bluuebunny/crossref_metadata_2025 huggingface dataset:
Activation of theAndrogen Receptorgene by BORIS/CTCFL in prostate cancer cells
Authors: Hari-Gupta Yukti , Kita Georgia-Xanthi , Farrar Dawn , Klenova Elena
Published: September 2017

BORIS/CTCFL, a paralogue of the chromatin architectural protein CTCF, is a member of the cancer-testis antigen family, normally present in the testes. BORIS is expressed in various tumours, including prostate cancers, however the function of BORIS in cancer cells is not well defined. The androgen receptor (AR) plays a critical role in the normal development of a human prostate gland and pathogenesis of prostate cancer. In our previous study we described a positive correlation between elevated levels of BORIS and AR in prostate cancers, and activation of theARgene by BORIS in prostate cancer cells. Elucidation of the mechanisms involved in the modulation of AR activity is important to understand prostate tumourigenesis and investigation of transcriptional regulation of theARgene by BORIS may provide new insights into this issue. Here we report the ability of BORIS to not only positively regulateARin androgen-dependent prostate cancer (ADPC) cells, but re-activate epigenetically silencedARin androgen-independent prostate cancer (AIPC) cells leading to the production of biologically active AR protein. CTCF, on the other hand, had repressive effects on theAR. In both, ADPC and AIPC cells, introduction of ectopic BORIS was associated with the reduction in theARpromoter methylation, increase in active and decrease in repressive chromatin marks, and decrease in CTCF occupancies at the two main upstream BORIS/CTCF binding sites. We propose a model of epigenetic regulation ofARby BORIS in prostate cells whereby BORIS remodels the chromatin at theARpromoter leading to transcriptional activation.
Estimating sampling completeness of interactions in quantitative bipartite ecological networks: incorporating variation in species’ specialisation
Authors: Macgregor Callum J. , Evans Darren M. , Pocock Michael J.O.
Published: September 2017

Background

The analysis of ecological networks can be affected by sampling effort, potentially leading to bias. Ecological network structure is often summarised by descriptive metrics but these metrics can vary according to the proportion of the total interactions that have been observed. Therefore, to know the likely degree of bias, it is valuable to estimate the total number of interactions in a network, and so calculate the proportion of interactions that have been observed (sampling completeness of interactions). Existing approaches to estimate sampling completeness of interactions use the Chao family of asymptotic species richness estimators to predict the total number of interactions, but do not fully utilise information about the relative specialisation of species within the network.

Results

Here, we propose a modification of previously-used methods, that places equal weight on each interaction (whether or not it has been observed), rather than on each species. Our approach is therefore equivalent to weighting the interaction sampling completeness of each species in the network according to its relative specialisation. We demonstrate that, for the subset of species that are observed and when assuming that species richness estimators accurately project the number of unobserved interactions per observed species, our approach is mathematically more accurate. Our approach can be universally applied to any quantitative, bipartite network.

We propose two methods to estimation using our approach, using abundance-based and incidence-based species richness estimators respectively, and give recommendations when each should be applied. We discuss the effect of unobserved species and the potential use of a threshold of minimum abundance for species inclusion. Finally, we consider these advances in the context of some of the main issues surrounding estimation of interaction sampling completeness in network ecology.

Conclusions

We recommend that future studies of bipartite networks utilise our approach and methods to estimate the sampling completeness of interactions, to assist with the quantitative and comparative analysis and interpretation of network properties.
Genome-wide association analysis of 350,000 Caucasians from the UK Biobank identifies novel loci for asthma, hay fever and eczema
Authors: Johansson Åsa , Rask-Andersen Mathias , Karlsson Torgny , Ek Weronica E.
Published: September 2017

Even though heritability estimates suggest that the risk of asthma, hay fever and eczema is largely due to genetic factors, previous studies have not explained a large part of the genetics behind these diseases. In this GWA study, we include 346,545 Caucasians from the UK Biobank to identify novel loci for asthma, hay fever and eczema. We further investigate if associated lead SNPs have a significantly larger effect for one disease compared to the other diseases, to highlight possible disease specific effects.

We identified 141 loci, of which 41 are novel, to be associated (P≤3×10−8) with asthma, hay fever or eczema, analysed separately or as disease phenotypes that includes the presence of different combinations of these diseases. The largest number of loci were associated with the combined phenotype (asthma/hay fever/eczema). However, as many as 20 loci had a significantly larger effect on hay fever/eczema-only compared to their effects on asthma, while 26 loci exhibited larger effects on asthma compared with their effects on hay fever/eczema. At four of the novel loci,TNFRSF8, MYRF, TSPAN8, andBHMG1, the lead SNPs were in LD (> 0.8) with potentially casual missense variants.

Our study shows that a large amount of the genetic contribution is shared between the diseases. Nonetheless, a number of SNPs have a significantly larger effect on one of the phenotypes suggesting that part of the genetic contribution is more phenotype specific. Identified loci and probable causal genes may in the future be used as targets for treatments of asthma, hay fever and eczema.
Parallel progress in perceived age and life expectancy
Authors: Steiner Ulrich K. , Larsen Lisbeth Aagaard , Christensen Kaare
Published: September 2017

Human life expectancy continues to rise in most populations. This rise not only leads to longer lives but is also accompanied by improved health at a given age, i.e. we see a reduction of biological age for a given chronological age in recent cohorts. Despite or even because of the diversity of biomarkers of aging, an accurate quantification of a general shift in biological age across time has been challenging. By comparing age perception of images taken in 2001 over a decade, we show that age perception changes substantially across time and parallels the progress in life expectancy. In 2012, people aged 70+ needed to look 2.3 years younger to be rated the same age as in 2002. Our results further suggest that age perception reflects the past life events better than predicts future length of life, i.e. it is written in your face how much you have aged so far, but does not predict well how fast you will age in the future. We draw this conclusion since age perception among elderly paralleled changes in life expectancy at birth but not changes in remaining life expectancies. We illustrate advantages of perceived age as a biomarker of aging and suggest that changes in age perception should be explored for younger age classes to inform on aging processes, including whether aging is delayed or slowed with increasing life expectancy.
Prediction of the intestinal resistome by a novel 3D-based method
Authors: Ruppé Etienne , Ghozlane Amine , Tap Julien , Pons Nicolas , Alvarez Anne-Sophie , Maziers Nicolas , Cuesta Trinidad , Hernando-Amado Sara , Martínez Jose Luís , Coque Teresa M. , Baquero Fernando , Lanza Val F. , Maiz Luis , Goulenok Tiphaine , Lastours Victoire de , Amor Nawal , Fantin Bruno , Wieder Ingrid , Andremont Antoine , Schaik Willem van , Rogers Malbert , Zhang Xinglin , Willems Rob J.L. , De Brevern Alexandre G. , Batto Jean-Michel , Blottière Hervé , Léonard Pierre , Léjard Véronique , Letur Aline , Levenez Florence , Weiszer Kevin , Haimet Florence , Doré Joël , Kennedy Sean P. , Dusko Ehrlich S.
Published: September 2017

The intestinal microbiota is considered to be a major reservoir of antibiotic resistance determinants (ARDs) that could potentially be transferred to bacterial pathogens. Yet, this question remains hypothetical because of the difficulty to identify ARDs from intestinal bacteria. Here, we developed and validated a new annotation method (called pairwise comparative modelling, PCM) based on homology modelling in order to characterize the Human resistome. We were able to predict 6,095 ARDs in a 3.9 million protein catalogue from the Human intestinal microbiota. We found that predicted ARDs (pdARDs) were distantly related to known ARDs (mean amino-acid identity 29.8%). Among 3,651 pdARDs that were identified in metagenomic species, 3,489 (95.6%) were assumed to be located on the bacterial chromosome. Furthermore, genes associated with mobility were found in the neighbourhood of only 7.9% (482/6,095) of pdARDs. According to the composition of their resistome, we were able to cluster subjects from the MetaHIT cohort (n=663) into 6 “resistotypes”. Eventually, we found that the relative abundance of pdARDs was positively associated with gene richness, but not when subjects were exposed to antibiotics. Altogether, our results support that most ARDs in the intestinal microbiota should be considered as intrinsic genes of commensal microbiota with a low risk of transfer to bacterial pathogens.
Cognitive deficits and increases in creatine precursors in a brain-specific knockout of the creatine transporter geneSlc6a8
Authors: Udobi Kenea C. , Kokenge Amanda N. , Hautman Emily R. , Ullo Gabriela , Coene Julie , Williams Michael T. , Vorhees Charles V. , Mabondzo Aloïse , Skelton Matthew R
Published: September 2017

Creatine transporter (CrT; SLC6A8) deficiency (CTD) is an X-linked disorder characterized by severe cognitive deficits, impairments in language, and an absence of brain creatine (Cr). In a previous study, we generated floxedSlc6a8 (Slc6a8flox)mice to create ubiquitousSlc6a8knockout(Slc6a8-/y)mice.Slc6a8-/ymice lacked whole body Cr and exhibited cognitive deficits. WhileSlc6a8-/ymice have a similar biochemical phenotype to CTD patients, they also showed a reduction in size and reductions in swim speed that may have contributed to the observed deficits. To address this, we created brain-specificSlc6a8knockout (bKO) mice by crossingSlc6a8Floxmice withNestin-cremice. bKO mice had reduced cerebral Cr levels while maintaining normal Cr levels in peripheral tissue. Interestingly, brain concentrations of the Cr synthesis precursor guanidinoacetic acid were increased in bKO mice. bKO mice had longer latencies and path lengths in the Morris water maze, without reductions in swim speed. In accordance with data fromSlc6a8-/ymice, bKO mice showed deficits in novel object recognition as well as contextual and cued fear conditioning. bKO mice were also hyperactive, in contrast with data from theSlc6a8-/ymice. The results demonstrate that the loss of cerebral Cr is responsible for the learning and memory deficits seen in ubiquitousSlc6a8-/ymice.
Transplanted Adult Neural Stem Cells Express Sonic HedgehogIn Vivoand Suppress White Matter Neuroinflammation After Experimental Traumatic Brain Injury
Authors: Sullivan Genevieve M. , Armstrong Regina C.
Published: September 2017

Neural stem cells (NSCs) delivered intraventricularly may be therapeutic for diffuse white matter pathology after traumatic brain injury (TBI). To test this concept, NSCs isolated from adult mouse subventricular zone (SVZ) were transplanted into the lateral ventricle of adult mice at two weeks post-TBI followed by analysis at four weeks post-TBI. We examined Sonic hedgehog (Shh) signaling as a candidate mechanism by which transplanted NSCs may regulate neuroregeneration and/or neuroinflammation responses of endogenous cells. Mouse fluorescent reporter lines were generated to enablein vivogenetic labeling of cells actively transcribingShhorGli1after transplantation and/or TBI.Gli1transcription is an effective readout for canonical Shh signaling. InShhCreERT2;R26tdTomatomice,Shhwas primarily expressed in neurons and was not upregulated in reactive astrocytes or microglia after TBI. Corroborating results inGli1CreERT2;R26tdTomatohost mice demonstrated Shh signaling was not upregulated in the corpus callosum, even after TBI or NSC transplantation. Transplanted NSC expressedShh in vivobut did not increaseGli1labeling of host SVZ cells. Importantly, NSC transplantation significantly reduced reactive astrogliosis and microglial/macrophage activation in the corpus callosum after TBI. Therefore, intraventricular NSC transplantation after TBI significantly attenuated neuroinflammation, but did not activate host Shh signaling viaGli1transcription.
A Connectome Wide Functional Signature of Transdiagnostic Risk for Mental Illness
Authors: Elliott Maxwell L. , Romer Adrienne , Knodt Annchen R. , Hariri Ahmad R.
Published: September 2017

Background

High rates of comorbidity, shared risk, and overlapping therapeutic mechanisms have led psychopathology research towards transdiagnostic dimensional investigations of clustered symptoms. One influential framework accounts for these transdiagnostic phenomena through a single general factor, sometimes referred to as the ‘p’ factor, associated with risk for all common forms of mental illness.

Methods

Here we build on past research identifying unique structural neural correlates of the p factor by conducting a data-driven analysis of connectome wide intrinsic functional connectivity (n = 605).

Results

We demonstrate that higher p factor scores and associated risk for common mental illness maps onto hyper-connectivity between visual association cortex and both frontoparietal and default mode networks.

Conclusions

These results provide initial evidence that the transdiagnostic risk for common forms of mental illness is associated with patterns of inefficient connectome wide intrinsic connectivity between visual association cortex and networks supporting executive control and self-referential processes, networks which are often impaired across categorical disorders.
Relationship between sustainable operations practices and performance: a meta-analysis
Authors: D’Agostini Marina , Tondolo Vilmar Antonio Gonçalves , Camargo Maria Emília , Dullius Angela Isabel dos Santos , Tondolo Rosana da Rosa Portella , Russo Suzana Leitão
Published: October 2017

Purpose

The purpose of this paper is to examine the relationship between sustainable operations practices (SOP) and performance.

Design/methodology/approach

This study was conducted through a systematic literature review followed by a meta-analysis of correlations.

Findings

In the results, 14 of the relationships examined showed a positive relationship and 12 the presence of moderators. The study findings indicate that contingency affects the relationship between SOPs and performance.

Research limitations/implications

The research presented in this paper is mainly limited to databases that were searched. Among the quantitative articles selected from the databases, many did not have the data needed to conduct the meta-analysis, which may have limited the results of this study.

Practical implications

Using the results of this study, practitioners can become aware of to the occurrence of moderating factors in the relationships, which can range from interference from other practices and variables to characteristics of the organization itself or the market in which organizations operate.

Originality/value

This study uses a multidimensional approach for both SOP and performance. This approach allowed a more complete and comprehensive result, showing how these SOPs influence the different categories of performance, expanding the understanding of the relationship between practices and performance.
Cash flow disaggregation and prediction of cash flow
Authors: Khansalar Ehsan , Namazi Mohammad
Published: October 2017

Purpose

The purpose of this paper is to investigate the incremental information content of estimates of cash flow components in predicting future cash flows.

Design/methodology/approach

The authors examine whether the models incorporating components of operating cash flow from income statements and balance sheets using the direct method are associated with smaller prediction errors than the models incorporating core and non-core cash flow.

Findings

Using data from US and UK firms and multiple regression analysis, the authors find that around 60 per cent of a current year’s cash flow will persist into the next period’s cash flows, and that income statement and balance sheet variables persist similarly. The explanatory power and predictive ability of disaggregated cash flow models are superior to that of an aggregated model, and further disaggregating previously applied core and non-core cash flows provides incremental information about income statement and balance sheet items that enhances prediction of future cash flows. Disaggregated models and their components produce lower out-of-sample prediction errors than an aggregated model.

Research limitations/implications

This study improves our appreciation of the behaviour of cash flow components and confirms the need for detailed cash flow information in accordance with the articulation of financial statements.

Practical implications

The findings are relevant to investors and analysts in predicting future cash flows and to regulators with respect to disclosure requirements and recommendations.

Social implications

The findings are also relevant to financial statement users interested in better predicting a firm’s future cash flows and thereby, its firm’s value.

Originality/value

This paper contributes to the existing literature by further disaggregating cash flow items into their underlying items from income statements and balance sheets.
How do conflicts impact change in family businesses? The family system and familiness as a catalytic converter of change
Authors: Claßen Christina Anna Elisabeth , Schulte Reinhard
Published: October 2017

Purpose

The purpose of this paper is to develop an understanding of how conflicts, caused by the specifics of family businesses – the familiness – impact change in family businesses.

Design/methodology/approach

The analysis is based on 21 semi-structured in-depth interviews of German family business members. The authors followed the grounded theory approach.

Findings

This study gives evidence for family business-specific conflicts and family business-specific change and outlines how conflict impacts change. Findings show that a family system works like a recursive catalytic converter in family businesses.

Research limitations/implications

This paper offers researchers a broader understanding and a comprehensive view of change in the family business. Although still limited by its exploratory approach, its insights can be valuable for researchers, practitioners and policy makers. The findings offer an operational base for future quantitative studies.

Originality/value

Using the new system theories approach the authors develop an understanding of how conflicts impact change in family businesses. The study explains how conflicts are managed in family business practice.
Evolution of human diet and effect of globalization on regional diet with emphasis to the Mediterranean diet
Authors: Haile Belay , Neme Kumera , Belachew Tefera
Published: October 2017

Purpose

The Mediterranean Diet (MD) is an expression of different Mediterranean food cultures and lifestyles. It is characterized by high consumption of olive oil, vegetables, legumes, whole grain products, fruits and nuts. This paper aims to emphasize on the evolution of human diet from earliest human ancestors to current civilization, the effect of MD on human health and the role of globalization to shift traditional diet, particularly MD to processed foods.

Design/methodology/approach

Different published papers were collected from the internet by using the following phrases: evolution of human diet, human ancestors, the effect of globalization on a regional diet, Mediterranean diet, healthy food, food pyramid, evolution of human diet and effect of globalization on diet. Finally, the papers were read and summarized as a review paper.

Findings

MD has been accepted worldwide owing to its health impact such as prevention and control of type 2 diabetes, anti-inflammatory effects and decrease in the risk of cardiovascular diseases and incidence of Parkinson’s disease and Alzheimer’s disease. However, in conjunction with this discordance between our ancient, genetically determined biology and the nutritional, cultural and activity patterns of contemporary Western populations, many of the so-called diseases of civilization have emerged. Particularly, the food staples and food-processing procedures introduced during the Neolithic and Industrial periods have fundamentally altered nutritional characteristics of ancestral hominin diets. MD is currently under the risk of extinction for a result of the effects of globalization.

Originality/value

The review paper focuses on the evolution of human diet as an effect of globalization on the regional diet with emphasis on the MD. It specifically focuses on the link between diet and earliest human ancestors, about MD and its health benefit, diet pyramid and effect of globalization on regional diet.
Mutualistic interaction between dichloromethane‐ and chloromethane‐degrading bacteria in an anaerobic mixed culture
Authors: Chen Gao , Kleindienst Sara , Griffiths Daniel R. , Mack E. Erin , Seger Edward S. , Löffler Frank E.
Published: October 2017

The microbial mixed culture RM grows with dichloromethane (DCM) as the sole energy source generating acetate, methane, chloride and biomass as products. Chloromethane (CM) was not an intermediate during DCM utilization consistent with the observation that CM could not replace DCM as a growth substrate. Interestingly, cultures that received DCM and CM together degraded both compounds concomitantly. Transient hydrogen (H2) formation reaching a maximum concentration of 205 ± 13 ppmv was observed in cultures growing with DCM, and the addition of exogenous H2 at concentrations exceeding 3000 ppmv impeded DCM degradation. In contrast, CM degradation in culture RM had a strict requirement for H2. Following five consecutive transfers on CM and H2, Acetobacterium 16S rRNA gene sequences dominated the culture and the DCM‐degrader Candidatus Dichloromethanomonas elyunquensis was eliminated, consistent with the observation that the culture lost the ability to degrade DCM. These findings demonstrate that culture RM harbours different populations responsible for anaerobic DCM and CM metabolism, and further imply that the DCM and CM degradation pathways are mechanistically distinct. H2 generated during DCM degradation is consumed by the hydrogenotrophic CM degrader, or may fuel other hydrogenotrophic processes, including organohalide respiration, methanogenesis and H2/CO2 reductive acetogenesis.
Metagenomic assessment of the interplay between the environment and the genetic diversification of Acinetobacter
Authors: Garcia‐Garcera Marc , Touchon Marie , Brisse Sylvain , Rocha Eduardo P.C.
Published: October 2017

Most bacteria have poorly characterized environmental reservoirs and unknown closely related species. This hampers the study of bacterial evolutionary ecology because both the environment and the genetic background of ancestral lineages are unknown. We combined metagenomics, comparative genomics and phylogenomics to overcome this limitation, to identify novel taxa and to propose environments where they can be isolated. We applied this method to characterize the ecological distribution of known and novel lineages of Acinetobacter spp. We observed two major environmental transitions at deep phylogenetic levels, splitting the genus into three ecologically differentiated clades. One of these has rapidly shifted towards host‐association by acquiring genes involved in bacteria‐eukaryote interactions. We show that environmental perturbations affect species distribution in predictable ways: bovines have very diverse communities of Acinetobacter, unless they were administered antibiotics, in which case they show highly uniform communities of Acinetobacter spp. that resemble those of humans. Our results uncover the diversity of bacterial lineages, overpassing the limitations of classical cultivation methods and highlight the role of the environment in shaping their evolution.
Transfer and analysis of Salmonella pdu genes in a range of Gram‐negative bacteria demonstrate exogenous microcompartment expression across a variety of species
Authors: Graf Laura , Wu Kent , Wilson James W.
Published: October 2017

Bacterial microcompartments (MCPs) are protein organelles that typically house toxic or volatile reaction intermediates involved in metabolic pathways. Engineering bacteria to express exogenous MCPs will allow these cells to gain useful functions involving molecule compartmentalization. We cloned a 38 kb region from the Salmonella enterica serovar Typhimurium genome containing the pdu 1,2 propanediol (1,2 PD) utilization and cob/cbi genes using the FRT‐Capture strategy to clone and transfer large genomic segments. We transferred this clone to a range of Gram‐negative bacteria and found the clone to be functional for 1,2 PD metabolism in a variety of species including S. Typhimurium Δpdu, Escherichia coli, Salmonella bongori, Klebsiella pneumoniae, Cronobacter sakazakii, Serratia marcescens, and different Pseudomonas species. We successfully isolated MCPs expressed from the clone from several, but not all, of these strains, and we observed this utilizing a range of different media and in the absence of protease inhibitor. We also present a mini‐prep protocol that allows rapid, small‐scale screening of strains for MCP production. To date, this is the first analysis of cloned, exogenous microcompartment expression across several different Gram‐negative backgrounds and provides a foundation for MCP use in a variety of bacterial species using a full, intact clone.
Simulation‐based Education to Ensure Provider Competency Within the Health Care System
Authors: Griswold Sharon , Fralliccardi Alise , Boulet John , Moadel Tiffany , Franzen Douglas , Auerbach Marc , Hart Danielle , Goswami Varsha , Hui Joshua , Gordon James A.
Published: September 2017

The acquisition and maintenance of individual competency is a critical component of effective emergency care systems. This article summarizes consensus working group deliberations and recommendations focusing on the topic “Simulation‐based education to ensure provider competency within the healthcare system.” The authors presented this work for discussion and feedback at the 2017 Academic Emergency Medicine Consensus Conference on “Catalyzing System Change Through Healthcare Simulation: Systems, Competency, and Outcomes,” held on May 16, 2017, in Orlando, Florida. Although simulation‐based training is a quality and safety imperative in other high‐reliability professions such as aviation, nuclear power, and the military, health care professions still lag behind in applying simulation more broadly. This is likely a result of a number of factors, including cost, assessment challenges, and resistance to change. This consensus subgroup focused on identifying current gaps in knowledge and process related to the use of simulation for developing, enhancing, and maintaining individual provider competency. The resulting product is a research agenda informed by expert consensus and literature review.
Body size variation and sexual size dimorphism across climatic gradients in the widespread treefrog Scinax fuscovarius (Anura, Hylidae)
Authors: Goldberg Javier , Cardozo Darío , Brusquetti Francisco , Bueno Villafañe Diego , Caballero Gini Andrea , Bianchi Carlos
Published: September 2017

Variation in body size represents one of the crucial raw materials for evolution. However, at present, it is still being debated what is the main factor affecting body size or if the final body size is the consequence of several factors acting synergistically. To evaluate this, widespread species seem to be suitable models because the different populations occur along a geographical gradient and under contrasted climatic and environmental conditions. Here we describe the spatial pattern of variation in body size and sexual size dimorphism in the snouted treefrog Scinax fuscovarius (Anura, Hylidae) along a 10° range in latitude, 25° longitude, and 2000 m in altitude from Argentina, Brazil and Paraguay using an information‐theoretic approach to evaluate the support of the data for eight a priori hypotheses proposed in the literature to account for geographical body size, and three hypotheses for sexual size dimorphism variation. Body size of S. fuscovarius varied most dramatically with longitude and less so with latitude; frogs were largest in the northwestern populations. Body size was positively related with precipitation seasonality, and negatively with annual precipitation. Furthermore, the degree of sexual size dimorphism was greatest in the western populations with less annual precipitation, as the increase in body size was stronger for females. Our results on body size variation are consistent with two ecogeographical hypotheses, the starvation resistance and the water availability hypotheses, while our results on sexual size dimorphism in S. fuscovarius supports the differential‐plasticity hypothesis but the inverse to Rensch's rule and the parental investment hypothesis. Due to the weak association between environmental variables and body size and sexual size dimorphism variation, we stress that there are other factors, mainly those related to the life history, driving the geographical variation of S. fuscovarius.
The monoacylglycerol lipase inhibitor KML29 with gabapentin synergistically produces analgesia in mice
Authors: Crowe Molly S , Wilson Catheryn D , Leishman Emma , Prather Paul L , Bradshaw Heather B , Banks Matthew L , Kinsey Steven G
Published: September 2017

Background and Purpose

Gabapentin is commonly prescribed for nerve pain but may also cause dizziness, sedation and gait disturbances. Similarly, inhibition of the endogenous cannabinoid enzyme monoacylglycerol lipase (MAGL) has antinociceptive and anti‐inflammatory properties but also induces sedation in mice at high doses. To limit these side effects, the present study investigated the analgesic effects of coadministering a MAGL inhibitor with gabapentin.

Experimental Approach

Mice subjected to the chronic constriction injury model of neuropathic pain were administered the MAGL inhibitor KML29 (1–40 mg·kg−1, i.p.), gabapentin (1–50 mg·kg−1, i.p.) or both compounds. Mice were tested for mechanical and cold allodynia. The function and expression of cannabinoid CB1 receptors in whole brain homogenates and lipid profile of spinal cords were assessed after repeated drug administration.

Key Results

The combination of low‐dose KML29:gabapentin additively attenuated mechanical allodynia and synergistically reduced cold allodynia. The CB1 antagonist, rimonabant, partially reversed the anti‐allodynic effects of KML29:gabapentin in mechanical allodynia but not cold allodynia. The anti‐allodynic effects of KML29:gabapentin did not undergo tolerance in mechanical allodynia after repeated administration but produced mild tolerance in cold allodynia. High dose KML29 alone reduced CB1 receptor expression and function, but KML29:gabapentin reduced the density of CB1 receptors but did not alter their function. KML29:gabapentin influenced additional signalling pathways (including fatty acids) other than the pathways activated by a higher dose of either drug alone.

Conclusion and Implications

These data support the strategy of combining MAGL inhibition with a commonly prescribed analgesic as a therapeutic approach for attenuating neuropathic pain.
Dopamine D2 receptor signalling controls inflammation in acute pancreatitis via a PP2A‐dependent Akt/NF‐κB signalling pathway
Authors: Han Xiao , Li Bin , Ye Xin , Mulatibieke Tunike , Wu Jianghong , Dai Juanjuan , Wu Deqing , Ni Jianbo , Zhang Ruling , Xue Jing , Wan Rong , Wang Xingpeng , Hu Guoyong
Published: September 2017

Background and Purpose

Dopamine has multiple anti‐inflammatory effects, but its role and molecular mechanism in acute pancreatitis (AP) are unclear. We investigated the role of dopamine signalling in the inflammatory response in AP.

Experimental Approach

Changes in pancreatic dopaminergic system and effects of dopamine, antagonists and agonists of D1 and D2 dopamine receptors were analysed in wild‐type and pancreas‐specific Drd2−/− mice with AP (induced by caerulein and LPS or L‐arginine) and pancreatic acinar cells with or without cholecystokinin (CCK) stimulation. The severity of pancreatitis was assessed by measuring serum amylase and lipase and histological assessments. The NF‐κB signalling pathway was evaluated, and macrophage and neutrophil migration assessed by Transwell assay.

Key Results

Pancreatic dopamine synthetase and metabolic enzyme levels were increased, whereas D1 and D2 receptors were decreased in AP. Dopamine reduced inflammation in CCK‐stimulated pancreatic acinar cells by inhibiting the NF‐κB pathway. Moreover, the protective effects of dopamine were blocked by a D2 antagonist, but not a D1 antagonist. A D2 agonist reduced pancreatic damage and levels of p‐IκBα, p‐NF‐κBp65, TNFα, IL‐1β and IL‐6 in AP. Pancreas‐specific Drd2−/− aggravated AP. Also, the D2 agonist activated PP2A and inhibited the phosphorylation of Akt, IKK, IκBα and NF‐κB and production of inflammatory cytokines and chemokines. Furthermore, it inhibited the migration of macrophages and neutrophils by reducing the expression of CCL2 and CXCL2. A PP2A inhibitor attenuated these protective effects of the D2 agonist.

Conclusions and Implications

D2 receptors control pancreatic inflammation in AP by inhibiting NF‐κB activation via a PP2A‐dependent Akt signalling pathway.
Epigenetic regulation of melatonin receptors in neuropsychiatric disorders
Authors: Bahna Sarra G , Niles Lennard P
Published: October 2017

Melatonin, the primary indoleamine hormone of the mammalian pineal gland, is known to have a plethora of neuroregulatory, neuroprotective and other properties. Melatonergic signalling is mediated by its two GPCRs, MT1 and MT2, which are widely expressed in the mammalian CNS. Melatonin levels and receptor expression often show a decrease during normal ageing, and this reduction may be accelerated in some disease states. Depleted melatonergic signalling has been associated with neuropsychiatric dysfunction and impairments in cognition, memory, neurogenesis and neurorestorative processes. The anticonvulsant and mood stabilizer, valproic acid (VPA), up‐regulates melatonin MT1 and/or MT2 receptor expression in cultured cells and in the rat brain. VPA is known to affect gene expression through several mechanisms, including the modulation of intracellular kinase pathways and transcription factors, as well as the inhibition of histone deacetylase (HDAC) activity. Interestingly, other HDAC inhibitors, such as trichostatin A, which are structurally distinct from VPA, can also up‐regulate melatonin receptor expression, unlike a VPA analogue, valpromide, which lacks HDAC inhibitory activity. Moreover, VPA increases histone H3 acetylation along the length of the MT1 gene promoter in rat C6 cells. These findings indicate that an epigenetic mechanism, linked to histone hyperacetylation/chromatin remodelling and associated changes in gene transcription, is involved in the up‐regulation of melatonin receptors by VPA. Epigenetic induction of MT1 and/or MT2 receptor expression, in areas where these receptors are lost because of ageing, injury or disease, may be a promising therapeutic avenue for the management of CNS dysfunction and other disorders.

Linked Articles

This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc
Antidepressant‐like effects of BU10119, a novel buprenorphine analogue with mixed κ/μ receptor antagonist properties, in mice
Authors: Almatroudi Abdulrahman , Ostovar Mehrnoosh , Bailey Christopher P , Husbands Stephen M , Bailey Sarah J
Published: October 2017

Background and Purpose

The κ receptor antagonists have potential for treating neuropsychiatric disorders. We have investigated the in vivo pharmacology of a novel buprenorphine analogue, BU10119, for the first time.

Experimental Approach

To determine the opioid pharmacology of BU10119 (0.3–3 mg·kg−1, i.p.) in vivo, the warm‐water tail‐withdrawal assay was applied in adult male CD1 mice. A range of behavioural paradigms was used to investigate the locomotor effects, rewarding properties and antidepressant or anxiolytic potential of BU10119. Additional groups of mice were exposed to a single (1 × 2 h) or repeated restraint stress (3× daily 2 h) to determine the ability of BU10119 to block stress‐induced analgesia.

Key Results

BU10119 alone was without any antinociceptive activity. BU10119 (1 mg·kg−1) was able to block U50,488, buprenorphine and morphine‐induced antinociception. The κ antagonist effects of BU10119 in the tail‐withdrawal assay reversed between 24 and 48 h. BU10119 was without significant locomotor or rewarding effects. BU10119 (1 mg·kg−1) significantly reduced the latency to feed in the novelty‐induced hypophagia task and reduced immobility time in the forced swim test, compared to saline‐treated animals. There were no significant effects of BU10119 in either the elevated plus maze or the light–dark box. Both acute and repeated restraint stress‐induced analgesia were blocked by pretreatment with BU10119 (1 mg·kg−1). Parallel stress‐induced increases in plasma corticosterone were not affected.

Conclusions and Implications

BU10119 is a mixed κ/μ receptor antagonist with relatively short‐duration κ antagonist activity. Based on these preclinical data, BU10119 has therapeutic potential for the treatment of depression and other stress‐induced conditions.

Linked Articles

This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc
In-vitro effect of pembrolizumab on different T regulatory cell subsets
Authors: Toor S M , Syed Khaja A S , Alkurd I , Elkord E
Published: September 2017

Programmed death-1 (PD-1) and interactions with PD-ligand 1 (PD-L1) play critical roles in the tumour evasion of immune responses through different mechanisms, including inhibition of effector T cell proliferation, reducing cytotoxic activity, induction of apoptosis in tumour-infiltrating T cells and regulatory T cell (Treg) expansion. Effective blockade of immune checkpoints can therefore potentially eliminate these detrimental effects. The aim of this study was to investigate the effect of anti-PD-1 antibody, pembrolizumab, on various Treg subpopulations. Peripheral blood mononuclear cells (PBMC) from healthy donors (HD) and primary breast cancer patients (PBC) were treated in vitro with pembrolizumab, which effectively reduced PD-1 expression in both cohorts. We found that PD-1 was expressed mainly on CD4+CD25+ T cells and pembrolizumab had a greater effect on PD-1 expression in CD4+CD25− T cells, compared to CD4+CD25+ cells. In addition, pembrolizumab did not affect the expression levels of Treg-related markers, including cytotoxic T lymphocyte antigen-4 (CTLA-4), CD15s, latency-associated peptide (LAP) and Ki-67. Moreover, we report that CD15s is expressed mainly on forkhead box P3 (FoxP3)−Helios+ Treg in HD, but it is expressed on FoxP3+Helios− Treg subset in addition to FoxP3−Helios+ Treg in PBC. Pembrolizumab did not affect the levels of FoxP3+/−Helios+/− Treg subsets in both cohorts. Taken together, our study suggests that pembrolizumab does not affect Treg or change their phenotype or function but rather blocks signalling via the PD-1/PD-L1 axis in activated T cells.
Expression of vascular endothelial growth factor and its correlation with clinical symptoms and endoscopic findings in patients with chronic radiation proctitis
Authors: Trzcinski R. , Dziki A. , Brys M. , Moszynska‐Zielinska M. , Chalubinska‐Fendler J. , Mik M. , Kujawski R. , Dziki L.
Published: September 2017

Aim

The aim of this study was to assess the expression of vascular endothelial growth factor (VEGF) as a key proangiogenic factor and determine whether there is any correlation between its expression and clinical symptoms or endoscopic changes in patients with chronic radiation proctitis (ChRP).

Method

Fifty patients who had all undergone radiotherapy for prostate, cervical or uterine cancer were included in the study (37 women, 13 men). There was a control group of 20 patients (9 women, 11 men). The Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scoring system was used for grading the severity of the proctitis. Endoscopic scoring of late rectal mucosal damage was performed using Gilinsky's classification. Serum levels of VEGF were analysed by the enzyme‐linked immunosorbent assay method.

Results

Most patients presented with Grade 1 symptoms. Endoscopic assessment showed that most patients had Grade 1 late rectal mucosal damage. The predominant endoscopic finding was the presence of telangiectasia. Assessment of VEGF correlation between the control group and the degrees of endoscopic changes showed statistically significant differences for all three degrees (P < 0.0001, P = 0.0251 and P = 0.0005, respectively). Due to the small numbers of patients with Grades 2 and 3 symptoms using the RTOG/EORTC scoring system, they were grouped with Grades 1 and 4 respectively forming two groups for statistical purposes. VEGF expression differed significantly between controls and group I and between controls and group II (P = 0.0001, P = 0.0009, respectively).

Conclusion

A significant increase in VEGF expression was found to correlate with clinical symptoms and endoscopic rectal mucosa changes in patients with ChRP, suggesting that it may play an important role in pathological angiogenesis.
Purification and characterization of three commercial phenylazoaniline disperse dyes
Authors: Umbuzeiro Gisela A. , Szymczyk Malgorzata , Li Min , Chen Yufei , Vendemiatti Josiane A. S. , de Albuquerque Anjaina F. , dos Santos Amanda , Maselli Bianca de S. , Kummrow Fábio , Vinueza Nelson R. , Freeman Harold S.
Published: October 2017

Although tons of disperse dyes are used worldwile, little information on their ecotoxicity is available. While in silico models can be used to predict their ecotoxicity, experimental results from Daphnia can show significantly higher toxicity than predicted. Thus the objective of this work was to extend the knowledge base in this area by evaluating the ecotoxicity of three widely used disperse dyes and comparing the results to predicted values. Bearing in mind that generating ecotoxicity data on azo disperse dyes is complicated because they are not readily found as homogeneous compounds, we employed chromatographic methods to purify three commercially dyes C.I. Disperse Violet 93, Blue 291, and Blue 373 already found in the aquatic environment. No acute toxicity was observed for Daphnia similis. These results seems to be in general agreement when compared with ECOSAR predicted values. We hypothesize that differences in Kow values could explain the variations in results.
Reassessing risks and benefits of living kidney donors with a history of thyroid cancer
Authors: Adler Joel T. , Yeh Heidi , Barbesino Giuseppe , Lubitz Carrie C.
Published: September 2017

Many potential and willing living kidney donors are excluded from donating for a history of malignancy. There is appropriate caution toward patients with a history of malignancy because of concern for transmission of donor‐derived malignancy. Thyroid cancer is common and increasing in incidence, and outcomes are very good in otherwise young, healthy potential donors. We review the evidence and guidelines regarding recurrence and transmission risk of thyroid cancer, and then we suggest a standardized guideline for otherwise healthy donors with a history of thyroid malignancy.
Metformin and β‐cell function in insulin‐treated patients with type 2 diabetes: A randomized placebo‐controlled 4.3‐year trial
Authors: Top Wiebe , Stehouwer Coen , Lehert Philippe , Kooy Adriaan
Published: October 2017

In this trial, 390 insulin‐treated patients with type 2 diabetes were randomized to either placebo or metformin. Fasting levels of glucose, insulin and C peptide were determined at baseline, after 4 months and yearly thereafter for 4 years to assess fasting estimates of beta cell function. The primary endpoint was the fasting C peptide‐to‐glucose ratio (FCPGR) and secondary measures were the disposition index (DI) and the fasting C peptide (FCP). We analysed the results with a general linear mixed model. Baseline FCPGR was 5.27 (95% CI, 4.83 – 5.71). Compared to placebo, FCPGR increased in the metformin group with 1.48 (95% CI, 1.09 – 1.87, P < 0.001). The DI showed comparable results with a treatment effect of 1.50 (95% CI, 1.17 – 1.83; P < 0.001). FCP also increased in the metformin group but did not reach statistical significance vs placebo (0.034 nmol, 95% CI, −0.005 – 0.072; P = 0.085). Treatment with metformin vs placebo, added to insulin in patients with type 2 diabetes, improves long‐term estimates of beta cell function in the fasting state.
Effectiveness of furosemide in attenuating exercise‐induced pulmonary haemorrhage in horses when administered at 4‐ and 24‐h prior to high‐speed training
Authors: Knych H. K. , Wilson W. D. , Vale A. , Kass P. H. , Arthur R. M. , Jones J. H.
Published: September 2017

Background

Due to the high prevalence ofEIPHin racehorses and its potential impact on the horse's health, furosemide administration is permitted up to 4‐h prior to post time in most North American racing jurisdictions. Anecdotal reports suggest that administration of furosemide 24‐h prior to strenuous exercise may be equally effective in decreasing the severity ofEIPH.

Objectives

To 1) compare the efficacy of furosemide in reducing the presence and severity ofEIPHwhen administered 4‐ or 24‐h prior to strenuous exercise 2) characterise electrolyte and blood parameters following administration of furosemide at 4‐ and 24‐h prior to exercise.

Study design

3‐way crossover.

Methods

Fifteen Thoroughbred racehorses received 5 mL of 0.9% NaCl or 250 mg of furosemide either 4‐ or 24‐h prior to a 5‐furlong simulated race. Blood samples were collected prior to and post‐run for determination of furosemide, lactate, haemoglobin and electrolyte concentrations. One‐hour post‐race, an endoscopic exam and bronchoalveolar lavage (BAL) were performed. Horses were assigned anEIPHscore based on predetermined criteria and the number of red blood cells inBALfluid was determined.

Results

EndoscopicEIPHscores were lower in the 4‐h vs. the 24‐h (P = 0.03) furosemide groups.RBCcounts inBALfluid were lower in the 4‐h furosemide vs. saline treatment groups (P = 0.01) but no difference was noted between the saline and 24‐h furosemide groups (P = 0.3), nor between the 4‐ and 24‐h groups (P = 0.5).

Main limitations

Small sample size and large range of running times for the 5‐furlong work.

Conclusions

While none of the treatments preventedEIPH, endoscopic scores andRBCcounts inBALfluid support the efficacy of furosemide in reducing the severity ofEIPH. Endoscopic scores were lower in the 4‐h furosemide group compared with 24‐h administration. Red blood cell counts were lower in the 4‐h furosemide group compared with saline treatment.