bluuebunny/crossref_metadata_2025 huggingface dataset:
Distribution-based measures of tumor heterogeneity are sensitive to mutation calling and lack strong clinical predictive power
Authors: Noorbakhsh Javad , Kim Hyunsoo , Namburi Sandeep , Chuang Jeffrey
Published: January 2018

Mutant allele frequency distributions in cancer samples have been used to estimate intratumoral heterogeneity and its implications for patient survival. However, mutation calls are sensitive to the calling algorithm. It remains unknown whether the relationship of heterogeneity and clinical outcome is robust to these variations. To resolve this question, we studied the robustness of allele frequency distributions to the mutation callers MuTect, SomaticSniper, and VarScan in 4722 cancer samples from The Cancer Genome Atlas. We observed discrepancies among the results, particularly a pronounced difference between allele frequency distributions called by VarScan and SomaticSniper. Survival analysis showed little robust predictive power for heterogeneity as measured by Mutant-Allele Tumor Heterogeneity (MATH) score, with the exception of uterine corpus endometrial carcinoma. However, we found that variations in mutant allele frequencies were mediated by variations in copy number. Our results indicate that the clinical predictions associated with MATH score are primarily caused by copy number aberrations that alter mutant allele frequencies. Finally, we present a mathematical model of linear tumor evolution demonstrating why MATH score is insufficient for distinguishing different scenarios of tumor growth. Our findings elucidate the importance of allele frequency distributions as a measure for tumor heterogeneity and their prognostic role.
Efficient computation of co-transcriptional RNA-ligand interaction dynamics
Authors: Wolfinger Michael T. , Flamm Christoph , Hofaeker Ivo L.
Published: January 2018

Riboswitches form an abundant class of cis-regulatory RNA elements that mediate gene expression by binding a small metabolite. For synthetic biology applications, they are becoming cheap and accessible systems for selectively triggering transcription or translation of downstream genes. Many riboswitches are kinetically controlled, hence knowledge of their co-transcriptional mechanisms is essential. We present here an efficient implementation for analyzing co-transcriptional RNA-ligand interaction dynamics. This approach allows for the first time to model concentration-dependent metabolite binding/unbinding kinetics. We exemplify this novel approach by means of the recently studied I-A 2’-deoxyguanosine (2’dG)-sensing riboswitch from Mesoplasma florum.
A genomic region containingREC8andRNF212Bis associated with individual recombination rate variation in a wild population of red deer (Cervus elaphus)
Authors: Johnston Susan E. , Huisman Jisca , Pemberton Josephine M.
Published: January 2018

Recombination is a fundamental feature of sexual reproduction, ensuring proper disjunction, preventing mutation accumulation and generating new allelic combinations upon which selection can act. However it is also mutagenic, and breaks up favourable allelic combinations previously built up by selection. Identifying the genetic drivers of recombination rate variation is a key step in understanding the causes and consequences of this variation, how lociassociated with recombination are evolving and how they affect the potential of a population to respond to selection. However, to date, few studies have examined the genetic architecture of recombination rate variation in natural populations. Here, we use pedigree data from ‐2,600 individuals genotyped at ‐38,000 SNPs to investigate the genetic architecture of individual autosomal recombination rate in a wild population of red deer (Cervus elaphus). Female red deer exhibited a higher mean and phenotypic variance in autosomal crossover counts (ACC). Animal models fitting genomic relatedness matrices showed that ACC was heritable in females (h2= 0.12) but not in males. A regional heritability mapping approach showed that almost all heritable variation in female ACC was explained by a genomic region on deer linkage group 12 containing the candidate lociREC8andRNF212B, with an additional region on linkage group 32 containingTOP2Bapproaching genome-wide significance. TheREC8/RNF212Bregion and its paralogueRNF212have been associated with recombination in cattle, mice, humans and sheep. Our findings suggest that mammalian recombination rates have a relatively conserved genetic architecture in both domesticated and wild systems, and provide a foundation for understanding the association between recombination lociand individual fitness within this population.
Estradiol treatment in a nonhuman primate model of menopause preserves affective reactivity
Authors: Bliss-Moreau Eliza , Baxter Mark G.
Published: January 2018

As humans age, their affective lives tend to become more positive and less negative. This phenomenon, known as the positivity effect (or positivity bias), occurs even as aging leads to declines in health and cognitive outcomes. Despite these well documented effects in humans, extent to which affective processes change in nonhuman animals, and in particular nonhuman primates – is unclear. As a first step towards developing a model for human affective aging in rhesus monkeys (Macaca mulatta), we tested aged, surgically menopausal aged and middle-aged gonadally intact female rhesus monkeys on a classic index of affective reactivity in monkeys, the Human Intruder task. The Human Intruder task evaluates behavioral responses to varying levels of threat. Aged, surgically menopausal monkeys received hormone replacement therapy consisting of a cyclic estradiol regimen, or vehicle injections as a control. Average responsivity to threat did not vary by condition, but middle aged monkeys and aged monkeys on estradiol were more reactive to the most potent level of threat than to a moderate level of threat, replicating previously published results in other age groups and male monkeys. In contrast, aged monkeys not on estradiol did not show such calibration to threat level. These findings suggest that estrogen may be important for maintaining more youthful affective responding. They also illustrate the utility of behavioral assays of affective reactivity in nonhuman primate models of cognitive and reproductive aging in humans.
Zebrabase: An intuitive tracking solution for aquatic model organisms
Authors: Oltova Jana , Jindrich Jindrich , Skuta Ctibor , Svoboda Ondrej , Machonova Olga , Bartunek Petr
Published: January 2018

Small fish species, like zebrafish or medaka, are constantly gaining popularity in basic research and disease modeling as a useful alternative to rodent model organisms. However, the tracking options for fish within a facility are rather limited. Here, we present an aquatic species tracking database, Zebrabase, developed in our zebrafish research and breeding facility that represents a practical and scalable solution and an intuitive platform for scientists, fish managers and caretakers, in both small and large facilities. Zebrabase is a scalable, crossplatform fish tracking database developed especially for research fish facilities but can be easily adapted for a wide variety of aquatic model organisms housed in tanks. It provides sophisticated tracking, reporting, and management functions that help keep the animalrelated records well-organized including a QR code functionality for tank labeling. The implementation of various user roles ensures a functional hierarchy and customized access to specific functions and data. In addition, Zebrabase enables easy personalization of rooms and racks, and its advanced statistics and reporting options make it an excellent tool for creating periodic reports of animal usage and productivity. The communication between the facility and researchers can be streamlined by the requesting capabilities of the database. Finally, Zebrabase also features an interactive breeding history and a smart interface with advanced visualizations and intuitive color coding allowing to speed up the processes.
A high-throughput in vitro translation screen towards discovery of novel antimalarial protein translation inhibitors
Authors: Baumann Hella , Matthews Holly , Li Mengqiao , Hu Jenny J. , Willison Keith R. , Baum Jake
Published: January 2018

Drugs that target protein synthesis are well-validated for use as antimicrobials, yet specific high throughput (HTP) methods to screen for those targeting malaria are lacking. Here, we have developed a cell free in vitro translation (IVT) assay for the human malaria parasite, Plasmodium falciparum, which reconstitutes the native parasite protein translation machinery. Combining clarified IVT lysate with a click beetle luciferase reporter gene fused to untranslated regions of Pf histidine-rich proteins (hrp)-2 and 3, the HTP IVT assay accurately reports protein translation in a 384-well plate format using a standard spectrofluorometer. We validate the assay as effective in detecting compounds targeting the ribosome, ribosome co-factors (elongation factor 2) and cytosolic tRNA synthetases as well as its ability to find translation inhibitors in a blind screen using a high-density assay format amenable for high throughput. This demonstrates an ability to reconstitute the breadth of the parasite eukaryotic protein translation machinery in vitro and use it as a powerful platform for antimalarial drug discovery.
Identifying differentially methylated sites in samples with varying tumor purity
Authors: Häkkinen Antti , Alkodsi Amjad , Facciotto Chiara , Zhang Kaiyang , Kaipio Katja , Leppä Sirpa , Carpén Olli , Grénman Seija , Hynninen Johanna , Hietanen Sakari , Lehtonen Rainer , Hautaniemi Sampsa
Published: January 2018

DNA methylation aberrations are common in many cancer types. A major challenge hindering comparison of patient-derived samples is that they comprise of heterogeneous collection of cancer and microenvironment cells. We present a computational method that allows comparing cancer methylomes in two or more heterogeneous tumor samples featuring differing, unknown fraction of cancer cells. The method is unique in that it allows comparison also in the absence of normal cell control samples and without prior tumor purity estimates, as these are often unavailable or unreliable in clinical samples. We use simulations and next-generation methylome, RNA, and whole-genome sequencing data from two cancer types to demonstrate that the method is accurate and outperforms alternatives. The results show that our method adapts well to various cancer types and to a wide range of tumor content, and works robustly without a control or with controls derived from various sources. The method is freely available athttps://bitbucket.org/anthakki/dmml.
Comparative transcriptomics reveals a conserved Bacterial Adaptive Phage Response (BAPR) to viral predation
Authors: Blasdel Bob G. , Ceyssens Pieter-Jan , Chevallereau Anne , Debarbieux Laurent , Lavigne Rob
Published: January 2018

Intrinsic and acquired defenses against bacteriophages, including Restriction/Modification, CRISPR/Cas, and Toxin/Anti-toxin systems have been intensely studied, with profound scientific impacts. However, adaptive defenses against phage infection analogous to adaptive resistance to antimicrobials have yet to be described. To identify such mechanisms, we applied an RNAseq-based, comparative transcriptomics approach in differentPseudomonas aeruginosastrains after independent infection by a set of divergent virulent bacteriophages. A common host-mediated adaptive stress response to phages was identified that includes the Pseudomonas Quinolone Signal, through which infected cells inform their neighbors of infection, and what may be a resistance mechanism that functions by reducing infection vigor. With host transcriptional machinery left intact, we also observe phage-mediated differential expression caused by phage-specific stresses and molecular mechanisms. These responses suggest the presence of a conserved Bacterial Adaptive Phage Response mechanism as a novel type of host defense mechanism, and which may explain transient forms of phage persistence.
ExomeSlicer: a resource for the development and validation of exome-based clinical panels
Authors: Niazi Rojeen , Gonzalez Michael A. , Balciuniene Jorune , Evans Perry , Sarmady Mahdi , Abou Tayoun Ahmad N.
Published: January 2018

Exome-based panels (exome slices) are becoming the preferred diagnostic strategy in clinical laboratories, especially for genetically heterogeneous disorders. The advantages of this approach include enabling frequent updates to gene content without the need for re-designing, reflexing to exome analysis bioinformatically without requiring additional sequencing, and streamlining laboratory operation by using established exome kits and protocols. Despite their increasing use, there are currently no guidelines or appropriate resources to support their clinical implementation. Here, we highlight principles and important considerations for the clinical development and validation of exome-based panels, guided by clinical data from a diagnostic epilepsy panel using this approach. We also present a novel, publically accessible web-based resource, ExomeSlicer, and demonstrate its clinical utility in predicting gene-specific and exome-wide technically challenging regions that are not amenable to Next Generation Sequencing (NGS), and that might significantly lead to increased post hoc Sanger fill in burden. Using this tool, we also characterize > 2000 low complexity, GC-rich and/or high homology, regions across the exome that can be a source of false positive or false negative variant calls thus potentially leading to misdiagnoses in tested patients.
Phosphorylation of GMFγ by c-Abl coordinates lamellipodial and focal adhesion dynamics
Authors: Gerlach Brennan D. , Liao Guoning , Tubbesing Kate , Rezey Alyssa C. , Wang Ruping , Barroso Margarida , Tang Dale D.
Published: January 2018

During cell migration a critical interdependence between protrusion and focal adhesion dynamics is established and tightly regulated through signaling cascades. Here we demonstrate that c-Abl, a non-receptor tyrosine kinase, can control these migratory structures through the regulation of two actin-associated proteins, glia maturation factor-γ (GMFγ) and Neural Wiskott-Aldrich syndrome protein (N-WASP). Phosphorylation of GMFγ at tyrosine-104 by c-Abl directs activated N-WASP (pY256) to the leading edge, where it can promote protrusion extension. Non-phosphorylated GMFγ guides N-WASP (pY256) to maturing focal adhesions to enhance further growth. Antagonizing this signaling pathway through knockdown or mutation of tyrosine-104 to its non-phosphorylated form attenuates migration, whereas the phospho-mimic mutant GMFγ enhances migration, thus demonstrating c-Abl, GMFγ, and activated N-WASP (pY256) as a critical signaling cascade for regulating migration in a primary human cell line.
ORBIT: a new paradigm for genetic engineering of mycobacterial chromosomes
Authors: Murphy Kenan C. , Nelson Samantha J. , Nambi Subhalaxmi , Papavinasasundaram Kadamba , Baer Christina E. , Sassetti Christopher M.
Published: January 2018

Current methods for genome engineering in mycobacteria rely on relatively inefficient recombination systems that require the laborious construction of a long double-stranded DNA substrate for each desired modification. We combined two efficient recombination systems to produce a versatile method for high-throughput chromosomal engineering that obviates the need for the preparation of double-stranded DNA recombination substrates. A synthetic “targeting oligonucleotide” is incorporated into the chromosome via homologous recombination mediated by the phage Che9c RecT annelase. This oligo contains a site-specific recombination site for the directional Bxb1 integrase (Int), which allows the simultaneous integration of a “payload plasmid” that contains a cognate recombination site and selectable marker. The targeting oligo and payload plasmid are co-transformed into a RecT‐ and Int-expressing strain, and drug-resistant homologous recombinants are selected in a single step. A library of reusable target-independent payload plasmids is available to generate knockouts and promoter replacements, or to fuse the C-terminal-encoding regions of target genes with tags of various functionalities. This new system is called ORBIT (Oligo-mediated Recombineering followed by Bxb1 Integrase Targeting) and is ideally suited for the creation of libraries consisting of large numbers of deletions, insertions or fusions in a target bacterium. We demonstrate the utility of ORBIT by the construction of insertions or deletions in over 100 genes inM. tuberculosisandM. smegmatis. The report describes the first genetic engineering technique for making selectable chromosomal fusions and deletions that does not require the construction of target‐ or modification-specific double-stranded DNA recombination substrates.
Buffering relationship conflict consequences in teams working in real organizations
Authors: Benitez Miriam , Medina Francisco J. , Munduate Lourdes
Published: January 2018

Purpose

Relationship conflict has important negative organizational and personal consequences. However, papers analyzing how to buffer the negative effects of relationship conflict at work-unit level are lacking. This study aims to extend the literature by examining which specific conflict management styles used by work teams (avoiding, integrating and compromising) reduce or increase the link between relationship conflict and collective emotional exhaustion.

Design/methodology/approach

Regression analysis was conducted using 91 teams (398 employees) from 42 hotels and 42 restaurants.

Findings

Results revealed that, as it was expected, relationship conflict was positively related to emotional exhaustion at a team level; this relationship depended on how team members handle relationship conflicts. That is, avoiding and integrating conflict management styles buffered the link between relationship conflict and collective emotional exhaustion, whereas compromising increased this positive link.

Research limitations/implications

Organizations would include conflict management skills as a requirement for preventing negative consequences of conflict in teams, such as anxiety/depression and bullying.

Originality/value

By considering the unique perspective of team member’s shared perceptions of conflict management styles, important implications for the span of influence of collective perception of conflict on well-being have been indicated.
Transnational higher education
Authors: Heffernan Troy , Wilkins Stephen , Butt Muhammad Mohsin
Published: January 2018

Purpose

The purpose of this paper is to assess the extent to which the critical relational variables of university reputation, student trust and student-university identification influence student behaviour towards transnational education partnerships.

Design/methodology/approach

Students undertaking British degrees at two transnational partnership locations (Hong Kong,n=203 and Sri Lanka,n=325) completed a quantitative survey questionnaire. A conceptual model was developed and tested using structural equation modelling.

Findings

University reputation and student trust were found to be significant predictors of student identification with each partner institution, and student-university identification was a significant predictor of student satisfaction, loyalty and extra-role behaviours towards both the local and foreign educational organisations.

Practical implications

The findings suggest that student relationship management strategies should focus on strengthening the higher education institution’s reputation, and increasing the students’ trust and identification with the institution. Moreover, universities should also assess potential partners for these qualities when entering into transnational education partnerships.

Originality/value

Drawing on theories of social and organisational identification, this is the first study to consider student-university identification as the linchpin between the exogenous constructs of reputation and trust, and the endogenous constructs of student satisfaction, loyalty and extra-role behaviours in both the international education and international business literatures.
Entrepreneurial behaviour formation among Farmers
Authors: Yaseen Asif , Somogyi Simon , Bryceson Kim
Published: January 2018

Purpose

The purpose of this paper is to investigate how farmers perceive and exploit business opportunities to foster entrepreneurship in developing country agriculture.

Design/methodology/approach

In total, 174 milk producers completed a face-to-face survey within a posttest- pretest research design. Partial least squares structural equation modelling (PLS-SEM) was used to test the hypotheses.

Findings

Results revealed that intentions, channelled through desirability, feasibility and optimism, become a strong predictor to recognise the opportunity to be entrepreneurial; however, the presence of a munificent environment and participation in apprenticeship and training programmes are the main and direct source of exploiting farming business opportunities.

Research limitations/implications

The major limitation of the study is that cross-sectional data collected only from milk producers in Pakistan, signifying a need to include other agricultural sectors across different developing countries for further contextualising the results.

Originality/value

Research on entrepreneurial behaviour among farmers is scant. This study emphasises how cognitive heuristics guide intentions influencing the process of opportunity formation, and a munificent environment and entrepreneurial skills trainings are necessary for starting dairy farming business with modern practices.
Do seasonality, break and spillover effects explain commodity price volatility
Authors: Maitra Debashish
Published: January 2018

Purpose

The purpose of this paper is to understand the volatility in commodity futures and spot markets. The study starts with a few questions: first, the effect of seasonality on the volatility is studied. Thereafter, the presence of structural breaks in the variance is identified. At last the seasonality, structural shifts and spillover effects are examined together to find out their effects on volatility.

Design/methodology/approach

The methodology heavily employs econometric tools and techniques. The monthly seasonal dummies are incorporated to identify the effects of seasonality on volatility. Then, the presence of break in volatility is tested by cumulative sum of squares (CUSUM test), followed by generalized autoregressive conditional heteroscedastictity and EGARCH models are measured by including seasonal dummies, break dummies and the residuals of other market in the variance equation to determine spillover effects.

Findings

It is found that the effects of seasonality on volatility cannot be ignored as the effects are significant. The presence of asymmetry is detected in all the commodities. The presence of seasonality and structural breaks in the variance equation are statistically able to reduce the volatility but the magnitude is very negligible with an exception in cumin futures markets. Bi-directional volatility spillover between futures and spot markets is observed in all the commodities and the effect of spillover is more from spot markets to the futures markets.

Research limitations/implications

This study is limited to a few agro commodities which are well traded. This study could have been extended to the other thinly traded commodities. This study has also taken only near month futures contracts as it contains more information but the same could have been studied by taking far month contracts also.

Originality/value

The present study attempted to understand the conjugated effects of seasonality, structural breaks and spillover on volatility of commodity markets which is not apparent in the previous studies. This study has also employed methodological rigor to identify the breaks in the variance equation. In addition to this it has also investigated whether Indian commodity futures markets are informationally more efficient than the spot markets.
Multi-stakeholder partnerships in value chain development
Authors: Mutebi Kalibwani Rebecca , Twebaze Jennifer , Kamugisha Rick , Kakuru Medard , Sabiiti Moses , Kugonza Irene , Tenywa Moses , Nyamwaro Sospeter
Published: January 2018

Purpose

The purpose of this paper is to demonstrate that agricultural commodity value chain development using multi-stakeholder partnerships (MSPs) can fast-track improvement in the livelihoods of rural farming households. With the view that such partnerships can raise farmers’ incomes, the study uses the case of the organic pineapple (OP) value chain in Ntungamo, Western Uganda, to understand the governance features that hold the value chain partners together, to analyse the costs and margins to the participating farmers, to identify opportunities for demand-driven upgrading of the farmers’ skills and knowledge, and the role that partnerships play in such upgrading.

Design/methodology/approach

The study uses the qualitative tools of value chain analysis: value chain maps of stakeholders, processes and support services of the OP value chain, and a quantitative tool to analyse costs and margins to the participating farmers. Interviews were conducted with key informants from the OP innovation platform, and survey data collected for the planting season, February–July, 2014, across three farmer categories of certified organic, conventional, and farmers not participating in the innovation platform.

Findings

Careful selection of partnerships to develop the value chain is found to be critical. Partners to involve should be those that enable the upgrading of farmers’ knowledge, skills and technologies to position them for better markets. Partners should also include those that enable the improvement of margins to the farmers and efficiency of the value chain. The strategic MSPs should be bound by formal contracts, to ensure stable relationships in the value chain and hence sustainable market access for the farmers.

Research limitations/implications

Although carried out on a specific value chain in a specific local context, this is not likely to limit the applicability of the findings to commodity value chains in a range of local contexts.

Originality/value

The study fulfils the need to highlight the role that stakeholder partnerships can play in value chain development and how they can be sustained by governance and institutional arrangements.
Acting and performing: influences of manager emotional intelligence
Authors: Prati L. Melita , Karriker Joy H.
Published: January 2018

Purpose

The purpose of this paper is to examine the predictive role of manager emotional intelligence (MEI) with regard to emotional labor efforts and outcomes relationships. Testing evaluated the influence of MEI on the effects of emotional labor activities employed by subordinates (e.g. surface and active deep acting).

Design/methodology/approach

Relationships were examined between the emotional labor efforts employed by subordinates and their levels of depressed mood, as well as the supervisory leaders’ evaluations of the subordinates’ emotional performance resulting indirectly and directly from the emotional labor activities. Specifically, hypotheses that MEI will influence the performance of emotional labor and the effects of such activities on depressed mood and emotional performance were tested.

Findings

Findings indicate that MEI moderates the impact of depressed mood on emotional performance.

Originality/value

This research adds to the emotional intelligence literature and enhances practical understanding of how organizations dependent on relationship-oriented, successful customer care can sponsor employee actions that facilitate results.
The effect of employee ability, hospital’s ethic and leadership on job satisfaction through employee commitment
Authors: Mardiana Yusuf Ria
Published: January 2018

Purpose

The purpose of this paper is to confirm the direct and indirect effect of employee ability, perceived ethic, and leadership and leadership to service quality through employee commitment.

Design/methodology/approach

A survey instrument is using to collect the data and to measure the effect of employee ability, perceived ethic, and leadership directly to the quality of inpatient health care services was developed. This study also used the self-perception, leadership evaluation and customer evaluation questionnaires. The effects among variables were also analysed by using the structural equation modelling method.

Findings

The results of the analysis show that the survey instrument was reliable and valid; the implementation of hospital ethic was more emphasised on the nurses (as a front liners); the study proved that there is a direct and indirect effect among variables of employee ability, hospital’s ethic, and leadership to the service quality through the employee commitment; the direct effect of employee commitment variables against the service quality was significantly negative.

Research limitations/implications

Analyses are developed within the context of a government single hospital of Type A. According to the time sequence of study, this field of study research considered for purpose only (one time study), and was not conducted for experimental study.

Originality/value

This paper’s main contribution is to propose and empirically test a set of constructs that complement the effect of employee ability, hospital’s perceived ethic, leadership on the service quality of inpatient health care through the employee commitment direct and indirectly in the Type A hospital.
A case report and literature review of autism and attention deficit hyperactivity disorder in paediatric chronic pain
Authors: Wiwe Lipsker Camilla , von Heijne Margareta , Bölte Sven , Wicksell Rikard K.
Published: January 2018

Psychiatric disorders are common in paediatric patients with chronic pain, but the overall prevalence of comorbid neurodevelopmental disorders is unclear. We report on a case of severe chronic pain in a child with undiagnosed comorbid autism spectrum disorder and attention deficit hyperactivity disorder, where significant improvements in pain and function occurred following methylphenidate medication and parental behavioural training.

Conclusion

The inclusion of behavioural assessment and screening for neurodevelopmental comorbidity may be essential in addressing complex paediatric chronic pain.
Autonomous Purkinje cell axonal dystrophy causes ataxia in peroxisomal multifunctional protein‐2 deficiency
Authors: De Munter Stephanie , Bamps Dorien , Malheiro Ana Rita , Kumar Baboota Ritesh , Brites Pedro , Baes Myriam
Published: January 2018

Peroxisomes play a crucial role in normal neurodevelopment and in the maintenance of the adult brain. This depends largely on intact peroxisomal β‐oxidation given the similarities in pathologies between peroxisome biogenesis disorders and deficiency of multifunctional protein‐2 (MFP2), the central enzyme of this pathway. Recently, adult patients diagnosed with cerebellar ataxia were shown to have mild mutations in the MFP2 gene, hydroxy‐steroid dehydrogenase (17 beta) type 4 (HSD17B4). Cerebellar atrophy also develops in MFP2 deficient mice but the cellular origin of the degeneration is unexplored. In order to investigate whether peroxisomal β‐oxidation is essential within Purkinje cells, the sole output neurons of the cerebellum, we generated and characterized a mouse model with Purkinje cell selective deletion of the MFP2 gene. We show that selective loss of MFP2 from mature cerebellar Purkinje neurons causes a late‐onset motor phenotype and progressive Purkinje cell degeneration, thereby mimicking ataxia and cerebellar deterioration in patients with mild HSD17B4 mutations. We demonstrate that swellings on Purkinje cell axons coincide with ataxic behavior and precede neurodegeneration. Loss of Purkinje cells occurs in a characteristic banded pattern, proceeds in an anterior to posterior fashion and is accompanied by progressive astro‐ and microgliosis. These data prove that the peroxisomal β‐oxidation pathway is required within Purkinje neurons to maintain their axonal integrity, independent of glial dysfunction.
Deferoxamine promotes mesenchymal stem cell homing in noise‐induced injured cochlea through PI3K/AKT pathway
Authors: Peyvandi A.A. , Abbaszadeh H.‐A. , Roozbahany N. Ahmady , Pourbakht A. , Khoshsirat S. , Niri H. Haddadzade , Peyvandi H. , Niknazar S.
Published: January 2018

Objective

Over 5% of the world's population suffers from disabling hearing loss. Stem cell homing in target tissue is an important aspect of cell‐based therapy, which its augmentation increases cell therapy efficiency. Deferoxamine (DFO) can induce the Akt activation, and phosphorylation status of AKT (p‐AKT) upregulates CXC chemokine receptor‐4 (CXCR4) expression. We examined whether DFO can enhance mesenchymal stem cells (MSCs) homing in noise‐induced damaged cochlea by PI3K/AKT dependent mechanism.

Materials and Methods

Mesenchymal stem cells were treated with DFO. AKT, p‐AKT protein and hypoxia inducible factor 1‐ α (HIF‐1α) and CXCR4 gene and protein expression was evaluated by RT‐ PCR and Western blot analysis. For in vivo assay, rats were assigned to control, sham, noise exposure groups without any treatment or receiving normal, DFO‐treated and DFO +LY294002 (The PI3K inhibitor)‐treated MSCs. Following chronic exposure to 115 dB white noise, MSCs were injected into the rat cochlea through the round window. Number of Hoechst‐ labelled cells was determined in the endolymph after 24 hours.

Results

Deferoxamine increased P‐AKT, HIF‐1α and CXCR4 expression in MSCs compared to non‐treated cells. DFO pre‐conditioning significantly increased the homing ability of MSCs into injured ear compared to normal MSCs. These effects of DFO were blocked by LY294002.

Conclusions

Pre‐conditioning of MSCs by DFO before transplantation can improve stem cell homing in the damaged cochlea through PI3K/AKT pathway activation.
Stiffness regulates the proliferation and osteogenic/odontogenic differentiation of human dental pulp stem cells via the WNT signalling pathway
Authors: Liu Nanxin , Zhou Mi , Zhang Qi , Zhang Tao , Tian Taoran , Ma Quanquan , Xue Changyue , Lin Shiyu , Cai Xiaoxiao
Published: January 2018

Objectives

Researches showed that stiffness of the extracellular matrix can affect the differentiation of many stem cells. Dental pulp stem cells (DPSCs) are a promising type of adult stem cell. However, we know little about whether and how the behaviour of DPSCs is influenced by stiffness.

Materials and methods

We carried out a study that cultured DPSCs on tunable elasticity polydimethylsiloxane substrates to investigate the influence on morphology, proliferation, osteogenic/odontogenic differentiation and its possible mechanism.

Results

Soft substrates changed the cell morphology and inhibited the proliferation of DPSCs. Expression of markers related to osteogenic/odontogenic differentiation was significantly increased as the substrate stiffness increased, including ALP (alkaline phosphatase), OCN (osteocalcin), OPN (osteopontin), RUNX‐2 (runt‐related transcription factor‐2), BMP‐2 (bone morphogenetic protein‐2), DSPP (dentin sialophosphoprotein) and DMP‐1 (dentin matrix protein‐1). Mechanical properties promote the function of DPSCs related to the Wnt signalling pathway.

Conclusions

Our results showed that mechanical factors can regulate the proliferation and differentiation of DPSCs via the WNT signalling pathway. This provides theoretical basis to optimize dental or bone tissue regeneration through increasing stiffness of extracelluar matrix.
The prescribable drugs with efficacy in experimental epilepsies (PDE3) database for drug repurposing research in epilepsy
Authors: Sivapalarajah Shayeeshan , Krishnakumar Mathangi , Bickerstaffe Harry , Chan YikYing , Clarkson Joseph , Hampden‐Martin Alistair , Mirza Ahmad , Tanti Matthew , Marson Anthony , Pirmohamed Munir , Mirza Nasir
Published: January 2018

Objective

Current antiepileptic drugs (AEDs) have several shortcomings. For example, they fail to control seizures in 30% of patients. Hence, there is a need to identify new AEDs. Drug repurposing is the discovery of new indications for approved drugs. This drug “recycling” offers the potential of significant savings in the time and cost of drug development. Many drugs licensed for other indications exhibit antiepileptic efficacy in animal models. Our aim was to create a database of “prescribable” drugs, approved for other conditions, with published evidence of efficacy in animal models of epilepsy, and to collate data that would assist in choosing the most promising candidates for drug repurposing.

Methods

The database was created by the following: (1) computational literature‐mining using novel software that identifies Medline abstracts containing the name of a prescribable drug, a rodent model of epilepsy, and a phrase indicating seizure reduction; then (2) crowdsourced manual curation of the identified abstracts.

Results

The final database includes 173 drugs and 500 abstracts. It is made freely available at www.liverpool.ac.uk/D3RE/PDE3. The database is reliable: 94% of the included drugs have corroborative evidence of efficacy in animal models (for example, evidence from multiple independent studies). The database includes many drugs that are appealing candidates for repurposing, as they are widely accepted by prescribers and patients—the database includes half of the 20 most commonly prescribed drugs in England—and they target many proteins involved in epilepsy but not targeted by current AEDs. It is important to note that the drugs are of potential relevance to human epilepsy—the database is highly enriched with drugs that target proteins of known causal human epilepsy genes (Fisher's exact test P‐value < 3 × 10−5). We present data to help prioritize the most promising candidates for repurposing from the database.

Significance

The PDE3 database is an important new resource for drug repurposing research in epilepsy.
Activation of the Hog1 MAPK by the Ssk2/Ssk22 MAP3Ks, in the absence of the osmosensors, is not sufficient to trigger osmostress adaptation in Saccharomyces cerevisiae
Authors: Vázquez‐Ibarra Araceli , Subirana Laia , Ongay‐Larios Laura , Kawasaki Laura , Rojas‐Ortega Eréndira , Rodríguez‐González Miriam , de Nadal Eulàlia , Posas Francesc , Coria Roberto
Published: January 2018

Yeast cells respond to hyperosmotic stress by activating the high‐osmolarity glycerol (HOG) pathway, which consists of two branches, Hkr1/Msb2‐Sho1 and Sln1, which trigger phosphorylation and nuclear internalization of the Hog1 mitogen‐activated protein kinase. In the nucleus, Hog1 regulates gene transcription and cell cycle progression, which allows the cell to respond and adapt to hyperosmotic conditions. This study demonstrates that the uncoupling of the known sensors of both branches of the pathway at the level of Ssk1 and Ste11 impairs cell growth in hyperosmotic medium. However, under these conditions, Hog1 was still phosphorylated and internalized into the nucleus, suggesting the existence of an alternative Hog1 activation mechanism. In the ssk1ste11 mutant, phosphorylated Hog1 failed to associate with chromatin and to activate transcription of canonical hyperosmolarity‐responsive genes. Accordingly, Hog1 also failed to induce glycerol production at the levels of a wild‐type strain. Inactivation of the Ptp2 phosphatase moderately rescued growth impairment of the ssk1ste11 mutant under hyperosmotic conditions, indicating that downregulation of the HOG pathway only partially explains the phenotypes displayed by the ssk1ste11 mutant. Cell cycle defects were also observed in response to stress when Hog1 was phosphorylated in the ssk1ste11 mutant. Taken together, these observations indicate that Hog1 phosphorylation by noncanonical upstream mechanisms is not sufficient to trigger a protective response to hyperosmotic stress.
Post‐translational incorporation of 3,4‐dihydroxyphenylalanine into the C terminus of α‐tubulin in living cells
Authors: Dentesano Yanela M. , Ditamo Yanina , Hansen Cristian , Arce Carlos A. , Bisig Carlos Gaston
Published: January 2018

The C‐terminal tyrosine (Tyr) of the α‐tubulin chain is subjected to post‐translational removal and readdition in a process termed the “detyrosination/tyrosination cycle”. We showed in previous studies using soluble rat brain extracts that l‐3,4‐dihydroxyphenylalanine (l‐Dopa) is incorporated into the same site as Tyr. We now demonstrate that l‐Dopa incorporation into tubulin also occurs in living cells. We detected such incorporation by determining the “tyrosination state” of tubulin before and after incubation of cells in the presence of l‐Dopa. The presence of a tubulin isospecies following l‐Dopa incubation that was not recognized by antibodies specific to Tyr‐ and deTyr‐tubulin was presumed to reflect formation of Dopa‐tubulin. l‐Dopa was identified by HPLC as the C‐terminal compound bound to α‐tubulin. l‐Dopa incorporation into tubulin was observed in Neuro 2A cells and several other cell lines, and was not due to de novo protein biosynthesis. Dopa‐tubulin had microtubule‐forming capability similar to that of Tyr‐ and deTyr‐tubulin. l‐Dopa incorporation into tubulin did not notably alter cell viability, morphology, or proliferation rate. CAD cells (a neuron‐like cell line derived from mouse brain) are easily cultured under differentiating and nondifferentiating conditions, and can be treated with l‐Dopa. Treatment of CAD cells with l‐Dopa and consequent increase in l‐Dopa‐tubulin resulted in reduction of microtubule dynamics in neurite‐like processes.
P2Y12 deficiency in mouse impairs noradrenergic system in brain, and alters anxiety‐like neurobehavior and memory
Authors: Zheng F. , Zhou Q. , Cao Y. , Shi H. , Wu H. , Zhang B. , Huang F. , Wu X.
Published: January 2018

Purinergic receptor P2Y12 (P2Y12), a G protein‐coupled purinergic receptor, is widely distributed in nervous system and involved in the progression of neurological diseases such as multiple sclerosis and neuropathic pain. The central noradrenergic system actively participates in a number of neurophysiological processes. Nevertheless, whether there is any direct relevance between P2Y12 and noradrenergic signal transduction remains unknown. In the present study, we tested the hypothesis that lack of P2Y12 impaired noradrenergic signal transduction in mouse brain. Our results showed that P2Y12 knockout (KO) mice exhibited increased anxiety‐like behavior in the open‐field test (OFT) and elevated plus maze test and displayed deficits in memory in the radial‐arm maze test (RAMT) and Morris water maze test (MWMT). They also exhibited reduced locomotion in the OFT and MWMT. Moreover, loss of P2Y12 decreased the level of noradrenaline and the expression of noradrenergic α receptors, subtypes α2 (ARα2b) in mouse cerebellum and hippocampus. Meanwhile, it hampered the protein kinase A (PKA)/cAMP response element‐binding protein (CREB)/brain‐derived neurotrophic factor (BDNF) signaling pathway in these brain regions. Taken together, our results showed for the first time that P2Y12 KO altered the anxiety, memory and locomotion of mice, which was closely associated with abnormal state of noradrenergic system in the brain. The findings implicate that P2Y12 plays an indispensable role in noradrenergic signal transduction; its deficit is insufficient to limit anxiety responses or supports cognitive performance and activity.
Transgenic mice specifically expressing amphiregulin in white adipose tissue showed less adipose tissue mass
Authors: Yang Bo , Kumoto Takahiro , Arima Takeshi , Nakamura Minako , Sanada Yohei , Kumrungsee Thanutchaporn , Sotomaru Yusuke , Shimada Masayuki , Yanaka Noriyuki
Published: January 2018

To determine adipocytokines that play a regulatory role during obesity development, we explored the genes that encode growth factors and investigated the physiological functions for adipose tissue development. Here, we isolated amphiregulin (Areg) gene whose expression was significantly up‐regulated in obese adipose tissues. Areg mRNA level was positively correlated with macrophage marker gene expression in adipose tissues in vivo. Unexpectedly, Areg transgenic mice showed less adipose tissue mass with increased mRNA expression levels of Tnf‐α and peroxisome proliferator‐activated receptor γ coactivator 1α (Pgc‐1α) and delayed white adipose tissue development during the convalescent stage in a dextran sodium sulfate‐induced colitis model. This study showed that Areg mRNA expression was significantly up‐regulated in obese adipose tissues and over‐expression of Areg in white adipose tissue caused less adipose tissue mass.
Do characteristics of pollinator‐friendly gardens predict the diversity, abundance, and reproduction of butterflies?
Authors: Majewska Ania A. , Sims Stuart , Wenger Seth J. , Davis Andrew K. , Altizer Sonia
Published: January 2018

Pollinator declines have motivated efforts to plant nectar and host plants for butterflies and other pollinators, but whether gardens promote pollinator conservation requires further investigation.

We established garden plots to determine whether plant type (native vs. exotic) and weed maintenance (low or high) influence adult butterfly abundance and species richness, and the abundance and survival of immature stages of four species (monarch, queen, black swallowtail, and gulf fritillary). To assess how predator activity and mortality of immature stages might differ inside gardens compared to other suitable habitat patches, we compared caterpillar survival on sentinel host plants placed within and outside of plots.

The abundance and species richness of adult butterflies (all taxa) increased with the number of flowering plants per plot, but did not depend on plant type or weeding treatment. Exotic plots had greater adult monarch and gulf fritillary abundances, greater monarch and queen egg counts, and lower black swallowtail caterpillar counts relative to native plots.

The survival of immature stages (egg to instar 5) ranged from 2 to 13% and was similar across plots, except for gulf fritillary larvae, which had higher survival in exotic plots. Monarch caterpillar mortality risk was higher on sentinel plants placed inside plots, relative to those outside of plots.

This study suggests that garden plots attracted a diversity of adult butterflies and supported the reproduction of focal species. Given lower immature monarch survival within versus outside of plots, further work is needed to examine natural enemy pressure within pollinator gardens.