested in additional features are encouraged to contact the authors.
Evaluation of acoustic telemetry grids for determining aquatic animal movement and survival
Authors: Kraus Richard T. , Holbrook Christopher M. , Vandergoot Christopher S. , Stewart Taylor R. , Faust Matthew D. , Watkinson Douglas A. , Charles Colin , Pegg Mark , Enders Eva C. , Krueger Charles C.
Published: March 2018

Acoustic telemetry studies have frequently prioritized linear configurations of hydrophone receivers, such as perpendicular from shorelines or across rivers, to detect the presence of tagged aquatic animals. This approach introduces unknown bias when receivers are stationed for convenience at geographic bottlenecks (e.g. at the mouth of an embayment or between islands) as opposed to deployments following a statistical sampling design.

We evaluated two‐dimensional acoustic receiver arrays (grids: receivers spread uniformly across space) as an alternative approach to provide estimates of survival, movement and habitat use. Performance of variably spaced receiver grids (5–25 km spacing) was evaluated by simulating (1) animal tracks as correlated random walks (speed: 0.1–0.9 m/s; turning angleSD: 5–30°); (2) variable tag transmission intervals along each track (nominal delay: 15–300 s); and (3) probability of detection of each transmission based on logistic detection range curves (mid‐point: 200–1,500 m). From simulations, we quantified (i) time between successive detections on any receiver (detection time), (ii) time between successive detections on different receivers (transit time), and (iii) distance between successive detections on different receivers (transit distance).

In the most restrictive detection range scenario (200 m), the 95th percentile of transit time was 3.2 days at 5 km, 5.7 days at 7 km and 15.2 days at 25 km grid spacing; for the 1,500 m detection range scenario, it was 0.1 days at 5 km, 0.5 days at 7 km and 10.8 days at 25 km. These values represented upper bounds on the expected maximum time that an animal could go undetected. Comparison of the simulations with pilot studies on three fishes (walleyeSander vitreus, common carpCyprinus carpioand channel catfishIctalurus punctatus) from two independent large lake ecosystems (lakes Erie and Winnipeg) revealed shorter detection and transit times than what simulations predicted.

By spreading effort uniformly across space, grids can improve understanding of fish migration over the commonly employed receiver line approach, but at increased time cost for maintaining grids.
Associations between personality disorders and cannabis use and cannabis use disorder: a population‐based twin study
Authors: Gillespie Nathan A. , Aggen Steven H. , Neale Michael C. , Knudsen Gun Peggy , Krueger Robert F. , South Susan C. , Czajkowski Nikolai , Nesvåg Ragnar , Ystrom Eivind , Kendler Kenneth S. , Reichborn‐Kjennerud Ted
Published: March 2018

Background and Aims

Individual differences in DSM‐IV personality disorders (PDs) are associated with increased prevalence of substance use disorders. Our aims were to determine which combination of PDs trait scores best predict cannabis use (CU) and cannabis use disorder (CUD), and to estimate the size and significance of genetic and environmental risks in PD traits shared with CU and CUD.

Design

Linear mixed‐effects models were used to identify PD traits for inclusion in twin analyses to explore the genetic and environmental associations between the traits and cannabis use.

Setting

Cross‐sectional data were obtained from Norwegian adult twins in a face‐to‐face interview in 1999–2004 as part of a population‐based study of mental health.

Participants

Subjects were 1419 twins (μage = 28.2 years, range = 19–36) from the Norwegian Institute of Public Health Twin Panel with complete PD and cannabis data.

Measurements

PD traits were assessed using DSM‐IV criteria. Life‐time CU and CUD were based on DSM‐IV abuse and dependence criteria, including withdrawal and craving.

Findings

After adjusting for age and sex, antisocial [β = 0.23, 95% confidence interval (CI) = 0.19–0.28] and borderline PDs (β = 0.20, 95% CI = 0.14–0.26) were associated strongly with CU. Antisocial (β = 0.26, 95% CI = 0.21–0.31) and borderline PDs (β = 0.12, 95% CI = 0.06–0.18) were also linked strongly to CUD. Genetic risks in antisocial and borderline PD traits explained 32–60% of the total variance in CU and CUD. Dependent and avoidant PDs explained 11 and 16% of the total variance in CU and CUD, respectively.

Conclusions

Individual differences in the liability to cannabis use and cannabis use disorder appear to be linked to genetic risks correlated with antisocial and borderline personality disorder traits.
The immunophenotype of amniotic fluid leukocytes in normal and complicated pregnancies
Authors: Gomez‐Lopez Nardhy , Romero Roberto , Xu Yi , Miller Derek , Leng Yaozhu , Panaitescu Bogdan , Silva Pablo , Faro Jonathan , Alhousseini Ali , Gill Navleen , Hassan Sonia S , Hsu Chaur‐Dong
Published: March 2018

Problem

The immune cellular composition of amniotic fluid is poorly understood. Herein, we determined: 1) the immunophenotype of amniotic fluid immune cells during the second and third trimester in the absence of intra‐amniotic infection/inflammation; 2) whether amniotic fluid T cells and ILCs display different phenotypical characteristics to that of peripheral cells; and 3) whether the amniotic fluid immune cells are altered in women with intra‐amniotic infection/inflammation.

Method of Study

Amniotic fluid samples (n = 57) were collected from 15 to 40 weeks of gestation in women without intra‐amniotic infection/inflammation. Samples from women with intra‐amniotic infection/inflammation were also included (n = 9). Peripheral blood mononuclear cells from healthy adults were used as controls (n = 3). Immunophenotyping was performed using flow cytometry.

Results

In the absence of intra‐amniotic infection/inflammation, the amniotic fluid contained several immune cell populations between 15 and 40 weeks. Among these immune cells: (i) T cells and ILCs were greater than B cells and natural killer (NK) cells between 15 and 30 weeks; (ii) T cells were most abundant between 15 and 30 weeks; (iii) ILCs were most abundant between 15 and 20 weeks; (iv) B cells were scarce between 15 and 20 weeks; yet, they increased and were constant after 20 weeks; (v) NK cells were greater between 15 and 30 weeks than at term; (vi) ILCs expressed high levels of RORγt, CD161, and CD103 (ie, group 3 ILCs); (vii) T cells expressed high levels of RORγt; (viii) neutrophils increased as gestation progressed; and (ix) monocytes/macrophages emerged after 20 weeks and remained constant until term. All of the amniotic fluid immune cells, except ILCs, were increased in the presence of intra‐amniotic infection/inflammation.

Conclusion

The amniotic fluid harbors a diverse immune cellular composition during normal and complicated pregnancies.
IL‐33/ST2 axis affects the polarization and efferocytosis of decidual macrophages in early pregnancy
Authors: Sheng Yan‐Ran , Hu Wen‐Ting , Wei Chun‐Yan , Tang Ling‐Li , Liu Yu‐Kai , Liu Yu‐Yin , Qiu Jian‐Ping , Li Da‐Jin , Zhu Xiao‐Yong
Published: March 2018

Problem

To explore whether IL‐33/ST2 axis modulates the polarization and efferocytosis of decidual macrophages (dMφs).

Method of study

The phenotype characteristics of dMφs from both normal pregnant women and recurrent spontaneous abortion (RSA) patients were determined by real‐time polymerase chain reaction (RT‐PCR) and flow cytometry (FCM). Then, the efferocytosis and expression of IL‐33 and its receptor (ST2) in dMφs were analyzed by FCM. Finally, the effects of sST2, a decoy receptor for IL‐33 that inhibits the IL‐33/ST2 signaling pathway, on the polarization and efferocytosis of dMφs and human macrophage cell line U937 were investigated.

Results

Compared with normal pregnancy, dMφs from RSA patients presented a M1 phenotype with high secretion of IL‐33, whereas the expression of ST2 decreased. However, dMφs from RSA patients possessed a more powerful efferocytosis ability to clear the apoptotic decidual stromal cells (DSCs) compared with dMφs from normal pregnancy patients. Treatment with recombinant human sST2 led to the up‐regulation of M1 bias and efferocytosis ability of both normal dMφs and U937.

Conclusion

This study indicates that IL‐33 secreted by dMφs promotes M2 bias at the feto‐maternal interface, and as a result, RSA might attribute to the disturbance of IL‐33/ST2 axis and the enhancement of efferocytosis of dMφs subsequently.
Characterization of microbiota in male infertility cases uncovers differences in seminal hyperviscosity and oligoasthenoteratozoospermia possibly correlated with increased prevalence of infectious bacteria
Authors: Monteiro Catarina , Marques Patrícia I. , Cavadas Bruno , Damião Isabel , Almeida Vasco , Barros Nuno , Barros Alberto , Carvalho Filipa , Gomes Sílvia , Seixas Susana
Published: March 2018

Problem

Sexually transmitted diseases and other infections of male genitourinary tract are thought to negatively impact reproductive health, affecting semen quality. Despite a possible link between bacteria and infertility, few studies attempted to characterize seminal microbiota in healthy and diseased subjects.

Methods of the study

A high‐throughput sequencing of 16S ribosomal RNA gene was performed in a cohort of infertility‐related cases (N = 89) and controls (N = 29) using a pooled sample approach.

Results

A global characterization of microbiota was obtained at low cost, without compromising the identification of bacterial taxa. This strategy allowed us to detect changes in the microbiota of infertility‐related phenotypes, such as an increment of Proteobacteria in seminal hyperviscosity, and to separate this later group from oligoasthenoteratozoospermia based in bacterial (family/genus) abundances.

Conclusion

We provide data for a likely contribution of bacteria into seminal hyperviscosity and oligoasthenoteratozoospermia, partially correlated with an increment of Neisseria, Klebsiella, and Pseudomonas pathogens and a reduction in Lactobacillus probiotic agent.
A comparative analysis of testicular sperm morphology in fossorial and surface‐living skinks in South Africa
Authors: Verdú‐Ricoy Joaquín , Matla Tankiso , Gregory Michael , Lambiris Angelo , Jordaan Adriaan , Zhao Zhongning , Heideman Neil
Published: March 2018

We described for the first time the spermatozoan ultrastructure of the fully pentadactyl surface‐living skink Trachylepis punctatissima, and limbless fossorial skink Acontias meleagris. The spermatozoa of both species follow the general patterns observed within the Squamata. However, several important differences were detected between the two species in the head region (shape of the anterior acrosome, size of acrosome and nucleus) and especially in the midpiece (size of the midpiece, the presence of regular rows of dense bodies, size and number of mitochondria and beginning of the fibrous sheath). Both species shared more characters with the Sphenomorphus + Egernia group than with the Eugongylus group proposed by Jamieson, Oliver, and Scheltinga (Acta Zoologica, 77, 85). Differences in the spermatozoan ultrastructure between T. punctatissima and A. meleagris could be due to distinct ecological and physiological requirements for fertilization, but additional research on these genera and within the Scincidae is required to disentangle this hypothesis, and to disentangle the phylogenetic relationships among skinks.
A penalized likelihood method for multi‐group structural equation modelling
Authors: Huang Po‐Hsien
Published: March 2018

In the past two decades, statistical modelling with sparsity has become an active research topic in the fields of statistics and machine learning. Recently, Huang, Chen and Weng (2017,Psychometrika, 82, 329) and Jacobucci, Grimm, and McArdle (2016,Structural Equation Modeling: A Multidisciplinary Journal, 23, 555) both proposed sparse estimation methods for structural equation modelling (SEM). These methods, however, are restricted to performing single‐group analysis. The aim of the present work is to establish a penalized likelihood (PL) method for multi‐groupSEM. Our proposed method decomposes each group model parameter into a common reference component and a group‐specific increment component. By penalizing the increment components, the heterogeneity of parameter values across the population can be explored since the null group‐specific effects are expected to diminish. We developed an expectation‐conditional maximization algorithm to optimize thePLcriteria. A numerical experiment and a real data example are presented to demonstrate the potential utility of the proposed method.
Activity of novel lipid glycine transporter inhibitors on synaptic signalling in the dorsal horn of the spinal cord
Authors: Winters Bryony L , Rawling Tristan , Vandenberg Robert J , Christie Macdonald J , Bhola Rebecca F , Imlach Wendy L
Published: March 2018

Background and Purpose

Inhibitory neurotransmission plays an important role in controlling excitability within nociceptive circuits of the spinal cord dorsal horn. Loss of inhibitory signalling is thought to contribute to the development of pathological pain. Preclinical studies suggest that increasing inhibitory glycinergic signalling is a good therapeutic strategy for treating pain. One approach to increase synaptic glycine is to inhibit the activity of the glycine transporter 2 (GlyT2) on inhibitory nerve terminals. These transporters are involved in regulating glycine concentrations and recycling glycine into presynaptic terminals. Inhibiting activity of GlyT2 increases synaptic glycine, which decreases excitability in nociceptive circuits and provides analgesia in neuropathic and inflammatory pain models.

Experimental Approach

We investigated the effects of reversible and irreversible GlyT2 inhibitors on inhibitory glycinergic and NMDA receptor‐mediated excitatory neurotransmission in the rat dorsal horn. The effect of these drugs on synaptic signalling was determined using patch‐clamp electrophysiology techniques to measure glycine‐ and NMDA‐mediated postsynaptic currents in spinal cord slices in vitro.

Key Results

We compared activity of four compounds that increase glycinergic tone with a corresponding increase in evoked glycinergic postsynaptic currents. These compounds did not deplete synaptic glycine release over time. Interestingly, none of these compounds increased glycine‐mediated excitatory signalling through NMDA receptors. The results suggest that these compounds preferentially inhibit GlyT2 over G1yT1 with no potentiation of the glycine receptor and without inducing spillover from inhibitory to excitatory synapses.

Conclusions and Implications

GlyT2 inhibitors increase inhibitory neurotransmission in the dorsal horn and have potential as pain therapeutics.

Linked Articles

This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc
Exchange factor directly activated by cAMP–PKCε signalling mediates chronic morphine‐induced expression of purine P2X3 receptor in rat dorsal root ganglia
Authors: Wang Wenying , Ma Xiaqing , Luo Limin , Huang Min , Dong Jing , Zhang Xiaoli , Jiang Wei , Xu Tao
Published: March 2018

Background and Purpose

The P2X3 receptor is a major receptor in the processing of nociceptive information in dorsal root ganglia. We investigated the role of the P2X3 receptor and the detailed mechanisms underlying chronic morphine‐induced analgesic tolerance in rats.

Experimental Approach

Repeated i.t. morphine treatment was used to induce anti‐nociceptive tolerance. The expression of spinal P2X3 receptor, phosphorylated PKCε and exchange factor directly activated by cAMP (Epac) were evaluated. Effects of A‐317491 (P2X3 antagonist), ε‐V1‐2 (PKCε inhibitor) and ESI‐09 (Epac inhibitor) on mechanical pain thresholds and tail‐flick latency after chronic morphine treatment were determined. Co‐localization of P2X3 receptor with NeuNs (marker of neuron), IB4 (marker of small DRG neurons), peripherin, PKCε and Epac were performed by double immunofluorescence staining.

Key Results

Chronic morphine time‐dependently increased the expression of P2X3 receptor, phosphorylated PKCε and Epac in DRGs. ε‐V1‐2 prevented chronic morphine‐induced expression of P2X3 receptor. ESI‐09 decreased the phosphorylation of PKCε and up‐regulated expression of Epac after chronic morphine exposure. Mechanical pain thresholds and tail‐flick latency showed that A317491, ε‐V1‐2 and ESI‐09 significantly attenuated the loss of morphine's analgesic potency. Morphine‐induced P2X3 receptor expression mainly occurred in neurons staining for IB4 and peripherin. Co‐localization of P2X3 receptor with PKCε and Epac was demonstrated in the same neurons.

Conclusions and Implications

Chronic morphine exposure increased the expression of P2X3 receptor, and i.t. P2X3 receptor antagonists attenuated the loss of morphine's analgesic effect. Inhibiting Epac/PKCε signalling was shown to play a significant inhibitory role in chronic morphine‐induced P2X3 receptor expression and attenuate morphine‐induced tolerance.
Mapping ligand binding pockets in chloride ClC‐1 channels through an integrated in silico and experimental approach using anthracene‐9‐carboxylic acid and niflumic acid
Authors: Altamura C , Mangiatordi G F , Nicolotti O , Sahbani D , Farinato A , Leonetti F , Carratù M R , Conte D , Desaphy J‐F , Imbrici P
Published: March 2018

Background and Purpose

Although chloride channels are involved in several physiological processes and acquired diseases, the availability of compounds selectively targeting CLC proteins is limited. ClC‐1 channels are responsible for sarcolemma repolarization after an action potential in skeletal muscle and have been associated with myotonia congenita and myotonic dystrophy as well as with other muscular physiopathological conditions. To date only a few ClC‐1 blockers have been discovered, such as anthracene‐9‐carboxylic acid (9‐AC) and niflumic acid (NFA), whereas no activator exists. The absence of a ClC‐1 structure and the limited information regarding the binding pockets in CLC channels hamper the identification of improved modulators.

Experimental Approach

Here we provide an in‐depth characterization of drug binding pockets in ClC‐1 through an integrated in silico and experimental approach. We first searched putative cavities in a homology model of ClC‐1 built upon an eukaryotic CLC crystal structure, and then validated in silico data by measuring the blocking ability of 9‐AC and NFA on mutant ClC‐1 channels expressed in HEK 293 cells.

Key Results

We identified four putative binding cavities in ClC‐1. 9‐AC appears to interact with residues K231, R421 and F484 within the channel pore. We also identified one preferential binding cavity for NFA and propose R421 and F484 as critical residues.

Conclusions and Implications

This study represents the first effort to delineate the binding sites of ClC‐1. This information is fundamental to discover compounds useful in the treatment of ClC‐1‐associated dysfunctions and might represent a starting point for specifically targeting other CLC proteins.
Treatment withIL‐19improves locomotor functional recovery after contusion trauma to the spinal cord
Authors: Guo Jidong , Wang Huadong , Li Li , Yuan Yanli , Shi Xiuxiu , Hou Shuxun
Published: March 2018

Background and Purpose

IL‐19 skews the immune response towards a Th2 type and appears to stimulate angiogenesis. In the current study, we tested if IL‐19 treatment could reduce secondary injury and improve functional recovery after contusion spinal cord injury (SCI).

Experimental Approach

Firstly, mice were given a moderate–severe thoracic SCI at the T9–10level and expression of IL‐19 and its receptor was measured in the injured spinal cord. Then SCI mice were treated with mouse recombinant IL‐19 and its blocking antibody to investigate the therapeutic effect of IL‐19.

Key Results

Protein expression of IL‐19 and its receptor IL‐20R1 and IL‐20R2 was up‐regulated in the injured spinal cord of mice. IL‐19 treatment promoted the recovery of locomotor function dose‐dependently and reduced loss of motor neurons and microglial and glial activation following SCI. Treatment of SCI mice with IL‐19 attenuated macrophage accumulation, reduced protein levels of TNF‐α and CCL2 and promoted Th2 response and M2 macrophage activation in the injured region. Treatment of SCI mice with IL‐19 promoted angiogenesis through up‐regulating VEGF in the injured region. Treatment of SCI mice with IL‐19 up‐regulated HO‐1 expression and decreased oxidative stress in the injured region. The beneficial effect of IL‐19 was abolished by coadministration of the blocking antibody. Additionally, IL‐19 deficiency in mice delayed the recovery of locomotor function following SCI.

Conclusions and Implications

IL‐19 treatment reduced secondary injuries and improved locomotor functional recovery after contusion SCI, through diverse mechanisms including immune cell polarization, angiogenesis and anti‐oxidative responses.
Phase I study of taselisib in Japanese patients with advanced solid tumors or hormone receptor‐positive advanced breast cancer
Authors: Tamura Kenji , Kodaira Makoto , Shimizu Chikako , Yonemori Kan , Yunokawa Mayu , Shimomura Akihiko , Kobayashi Takayuki , Nakano Kenji , Tomomatsu Junichi , Ito Yoshinori , Tanaka Jun , Kuriki Hiroshi , Gu Zhaodi , Takahashi Shunji
Published: March 2018

Taselisib is a potent and selective phosphatidylinositide 3‐kinase (PI3K) inhibitor. The present article reports the first study of taselisib administration in Japanese patients. The aim of this 2‐stage, phase I, multicenter, open‐label, dose‐escalation study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of taselisib as monotherapy in Japanese patients with advanced solid tumors (stage 1), and as part of combination therapy in Japanese patients with hormone receptor (HR)‐positive locally advanced or recurrent breast cancer (stage 2). In stage 1, oral taselisib tablets 2, 4, and 6 mg/d were given in 28‐day cycles. In stage 2, successive cohorts of patients received oral taselisib tablets (2 or 4 mg/d) with i.m. fulvestrant 500 mg. Nine and 6 patients were enrolled in stage 1 and stage 2, respectively. Taselisib was well tolerated. No dose‐limiting toxicities were experienced in any cohort of patients and no deaths were observed. The most common treatment‐related adverse events in stage 1 and stage 2, respectively, were rash (55.6%, 66.7%), diarrhea (44.4%, 66.7%), and stomatitis (44.4%, 66.7%). Taselisib was rapidly absorbed after dosage; its half‐life was 12.9‐32.0 hours in stage 1 and 16.1‐26.5 hours in stage 2. Two patients achieved partial response (PR), 5 patients had stable disease (SD) and 2 patients had progressive disease (PD) in stage 1, and 1 patient had PR and 3 patients had SD in stage 2. All patients with PR were positive for PIK3CA gene mutations. These preliminary data suggest that taselisib may be effective in patients with PIK3CA‐mutated solid tumors or HR‐positive advanced breast cancer.
Identification of inhibitors of Tartrate‐resistant acid phosphatase (TRAP/ACP5) activity by small‐molecule screening
Authors: Reithmeier Anja , Lundbäck Thomas , Haraldsson Martin , Frank Martin , Ek‐Rylander Barbro , Nyholm Per‐Georg , Gustavsson Anna‐Lena , Andersson Göran
Published: March 2018

Tartrate‐resistant acid phosphatase (TRAP/ACP5) occurs as two isoforms—TRAP 5a with low enzymatic activity due to a loop interacting with the active site and the more active TRAP isoform 5b generated upon proteolytic cleavage of this loop. TRAP has been implicated in several diseases, including cancer. Thus, this study set out to identify small‐molecule inhibitors of TRAP activity. A microplate‐based enzymatic assay for TRAP 5b was applied in a screen of 30,315 compounds, resulting in the identification of 90 primary hits. After removal of promiscuous compounds, unwanted groups, and false positives by orthogonal assays and three‐concentration validation, the properties of 52 compounds were further investigated to better understand their mechanism of action. Full‐concentration–response curves for these compounds were established under different enzyme concentrations and (pre)incubation times to remove compounds with inconsistent results and low potencies. Full‐concentration–response curves were also performed for both isoforms, to examine isoform prevalence. Filtering led to six prioritized compounds, representing different clusters. One of these, CBK289001 or (6S)‐6‐[3‐(2H‐1,3‐benzodioxol‐5‐yl)‐1,2,4‐oxadiazol‐5‐yl]‐N‐(propan‐2‐yl)‐1H,4H,5H,6H,7H‐imidazo[4,5‐c]pyridine‐5‐carboxamide, demonstrated efficacy in a migration assay and IC50 values from 4 to 125 μm. Molecular docking studies and analog testing were performed around CBK289001 to provide openings for further improvement toward more potent blockers of TRAP activity.
Inhibition of phosphodiesterases as a strategy to achieve neuroprotection in Huntington's disease
Authors: Cardinale Antonella , Fusco Francesca R.
Published: March 2018

Huntington's disease (HD) is a fatal neurodegenerative condition, due to a mutation in the IT15 gene encoding for huntingtin. Currently, disease‐modifying therapy is not available for HD, and only symptomatic drugs are administered for the management of symptoms. In the last few years, preclinical and clinical studies have indicated that pharmacological strategies aimed at inhibiting cyclic nucleotide phosphodiesterase (PDEs) may develop into a novel therapeutic approach in neurodegenerative disorders. PDEs are a family of enzymes that hydrolyze cyclic nucleotides into monophosphate isoforms. Cyclic nucleotides are second messengers that transduce the signal of hormones and neurotransmitters in many physiological processes, such as protein kinase cascades and synaptic transmission. An alteration in their balance results in the dysregulation of different biological mechanisms (transcriptional dysregulation, immune cell activation, inflammatory mechanisms, and regeneration) that are involved in neurological diseases. In this review, we discuss the action of phosphodiesterase inhibitors and their role as therapeutic agents in HD.
Abnormal resting‐state functional connectivity in posterior cingulate cortex of Parkinson's disease with mild cognitive impairment and dementia
Authors: Zhan Zhou‐Wei , Lin Li‐Zhen , Yu Er‐Han , Xin Jia‐Wei , Lin Lin , Lin Hai‐Long , Ye Qin‐Yong , Chen Xiao‐Chun , Pan Xiao‐Dong
Published: March 2018

Objective

To investigate changes in the functional connectivity (FC) pattern in the posterior cingulate cortex (PCC) of Parkinson's disease (PD) patients with mild cognitive impairment and dementia by employing resting‐state functional magnetic resonance imaging (RS‐fMRI).

Methods

Twenty‐seven PD patients with different cognitive status and 9 healthy control subjects (control group) were enrolled for RS‐fMRI. The RS‐fMRI data were analyzed with DPARSF and REST software. Regions with changed functional connectivity were determined by the seed‐based voxelwise method and compared between groups. Correlation between the intensity of FC and the MoCA scores of PD group was analyzed.

Results

Parametric maps showed statistical increases in PCC functional connectivity in PD‐MCI patients and decreases in PCC connectivity in PDD patients. The latter group of patients also showed evidence for increased connectivity between prefrontal cortices and posterior cerebellum. A significant positive correlation was found between the MoCA scores and the strength of PCC connectivity in the angular gyrus and posterior cerebellum and a negative correlation between MoCA scores and PCC connectivity in all other brain regions.

Conclusion

When patients transition from PD‐NCI to PD‐MCI, there appears to be an increase in functional connectivity in the PCC, suggesting an expansion of the cortical network. Another new network (a compensatory prefrontal cortical‐cerebellar loop) later develops during the transition from PD‐MCI to PDD.
Efficacy of a new nail brace for the treatment of ingrown toenails
Authors: Liu Che‐Wei , Huang Yu‐Chen
Published: March 2018

Background and objectives

Surgery is the mainstay of treatment for complicated ingrown toenails. However, alternative treatments using nail braces have been reported to show good efficacy. The objective of the present study was to investigate the efficacy of a new nail brace for the treatment of ingrown toenails.

Patients and methods

We conducted a retrospective study on patients with ingrown toenails treated at Wan Fang Hospital between June 1, 2015 and May 30, 2016. Ingrown toenails were classified into acute inflamed/infected (AI) and chronic dystrophic (CD) types. Using physician global assessment scores, the efficacy of nail braces for the two types of ingrown toenails was compared 1, 2, 3, and 6 months after treatment initiation and during the final visit.

Results

Twenty‐one patients (42 sites) had CD‐type ingrown toenails; 25 patients (36 sites) had ingrown toenails of the AI type. Of the affected sites, 81 %, 94 %, and 100 % showed an excellent or fair outcome at 1, 3, and 6 months, respectively. Recurrence rates were 10.3 %; complication rates, 7.7 %. While, in the first three months, AI‐type ingrown toenails tended to achieve excellent results more rapidly than CD‐type nails, outcomes were similar at six months.

Conclusions

Nail braces are an effective therapeutic option, particularly for CD‐type ingrown toenails.
Linking species richness and size diversity in birds and fishes
Authors: Yen Jian D. L. , Thomson James R. , Keith Jonathan M. , Paganin David M. , Fleishman Erica , Bennett Andrew F. , Nimmo Dale G. , Bennett Joanne M. , Dobkin David S. , Mac Nally Ralph
Published: March 2018

The rapid development of mechanistic, trait‐based models has resulted in increasingly reliable predictions of the functional diversity of individuals in populations and communities. However, a focus on individuals’ traits differs from the prevailing focus on species in much of community ecology. We sought to identify correlative links between species richness and size diversity, focusing on size diversity as one component of functional diversity. These links could be used to extend individual, size‐based models to predict patterns of species richness. We used the distribution of the sizes of individuals in a community – the individual–size distribution (ISD) – as a measure of size diversity, and constructed Bayesian regression models with species richness as the response variable and ISDs as the predictor variables. We used two methods to include ISDs in our analyses. First, we summarized the ISD with five common diversity indices and used these indices as predictor variables in our analyses. Second, we used functional data analysis to include the entire ISD (a continuous function) as a predictor variable in our analyses. Analyses of diversity indices identified consistent, positive associations between species richness and size diversity. Analyses of entire ISDs revealed that these associations were driven by numbers of small‐ and medium‐sized individuals. In general, a combination of diversity indices predicted species richness as well as or better than continuous ISDs. However, models with ISDs as predictor variables were less sensitive to technical details of model fitting (e.g. discretization method) than those based on diversity indices, and the use of ISDs avoids the arbitrary selection of one or several diversity indices. Our use of functional data analysis allows any trait distribution to be included as a variable in statistical analyses, and has the potential to reveal new diversity patterns in ecology.
Drought intensification drives turnover of structure and function in stream invertebrate communities
Authors: Aspin Thomas W. H. , Matthews Thomas J. , Khamis Kieran , Milner Alexander M. , Wang Zining , O'Callaghan Matthew J. , Ledger Mark E.
Published: March 2018

Climatic extremes are becoming more frequent and intense across much of the globe, potentially transforming the biodiversity and functioning of affected ecosystems. In freshwaters, hydrological extremes such as drought can regulate beta diversity, acting as powerful environmental filters to dictate the complement of species and functional traits found at local and landscape scales. New methods that enable beta diversity and its functional equivalent to be partitioned into turnover (replacement of species/functions) and nestedness‐resultant (gain/loss of species/functions) components may offer novel insights into the parallel impacts of drought on ecosystem structure and function. Using a series of artificial channels (mesocosms) designed to mimic perennial headwater streams, we experimentally manipulated streamflows to simulate a gradient of drought intensity. We then modelled taxonomic and functional turnover and nestedness of macroinvertebrate communities along this gradient, validating direct gradient approaches (bootstrapping, Mantel tests) against null models of nestedness. Drought intensification produced significant environmental distance decay trends (i.e. communities became increasingly taxonomically and functionally dissimilar the more differentially disturbed by drought they were). Taxonomic distance decay was primarily driven by turnover, while the functional trend reflected a combination of richness differences and turnover at different points along the gradient. Taxonomic and functional distance decay slopes were not significantly different, implying that communities were functionally vulnerable to drying. The increased frequency and intensity of droughts predicted under most climate change scenarios could thus profoundly modify not only the structure of running water invertebrate communities, but also the ecosystem functions they underpin.
Survival of Ralstonia solanacearum and Ralstonia pseudosolanacearum in drain water
Authors: Stevens L. H. , van der Zouwen P. S. , van Tongeren C. A. M. , Kastelein P. , van der Wolf J. M.
Published: March 2018

The survival in drain water of two strains of Ralstonia solanacearum and three strains of Ralstonia pseudosolanacearum, including two strains able to cause wilt in roses, was determined. Water draining from drip‐irrigated rock wool mats on which roses were grown was supplemented with the pathogen and survival was monitored at 4, 12, 20 and 28°C for up to 112 days. All strains were able to survive for at least 112 days in drain water at 12 and 20°C, but at 4°C maximum survival was 56 days. At 28°C, the survival period was strain dependent, but was at least 56 days. Populations declined gradually in non‐sterile drain water to a low level (maximum 100 cfu mL−1 after 112 days). In sterile drain water (autoclaved prior to addition of populations), no or only a limited decline in populations was found at 112 days, dependent on strain and temperature. Drain water that tested negative for Ralstonia in the dilution plating assay was tested for the presence of cells in a viable but non‐culturable state (VBNCs). Tomato plants were inoculated, but no symptoms developed, and plants sampled 22 days post‐inoculation were negative in a plating assay. Therefore, no indications were found that VBNCs were present.
Head and neck abscessation and thrombophlebitis following cheek tooth extraction in a pony
Authors: Horbal A. A. , Reardon R. J. M. , Froydenlund T. , Jago R. C. , Dixon P. M.
Published: March 2018

Due to their long hypsodont reserve crowns, extraction of equid cheek teeth can be difficult and result in more complications than the extraction of their shorter brachydont counterparts although the more recent resumption of oral extraction has greatly reduced such complications. The more common post‐extraction sequelae in equids include non‐healing alveoli due to retained dental or alveolar sequestrae which may lead to oromaxillary or oronasal fistula formation, chronic external sinus tract formation or osteomyelitis of the supporting bones. Collateral damage to adjacent teeth has also occasionally been reported during dental repulsion. Systemic complications following equine cheek tooth extraction have been infrequently described, including a small number of cases of exodontia‐related bacterial meningioencephalitis. This is surprising, as dental manipulation can lead to bacteraemia in many species, including horses. Infections at distant sites related to the spread of dental pathogens have been well described in humans and in small animals. This report describes deep abscessation of the masseter muscles followed by extensive thrombophlebitis of the jugular, facial and rostral cervical veins following oral cheek tooth extraction in a pony affected by pituitary pars intermedia dysfunction (PPID) that was successfully treated by abscess drainage and thrombectomy of the affected veins.
Role of CD81 and CD58 in minimal residual disease detection in pediatric B lymphoblastic leukemia
Authors: Tsitsikov E. , Harris M. H. , Silverman L. B. , Sallan S. E. , Weinberg O. K.
Published: March 2018

Introduction

Minimal residual disease (MRD) in B lymphoblastic leukemia has been demonstrated to be a powerful predictor of clinical outcome in numerous studies in both children and adults. In this study, we evaluated 86 pediatric patients with both diagnostic and remission flow cytometry studies and compared expression of CD81, CD58, CD19, CD34, CD20, and CD38 in the detection of MRD.

Methods

We evaluated 86 patients with B lymphoblastic leukemia who had both diagnostic studies and remission studies for the presence of MRD using multicolor flow cytometry. We established our detection limit for identifying abnormal lymphoblasts using serial dilutions. We also compared flow cytometry findings with molecular MRD detection in a subset of patients.

Results

We found that we can resolve differences between hematogones and lymphoblasts in 85 of 86 cases using a combination of CD45, CD19, CD34, CD10, CD20, CD38, CD58, and CD81. Our detection limit using flow cytometry is 0.002% for detecting a population of abnormal B lymphoblasts. Comparison with MRD assessment by molecular methods showed a high concordance rate with flow cytometry findings.

Conclusions

Our study highlights importance of using multiple markers to detect MRD in B lymphoblastic leukemia. Our findings indicate that including both CD58 and CD81 markers in addition to CD19, CD34, CD20, CD38, and CD10 are helpful in MRD detection by flow cytometry.
Gorilla Gorilla spp conservation – from zoos to the field and back: examples from the Mbeli Bai Study
Authors: Breuer T. , Manguette M. , Groenenberg M.
Published: March 2018

Zoos and aquariums undoubtably have an important role to play in supporting species conservation through a diverse range of activities, including public awareness and financial support of field‐conservation projects. Charismatic megafauna, such as gorillas Gorilla spp, play a crucial role as flagship species in their range countries, acting as ambassadors for conservation. Here, we present examples from the Mbeli Bai Study (MBS) in northern Congo, a long‐term Western lowland gorilla Gorilla gorilla gorilla field‐conservation project. We show how collaborations between zoos and field‐conservation projects can support each other in numerous ways. Over the last two decades the MBS has received substantial support from zoos. A large portion of the operational budget has been provided by zoos and this has ensured a degree of financial independence over the long term. Intensive exchange of conservation‐education techniques in terms of material and staff expertise has been helpful for MBS's education project ‘Club Ebobo’. This has not only provided training for field educators but has also given zoo personnel and visitors better insight into the realities of conservation in range countries. Such exchanges can further help to promote awareness, raising the role of zoos in supporting field‐conservation projects. Finally, the knowledge gained through scientific research has proven to be beneficial for animals both in the field (e.g. improved conservation measures) and in captivity (e.g. better‐adapted group structure, feeding strategies and environment). Here, we discuss our experience and describe some of the benefits and challenges of conservation collaborations between zoos and field‐conservation projects.
Offspring growth and mobility in response to variation in parental care: a comparison between populations
Authors: Sofaer Helen R. , Sillett T. Scott , Yoon Jongmin , Power Michael L. , Morrison Scott A. , Ghalambor Cameron K.
Published: March 2018

Life history theory emphasizes the importance of trade‐offs in how time and energy are allocated to the competing demands of growth, fecundity, and survival. However, avian studies have historically emphasized the importance of resource acquisition over resource allocation to explain geographic variation in fecundity, parental care, and offspring development. We compared the brood sizes and nestling mass and feather growth trajectories between orange‐crowned warblersOreothlypis celatabreeding in Alaska versus California, and used 24‐h video recordings to study the relationship between parental care and growth rates. Per‐offspring provisioning rates were highest in the smallest broods, and food delivery was positively correlated with nestling growth over the 24‐h period only in Alaska. Females in Alaska spent more time brooding, and juveniles there showed faster feather growth and earlier mobility compared with those in California. We also found differences in the energetic and nutritional content of insect larvae that could facilitate the observed differences in nestling growth relative to food provisioning. Our results point to the potential importance of food quality and parental provisioning of warmth, in addition to food, for explaining avian growth patterns. We highlight the need to quantify multiple dimensions of parental care and of offspring growth and development, and to better understand the relationships between feather growth, nestling period length, and fledgling mobility.