bluuebunny/crossref_metadata_2025 huggingface dataset:
Microhomology-mediated end joining drives complex rearrangements and over-expression of MYC and PVT1 in multiple myeloma
Authors: Mikulasova Aneta , Ashby Cody , Tytarenko Ruslana G. , Qu Pingping , Rosenthal Adam , Dent Judith A. , Ryan Katie R. , Bauer Michael A. , Wardell Christopher P. , Hoering Antje , Mavrommatis Konstantinos , Trotter Matthew , Deshpande Shayu , Yaccoby Shmuel , Tian Erming , Keats Jonathan , Auclair Daniel , Jackson Graham H. , Davies Faith E. , Thakurta Anjan , Morgan Gareth J. , Walker Brian A.
Published: January 2019

MYC is a widely acting transcription factor and its deregulation is a crucial event in many human cancers. MYC is important biologically and clinically in multiple myeloma, but the mechanisms underlying its dysregulation are poorly understood. We show that MYC rearrangements are present in 36.0% of newly diagnosed myeloma patients, as detected in the largest set of next generation sequencing data to date (n=1267). Rearrangements were complex and associated with increased expression of MYC and PVT1, but not other genes at 8q24. The highest effect on gene expression was detected in cases where the MYC locus is juxtaposed next to super-enhancers associated with genes such as IGH, IGK, IGL, TXNDC5/BMP6, FAM46C and FOXO3. We identified three hotspots of recombination at 8q24, one of which is enriched for IGH-MYC translocations. Breakpoint analysis indicates primary myeloma rearrangements involving the IGH locus occur through non-homologous end joining, whereas secondary MYC rearrangements occur through microhomology-mediated end joining. This mechanism is different to lymphomas, where non-homologous end joining generates MYC rearrangements. Rearrangements resulted in over-expression of key genes and ChIP-seq identified that HK2, a member of the glucose metabolism pathway, is directly over-expressed through binding of MYC at its promoter.
Microglia motility depends on neuronal activity and promotes structural plasticity in the hippocampus
Authors: Nebeling Felix C. , Poll Stefanie , Schmid Lena C. , Mittag Manuel , Steffen Julia , Keppler Kevin , Fuhrmann Martin
Published: January 2019

Microglia, the resident immune cells of the brain, play a complex role in health and disease. They actively survey the brain parenchyma by physically interacting with other cells and structurally shaping the brain. Yet, the mechanisms underlying microglia motility and their significance for synapse stability, especially during adulthood, remain widely unresolved. Here we investigated the impact of neuronal activity on microglia motility and its implication for synapse formation and survival. We used repetitive two-photon in vivo imaging in the hippocampus of awake mice to simultaneously study microglia motility and their interaction with synapses. We found that microglia process motility depended on neuronal activity. Simultaneously, more dendritic spines emerged in awake compared to anesthetized mice. Interestingly, microglia contact rates with individual dendritic spines were associated with their stability. These results suggest that microglia are not only sensing neuronal activity, but participate in synaptic rewiring of the hippocampus during adulthood, which has profound relevance for learning and memory processes.
Copy number aberrations drive kinase re-wiring leading to genetic vulnerabilities in cancer
Authors: Memon Danish , Gill Michael B. , Papachristou Eva , Ochoa David , D’Santos Clive , Miller Martin L. , Beltrao Pedro
Published: January 2019

Somatic DNA copy number variations (CNVs) are prevalent in cancer and can drive cancer progression albeit with often uncharacterized roles in altering cell signaling states. Here, we integrated genomic and proteomic data for 5598 tumor samples to identify CNVs leading to aberrant signal transduction. The resulting associations recapitulated known kinase-substrate relationships and further network analysis prioritized likely driver genes. A total of 44 robust pan-cancer gene-phosphosite associations were replicated in cell line samples. Of these, ARHGEF17, a predicted regulator of hippo-signaling, was further studied through (phospho)proteomics analysis where ARHGEF17 knockdown cells showed dys-regulation of hippo- and p38 signaling as well as immune related pathways. Using, RNAi, CRISPR and drug screening data we find evidence of kinase addiction in cancer cell lines identifying inhibitors for targeting of ‘kinase-dependent’ cell lines. We propose copy number status of genes as useful predictors of differential impact of kinase inhibition, a strategy that may be of use in the future for anticancer therapies.
The population dynamics of a canonical cognitive circuit
Authors: Chaudhuri Rishidev , Gerçek Berk , Pandey Biraj , Peyrache Adrien , Fiete Ila
Published: January 2019

The brain constructs distributed representations of key low-dimensional variables. These variables may be external stimuli or internal constructs of quantities relevant for survival, such as a sense of one’s location in the world. We consider that the high-dimensional population-level activity vectors are the fundamental representational currency of a neural circuit, and these vectors trace out a low-dimensional manifold whose dimension and topology matches those of the represented variable. This manifold perspective — applied to the mammalian head direction circuit across rich waking behaviors and sleep — enables powerful inferences about circuit representation and mechanism, including: Direct visualization and blind discovery that the network represents a one-dimensional circular variable across waking and REM sleep; fully unsupervised decoding of the coded variable; stability and attractor dynamics in the representation; the discovery of new dynamical trajectories during sleep; the limiting role of external rather than internal noise in the fidelity of memory states; and the conclusion that the circuit is set up to integrate velocity inputs according to classical continuous attractor models.
Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult haematopoiesis
Authors: Dobrzycki Tomasz , Mahony Christopher B. , Krecsmarik Monika , Koyunlar Cansu , Rispoli Rossella , Peulen-Zink Joke , Gussinklo Kirsten , Fedlaoui Bakhta , de Pater Emma , Patient Roger , Monteiro Rui
Published: January 2019

Haematopoietic stem and progenitor cells (HSPCs) maintain the vertebrate blood system throughout life and their emergence from haemogenic endothelium (HE) is regulated by transcription factors such as Gata2. Here we deleted a conserved enhancer (i4 enhancer) driving pan-endothelial expression ofgata2aand showed that Gata2a is required for HE programming by regulating expression ofrunx1and of the second zebrafish Gata2 orthologue,gata2b. By 5 days, homozygousgata2aΔi4/Δi4larvae showed normal numbers of HSPCs, a recovery mediated by Notch signalling drivinggata2bandrunx1expression in HE. However,gata2aΔi4/Δi4adults showed oedema, susceptibility to infections and marrow hypo-cellularity, consistent with bone marrow failure found in GATA2 deficiency syndromes. Thus,gata2aexpression driven by the i4 enhancer is required for HE programming in embryos and maintenance of steady-state haematopoietic stem cell output in the adult. These enhancer mutants are a new paradigm to explore the pathophysiology of GATA2-related deficienciesin vivo.
IMCC: Quantitative Analysis of the Inter-module Connectivity for Bio-network
Authors: Wang Pengqian , Liu Jun , Yu Yanan , Zhang Yingying , Li Bing , Li Dongfeng , Xu Wenjuan , Liu Qiong , Wang Zhong
Published: January 2019

Inter-module connectivity, which tend to connect different communities and maintain network architectural integrity, is contributing to functional coordination and information flow between modules in perturbations. Detecting the strength of inter-module connection is essential to characterize the reactive bio-systematical variation. A quantitative evaluation method for inter-module connections is needed. Here, based on the high-throughput microarray data from mouse, an evaluation approach (named as IMCC) for inter-module connectivity was developed. The IMCC model, which is an integration of direct and indirect inter-module connections, successfully excluded inter-module connections without statistical significance or below the cutoff value, and provided a more comprehensive landscape of inter-module relationships. We showed that the IMCC method reflected a more precise functional coordination between modules according to KEGG database, were validated by topological parameter. Application of IMCC in genome-scale stroke networks deciphered characteristic pathological “core-periphery” structure of modular map and functional coordination module pair.

Author summery

Inter-module connectivity, which tend to connect different communities and maintain network architectural integrity, is contributing to functional coordination and information flow between modules in perturbations. Moreover, modular rearrangements provide more efficient ways for phenotype alteration, inter-module connections have been considered to be ‘‘evolutionary interaction switches”. Such modular map rewiring can be used as a network biomarker to characterize the dynamics of drug responses. Detecting the strength of inter-module connection is essential to characterize the reactive bio-systematical variation response to disease or drug. We aim to construct a quantitative evaluation method for inter-module connections. Thus, this study has implications in systematical exploration detailed variation of inter-module pharmacological action mode of drugs.
Drinking earth for wine. Estimation of soil erosion in the Prosecco DOCG area (NE Italy), toward a soil footprint of bottled sparkling wine production
Authors: Pappalardo SE , Gislimberti L , Ferrarese F , Garlato A , Vinci IC , De Marchi M , Mozzi P
Published: January 2019

Prosecco, one of the most widespread sparkling wine in the world, is produced in Northeast Italy by a rate of 400 M bottles per year, with the fastest growing demand in the global market at present. A production of 90 M bottles year−1 is currently running in the historical Prosecco sector (215 km2), defined as the Controlled and Guaranteed Designation of Origin (DOCG) area, in a steep hilly landscape of Veneto Region (Conegliano-Valdobbiadene) registered in 2017 for the UNESCO World Heritage tentative list. To sustain wine production agricultural intensification boosted to re-setting of hillslopes and land use changes toward new vineyard plantations. The aim of this study is to assess soil erosion rate, calculating a sort of “soil footprint” for wine production by i) estimation of the total soil erosion, ii) identification of the most critical areas, iii) simulation of different nature-based mitigation scenarios. RUSLE model was adopted to estimate soil erosion in Mg ha−1 year−1, using high resolution topographic data (LiDAR), 10 years rainfall data analysis, detailed land use and local soil characteristics.

We found that the total soil erosion estimation for the Prosecco DOCG area is 546,263 Mg year−1, with an erosion rate of 25.4 t ha year−1, which is 11 times higher than the Italian average. Prosecco vineyards contributes to 400,000 Mg year−1, by a mean rate of 59.8 Mg ha−1 year−1, and encompass 74% of all the erosion in the whole DOCG area. Soil erosion modelled is mainly concentrated in cultivated hillslopes, highlighting critical areas with more than 40 Mg ha−1 year−1), mainly clustered on steep slopes.

The modelled soil loss of a single bottle of Prosecco is, therefore, about 4.4 kg year−1. In contrast, alternative scenarios of different nature-based mitigation measures (hedgerows, buffer strips, and grass cover) showed that total erosion in the Prosecco DOCG area would be reduced to 275,140 Mg year−1, saving about the 50% of soil. In vineyards a general decrease of almost 3 times (from 400,000 to 135,161 Mg year−1) is also demonstrated, reducing on average the erosion rate from 59.8 to 19.2 Mg ha−1 year−1. This study highlights, thus, that an integrated soil erosion monitor system is needed in the DOCG area as well as the implementation of nature-based mitigation measures as sustainable agricultural layout for modern agroecosystems.
A simple genetic architecture and low constraint allows rapid floral evolution in a diverse and recently radiating plant genus
Authors: Kostyun Jamie L. , Gibson Matthew J.S. , King Christian M. , Moyle Leonie C.
Published: January 2019

Genetic correlations among different components of phenotypes, especially resulting from pleiotropy, can constrain or facilitate trait evolution. These factors could especially influence the evolution of traits that are functionally integrated, such as those comprising the flower. Indeed, pleiotropy is proposed as a main driver of repeated convergent trait transitions, including the evolution of phenotypically-similar pollinator syndromes.

We assessed the role of pleiotropy in the differentiation of floral and other reproductive traits between two species—Jaltomata sinuosaandJ. umbellata(Solanaceae)—that have divergent suites of floral traits consistent with bee- and hummingbird-pollination, respectively. To do so, we generated a hybrid population and examined the genetic architecture (trait segregation and QTL distribution) underlying 25 floral and fertility traits.

We found that most floral traits had a relatively simple genetic basis (few, predominantly additive, QTL of moderate to large effect), as well as little evidence of antagonistic pleiotropy (few trait correlations and QTL co-localization, particularly between traits of different classes). However, we did detect a potential case of adaptive pleiotropy among floral size and nectar traits.

These mechanisms may have facilitated the rapid floral trait evolution observed withinJaltomata, and may be a common component of rapid phenotypic change more broadly.
Binding of an X-specific condensin correlates with a reduction in active histone modifications at gene regulatory elements
Authors: Street Lena Annika , Morao Ana Karina , Winterkorn Lara Heermans , Jiao Chen-Yu , Albritton Sarah Elizabeth , Sadic Mohammed , Kramer Maxwell , Ercan Sevinç
Published: January 2019

Condensins are evolutionarily conserved protein complexes that are required for chromosome segregation during cell division and genome organization during interphase. In C. elegans,, a specialized condensin, which forms the core of the dosage compensation complex (DCC), binds to and represses X chromosome transcription. Here, we analyzed DCC localization and the effect of DCC depletion on histone modifications, transcription factor binding, and gene expression using ChIP-seq and mRNA-seq. Across the X, DCC accumulates at accessible gene regulatory sites in active chromatin and not heterochromatin. DCC is required for reducing the levels of activating histone modifications, including H3K4me3 and H3K27ac, but not repressive modification H3K9me3. In X-to-autosome fusion chromosomes, DCC spreading into the autosomal sequences locally reduces gene expression, thus establishing a direct link between DCC binding and repression. Together, our results indicate that DCC-mediated transcription repression is associated with a reduction in the activity of X chromosomal gene regulatory elements.

Condensins are evolutionarily conserved protein complexes that mediate chromosome condensation during cell division and have been implicated in gene regulation during interphase. Here, we analyzed the gene regulatory role of an X-specific condensin (DCC) in C. elegans, by measuring its effect on histone modifications associated with transcription regulation. We found that in X-to-autosome fusion chromosomes, DCC spreading into autosomal sequences locally reduces gene expression, establishing a direct link between DCC binding and repression. DCC is required for reduced levels of histone modifications associated with transcription activation at X chromosomal promoters and enhancers. These results are consistent with a model whereby DCC binding directly or indirectly results in a reduction in the activity of X chromosomal gene regulatory elements through specific activating histone modifications.
Genomic signatures of somatic hybrid vigor due to heterokaryosis in the oomycete pathogen,Bremia lactucae
Authors: Fletcher Kyle , Gil Juliana , Bertier Lien D , Kenefick Aubrey , Wood Kelsey J , Zhang Lin , Reyes-Chin-Wo Sebastian , Cavanaugh Keri , Tsuchida Cayla , Wong Joan , Michelmore Richard
Published: January 2019

Lettuce downy mildew caused byBremia lactucaeis the most important disease of lettuce globally. This oomycete pathogen is highly variable and has rapidly overcome resistance genes and fungicides deployed in attempts to control it. The described high-quality genome assembly ofB. lactucaeprovides the foundation for detailed understanding of this economically important pathogen. The biotrophic nature ofB. lactucaecoupled with high levels of heterozygosity and the recently expanded repeat content made genome assembly challenging. The combined use of multiple read types, including synthetic long reads, single molecule sequences, and Hi-C, resulted in a high-quality, chromosome-scale, consensus assembly of this diploid organism. Phylogenetic analysis supports polyphyly in the downy mildews consistent with the biotrophic mode of pathogenesis evolving more than once in the Peronosporaceae. Flow cytometry plus resequencing of 30 field isolates as well as sexual offspring and asexual derivatives from multinucleate single sporangia demonstrated a high incidence of heterokaryosis inB. lactucae. Heterokaryons have phenotypic differences and increased fitness compared to homokaryotic derivatives. Consequently,B. lactucaeexhibits somatic hybrid vigor and selection should be considered as acting on a population of nuclei within coenocytic mycelia. This provides evolutionary flexibility to the pathogen enabling rapid adaptation to different repertoires of host resistance genes and other challenges. The advantages of asexual persistence of heterokaryons may have been one of the drivers of selection that resulted in the loss of uninucleate zoospores in multiple downy mildews.
Statistical test with sample size and power calculation for paired repeated measures designs of method comparison studies
Authors: Bai Yun , Wang Zengri , Lystig Theodore C. , Wu Baolin
Published: January 2019

The paired repeated measures (PRM) design has been commonly used in comparison studies to demonstrate that two measures agree sufficiently up to a pre-specified threshold. Due to the nature of dependence in repeated measures, existing methods for analyzing these comparison studies are often ad hoc and less than satisfactory. We propose a new test together with sample size and power calculation for PRM designs, which exhibit very good finite sample performance. We demonstrate favorable performance of the proposed methods through numerical studies. We provide very efficient R programs for our methods in a publicly available R package. Our proposed methods and developed R package provide practical tools which bridge an existing gap in the field.
MroQ is a Novel Abi-domain Protein That Influences Virulence Gene Expression in Staphylococcus aureus via Modulation of Agr Activity
Authors: Marroquin Stephanie , Gimza Brittney , Tomlinson Brooke , Stein Michelle , Frey Andrew , Keogh Rebecca A. , Zapf Rachel , Todd Daniel A. , Cech Nadja B. , Carroll Ronan K. , Shaw Lindsey N.
Published: January 2019

Numerous factors have to date been identified as playing a role in the regulation of Agr activity in S. aureus, including transcription factors, antisense RNAs, and host elements. Herein we investigate the product of SAUSA300_1984 (termed MroQ), a transmembrane Abi-domain/M79 protease-family protein, as a novel effector of this system. Using a USA300 mroQ mutant we observed a drastic reduction in proteolysis, hemolysis and pigmentation that was fully complementable. This appears to result from diminished agr activity, as transcriptional analysis revealed significant decreases in expression of both RNAII and RNAIII in the mroQ mutant. Such effects appear to be direct, rather than indirect, as known agr effectors demonstrated limited alterations in their activity upon mroQ disruption. A comparison of RNA-sequencing datasets for both mroQ and agr mutants reveal a profound overlap in their regulomes, with the majority of factors affected being known virulence determinants. Importantly, the preponderance of alterations in expression were more striking in the agr mutant, indicating that MroQ is necessary, but not sufficient, for Agr function. Mechanism profiling revealed that putative residues for metalloprotease activity within MroQ are required for its Agr controlling effect, however this is not wielded at the level of AgrD processing. Virulence assessment demonstrated that mroQ and agr mutants both exhibited increased formation of renal abscesses, but decreased skin abscess formation, alongside diminished dermonecrosis. Collectively, we present the characterization of a novel agr effector in S. aureus, which would appear to be a direct regulator, potentially functioning via interaction with the AgrC histidine kinase.
From the clinic to the bench and back again in one dog year: identifying new treatments for sarcoma using a cross-species personalized medicine pipeline
Authors: Rao Sneha , Somarelli Jason A. , Altunel Erdem , Selmic Laura E. , Byrum Mark , Sheth Maya U. , Cheng Serene , Ware Kathryn E. , Kim So Young , Prinz Joseph A. , Devos Nicolas , Corcoran David L. , Moseley Arthur , Soderblom Erik , Hsu S. David , Eward William C.
Published: January 2019

Cancer drug discovery is an inefficient process, with more than 90% of newly-discovered therapies failing to gain regulatory approval. Patient-derived models of cancer offer a promising new approach to identifying personalized treatments; however, for rare cancers, such as sarcomas, access to patient samples can be extremely limited, which precludes development of patient-derived models. To address the limited access to patient samples, we have turned to pet dogs with naturally-occurring sarcomas. Although sarcomas make up less than 1% of all cancers in humans, sarcomas represent at least 15% of all cancers in dogs. Dogs with naturally-occurring sarcomas also have intact immune systems, an accelerated pace of cancer progression, and share the same environment as humans, making them ideal models that bridge key gaps between mouse models and human sarcomas.

Here, we develop a framework for a personalized medicine pipeline that integrates drug screening, validation, and genomics to identify new therapies. We tested this paradigm through the study of a pet dog, Teddy, who presented with six synchronous leiomyosarcomas. By integrating patient-derived cancer models, in vitro drug screens, and in vivo validation we identified proteasome inhibitors as a potential therapy for Teddy. After showing an initial response to the proteasome inhibitor, bortezomib, Teddy developed rapid resistance, and tumor growth resumed. Whole exome sequencing revealed substantial genetic heterogeneity across Teddy’s multiple recurrent tumors and metastases, suggesting that intra-patient heterogeneity was responsible for the heterogeneous clinical response. Ubiquitin proteomics coupled with exome sequencing revealed multiple candidate driver mutations in proteins related to the proteasome pathway. Together, our results demonstrate how the comparative study of canine sarcomas can offer rapid insights into the process of developing personalized medicine approaches that can lead to new treatments for sarcomas in both humans and canines.
Attractor competition enriches cortical dynamics during awakening from anesthesia
Authors: Tort-Colet Núria , Capone Cristiano , Sanchez-Vives María V. , Mattia Maurizio
Published: January 2019

Cortical slow oscillations (≲ 1 Hz) are a hallmark of slow-wave sleep and deep anesthesia across animal species. They arise from spatiotemporal patterns of activity with low degree of complexity, eventually increasing as wakefulness is approached and cognitive functions emerge. The arousal process is then an open window on the widely unknown mechanisms underlying the emergence of the dynamical richness of awake cortical networks. Here, we investigated the changes in the network dynamics as anesthesia fades out and wakefulness is approached in layer 5 neuronal assemblies of the rat visual cortex. Far from being a continuum, this transition displays both gradual and abrupt activity changes. Starting from deep anesthesia, slow oscillations increase their frequency eventually expressing maximum regularity. This stage is followed by the abrupt onset of an infra-slow (~ 0.2 Hz) alternation between sleep-like oscillations and activated states. A population rate model reproduces this transition driven by an increased excitability that brings it to periodically cross a critical point. We conclude that dynamical richness emerges as a competition between two metastable attractor states whose existence is here experimentally confirmed.
Competency assessment of the medical interns and nurses and prevailing practices to provide family planning services in teaching hospitals in three states of India
Authors: Gupta Madhu , Verma Madhur , Kaur Kiranjit , Iyengar Kirti , Singh Tarundeep , Singh Anju
Published: January 2019

Objectives

The objectives of the study was to assess the knowledge and skills of medical interns and nurses regarding family planning (FP) services, and document the prevailing FP practices in the teaching hospitals in India.

Study Design

A cross-sectional study was conducted in three states (Delhi, Rajasthan, and Maharashtra) of India, among randomly selected 163 participants, including medical interns (n=81) and in-service nurses (n=82), during 2017. Semi-structured, pre-tested interview schedule, was used to assess the knowledge and status of training received; and objective structured clinical examination (OSCE) based checklist was used to assess the skills.

Results

About 60% of the interns and 48% of the nurses knew more than five contraceptives that could be offered to the clients. About 22% (11.1% interns and 33.3% nurses) respondents believed that contraceptives should not be given to a married woman coming alone, and 31.9% (17.3% interns and 46.3% nurses) respondents reported that it was illegal to provide contraceptives to unmarried people. Nearly 43.3% interns and 69.5% nurses refused to demonstrate intrauterine contraceptive device (IUCD) insertion in the dummy uterus as per OSCE, and among those who did, 12.3% interns and 18.3% nurses had failed. About 63% interns and 63.4% of nurses had observed IUCD insertion, and 12.3% interns and 17.1% had performed IUCD insertion, during their training.

Conclusions

Knowledge and skills of interns and nurses regarding FP services were only partial. The medical training during graduation or internship, and during the job, was found to be inadequate to provide quality FP services.

Implications

The partial knowledge and skills of medical interns and nurses regarding family planning services indicated inadequate training received, and substandard quality of services rendered by them, which may put the universal access to sexual and reproductive health care services and rights in the developing countries at risk.
Left Pulmonary Artery in 22q11.2 deletion syndrome. Echocardiographic evaluation in patients without cardiac defects and role of Tbx1 in mice
Authors: Mastromoro Gioia , Calcagni Giulio , Versacci Paolo , Putotto Carolina , Chinali Marcello , Lambiase Caterina , Unolt Marta , Pelliccione Elena , Anaclerio Silvia , Caprio Cinzia , Cioffi Sara , Bilio Marchesa , Baban Anwar , Drago Fabrizio , Digilio Maria Cristina , Marino Bruno , Baldini Antonio
Published: January 2019

Introduction and Hypothesis

Patients with 22q11 deletion syndrome (22q11.2DS) present, in about 75% of cases, typical patterns of cardiac defects, with a particular involvement on the ventricular outflow tract and great arteries. However, in this genetic condition the dimensions of the pulmonary arteries (PAs) never were specifically evaluated.

We measured both PAs diameter in patients with 22q11.2DS without cardiac defects, comparing these data to a normal control group. Moreover, we measured the PAs diameter in Tbx1 mutant mice. Finally, a cell fate mapping in Tbx1 mutants was used to study the expression of this gene in the morphogenesis of PAs.

Methods

We evaluated 58 patients with 22q11.2DS without cardiac defects. The control group consisted of 54 healthy subjects, matched for age and sex. All cases underwent a complete transthoracic echocardiography. Moreover, we crossed Tbx1+/- mice and harvested fetuses. We examined the cardiovascular phenotype of 8 wild type (WT), 37 heterozygous (Tbx1+/-) and 6 null fetuses (Tbx1-/-). Finally, we crossed Tbx1Cre/+mice with R26RmT-mG Cre reporter mice to study Tbx1 expression in the pulmonary arteries.

Results

The echocardiographic study showed that the mean of the LPA/RPA ratio in 22q11.2DS was smaller (0.80 ± 0.12) than in controls (0.97 ± 0.08; p < 0.0001).

Mouse studies resulted in similar data as the size of LPA and RPA was not significantly different in WT embryos, but in Tbx1+/- and Tbx1-/- embryos the LPA was significantly smaller than the RPA in both mutants (P=0.0016 and 0.0043, respectively). We found that Tbx1 is expressed near the origin of the PAs and in their adventitia.

Conclusions

Children with 22q11.2DS without cardiac defects show smaller LPA compared with healthy subjects. Mouse studies suggest that this anomaly is due to haploinsufficiency of Tbx1. These data may be useful in the clinical management of children with 22q11.2DS and should guide further experimental studies as to the mechanisms underlying PAs development.
Modeling impacts of climate change on the potential habitat of an endangered Brazilian endemic coral: discussion about deep sea refugia
Authors: de Oliveira Umberto Diego Rodrigues , de Lima Gislaine Vanessa , Gomes Paula Braga , Cordeiro Ralf Tarciso Silva , Pérez Carlos Daniel
Published: January 2019

Climate and environmental changes are determinant for coral distribution and their very existence. Effects of such changes on distribution can be predicted through ecological niche models, anticipating suitable habitats for subsistence of species.Mussismilia harttiiis one of the most widespread Brazilian endemic reef building corals, and in increasing risk of extinction. The ecological niche models were used through the maximal entropy approach to determine the potential present and future habitats forM. harttii, estimating suitable habitat losses and gains at the end of the 21st century. For this purpose, records published in the last 20 years and current and future environmental variables were correlated. The models were evaluated through the Area Under the Operational Curve of the Receiver, using the AUC values and additionally AUCratio, a new approach using independent occurrence data. Both approaches showed that the models performed satisfactorily in predicting areas of potential habitat for the species. The results showed that the area to the south of the São Francisco River is the most suitable for the current habitat of the species, and that nitrate was the most influential variable for the models. Simultaneously, the salinity and temperature exerted greater influence for the models in future scenarios, in which current northernmost and southernmost limits of the potential habitats shifted towards deeper regions, so these deeper sites may serve as a refugia for the species in global warming scenarios. Coral communities at such depths would be less susceptible to the impacts of climate change on temperature and salinity. However, deep sea is not free from human impacts and measures to protect deeper ecosystems should be prioritized in environmental policy for Brazilian marine conservation.
Doublecotin-like kinase 1 increases chemoresistance of colorectal cancer cells through the anti-apoptosis pathway
Authors: Li Lianna , Jones Kierra , Mei Hao
Published: January 2019

Colorectal cancer (CRC) is the third most common cancer diagnosed and the second leading cause of cancer-related deaths in the United States. About 50% of CRC patients relapsed after surgical resection and ultimately died of metastatic disease. Cancer stem cells (CSCs) are believed to be the primary reason for the recurrence of CRC. Specific stem cell marker, doublecortin-like kinase 1 (DCLK1) plays critical roles in initiating tumorigenesis, facilitating tumor progression, and promoting metastasis of CRC. It is up-regulated in CRC and up-regulation of DCLK1 indicates poor prognosis. Whether DCLK1 is correlated with enhanced chemoresistance of CRC cells is unclear. Our research aims to reveal association of DCLK1 with chemoresistance of CRC cells and the underlying molecular mechanisms. In order to achieve our goal, we established stable DCLK1 over-expression cells (DCLK1+) using the HCT116 cells (WT). DCLK1+ and WT cells were treated with 5-Fluorouracil (5-Fu) at different doses for 24 or 48 hours. MTT assay was used to evaluate cell viability and IC50 of 5-Fu was determined. Quantitative real time PCR was applied to determine gene expression of caspase-3 (casp-3), caspase-4 (casp-4), and caspase-10 (casp-10). Cleaved casp-3 expression was investigated using Western blot and immunofluorescence. Our results demonstrated that IC50 of 5-Fu for the DCLK1+ cells was significantly higher than that of the WT cells for both 24 and 48-hour treatment (P=0.002 and 0.048 respectively), indicating increased chemoresistance of the DCLK1+ cells. Gene expression of casp-3, casp-4, and casp-10 were significantly inhibited in the DCLK1+ cells after 5-Fu treatment compared to the WT cells (P=7.616e-08, 1.575e-05 and 5.307e-08, respectively). Cleaved casp-3 amount and casp-3 positive cells were significantly decreased in the DCLK1+ cells after 5-Fu treatment compared to the WT cells (P=0.015). In conclusion, our results demonstrated that DCLK1 overexpression enhanced the chemoresistance of CRC cells to 5-Fu treatment by suppressing gene expression of key caspases in the apoptosis pathway and activation of apoptosis pathway. DCLK1 can be an intriguing therapeutic target for the effective treatment of CRC patients.
Late-onset pattern macular dystrophy mimicking ABCA4 and PRPH2 disease is caused by a homozygous frameshift mutation in ROM1
Authors: Ma Chu Jian , Lee Winston , Stong Nicholas , Zernant Jana , Chang Stanley , Goldstein David , Nagasaki Takayuki , Allikmets Rando
Published: January 2019

ROM1 (retinal outer segment membrane protein 1) is a 351-amino acid integral membrane protein on Chromosome 11q, with high structural similarity to PRPH2/RDS. Localized at the rims of photoreceptor outer segments (OSs), it is required for the maintenance of OS structure. Here, we describe a case with a phenotypic manifestation of a homozygous single-base pair deletion, c.712delC (p.Leu238Cysfs*78) in the ROM1 gene, resulting in early termination at exon 2. The variant was detected by whole-exome sequencing (WES) in a 63-yr-old Caucasian woman with late-onset pattern macular dystrophy. Notably, although the phenotype resembles those caused by pathogenic variants in ABCA4 or RDS/PRPH2, no pathogenic variants in these, or any other plausible candidate genes, were identified by WES. Clinical features include the presence of hyperautofluorescent flecks, relative sparing of the central macula, and preserved visual acuity. Reduced visual sensitivity was detected among flecked regions in the retina; however, full-field electroretinogram testing revealed no generalized cone dysfunction. The described first case of the complete loss of ROM1 protein function in the retina suggests its sufficiency for late-onset macular dystrophy. ROM1 and PRPH2 pattern macular dystrophies exhibit phenotype overlap, which may be attributable to their shared role in maintenance of the photoreceptor outer segment structure.
What drives green persistence intentions?
Authors: Wu Hung-Che , Cheng Ching-Chan
Published: January 2019

Purpose

The purpose of this paper is to explore the structural relationship between green persistence intentions and their seven drivers – green authenticity, green perceptual evaluation, green co-creation, green experiential memorability, green experiential satisfaction, green passionate love and green need for cognition in a green hotel context.

Design/methodology/approach

The data used in this study were based on a sample of 589 customers staying at one green hotel in New Taipei City of Taiwan. The predicted relationship was tested using the structural equation modeling and the hierarchical regression analysis.

Findings

The results indicate that green perceptual evaluation, green co-creation and green experiential memorability influence green experiential satisfaction. Green passionate love is influenced by green experiential satisfaction. Green need for cognition moderates the effect of green experiential satisfaction on green persistence intentions. Green persistence intentions are influenced by green experiential satisfaction and green passionate love.

Practical implications

To increase green authenticity, green perceptual evaluation, green co-creation, green experiential memorability, green experiential satisfaction, green passionate love, green need for cognition and green persistence intentions, the study findings will help green hotels to develop and implement market-orientated product and/or service strategies.

Originality/value

This paper provides data that lead to a better understanding of the relationships among green authenticity, green perceptual evaluation, green co-creation, green experiential memorability, green experiential satisfaction, green passionate love, green need for cognition and green persistence intentions in a green hotel context.
Fuels sales through retail chains and their store traffics and revenue
Authors: Jung Hojin , Kwon Kyoung-min , Yu Gun Jea
Published: January 2019

Purpose

Using panel data on gasoline and grocery transactions in Korea, the purpose of this paper is to empirically explore the effect of a retail chain store’s establishment of on-site fuel sales. The empirical analyses present strong empirical evidence that the sale of fuel had statistically and economically significant effect on retail store traffic and revenue in the short run. However, the effect did not remain significant in the longer run. To explain the dramatic decrease in the effect of the fuel sale, the authors consider the enhanced competition in the local gasoline retail industry and examine cross-sectional price variations at the station level. The results suggest that the increased competition led to the reduction in the price dispersion across stations and thereby to an increase in consumer welfare.

Design/methodology/approach

Using a linear specification that has traditionally been used to model retail chain data, the authors developed a series of difference-in-differences models. This technique is ideal for estimating the effect of a treatment in the presence of possible selection bias and has been widely employed in many social-science studies on policy intervention.

Findings

In a certain environment, introducing fuel sales did not increase retail chain store traffic or revenue in the long run, despite having statistically and economically significant effects in the short run. The results document empirical evidence of myopic management in a common marketing practice, which often leads to a negative impact on the firm value in the long run.

Research limitations/implications

The span of data and sample size were limited to meet the company’s data protection policy.

Practical implications

Considering that many of developed countries are characterized by a gasoline retail environment similar to that which is investigated in this paper, the authors believe that the implications of the results are particularly valid for practitioners and policy makers.

Social implications

The findings document empirical evidence of myopic management in a common marketing practice, which often leads to a negative impact on the firm value in the long run. Marketing researchers should make efforts in establishing metrics to help identify myopic management decision.

Originality/value

This paper addresses an interesting and practical issue related to the effects of the introduction of gasoline sales by a supercenter store on its store traffic.
Corruption in Russia’s Primorsky Kray: is transparency the answer?
Authors: Levie Matthew Benjamin
Published: January 2019

Purpose

The purpose of this paper is to use open-source Russian government data to investigate the relationship between transparency and corruption. Russia is a developed country with a strong legal system and world-class transparency in government contracting, which according to many, should positively impact corruption. This study tests that hypothesis.

Design/methodology/approach

The paper statistically analyzes six months’ worth of Russian government contracts from a single Russian province and another month of data from a different province for comparison. The statistical analysis revealed individual instances of corruption, which were then analyzed qualitatively.

Findings

The paper found that competitiveness in Russian government contracting is extremely limited, and instances of corruption on a grand scale are easy to find in publicly available data.

Research limitations/implications

The paper only studied data from two Russian provinces, so readers should be careful about generalizing from the results. Further research should consider similar data, if obtainable, from other countries.

Practical implications

Countries seeking to limit corruption should consider cultural change, as well as modifications to government processes and legal systems.

Originality/value

The paper indicates that sound and transparent legal structures, by themselves, may be insufficient to prevent or discourage corruption.
Combatting public procurement criminality or simple rules for complex cases
Authors: Nowrousian Bijan
Published: January 2019

Purpose

Crimes that take place in the context of procurements, such as corruption and subsidy fraud, are a major problem for both integrity and fiscal accountability of public administration. Therefore, combatting such crimes is of great importance. However, this course of action works only if the prosecutors have the instruments designed for what is precisely needed for their fight. One of the things needed is elements of crimes that can be handled easily; and to show this is the purpose of this study.

Design/methodology/approach

The author’s practical experience as a state prosecutor dealing with corruption cases and enriched with philosophical thinking about the principles of law indicates that one thing is especially important with regard to the elements of crimes: simplicity.

Findings

Corruption and financial crime cases are quite often very complex, involving many participants and considerable effort by the perpetrators to disguise their real actions as normal business procedures. As a result, finding evidence is a difficult task. If the elements of crimes are complex and if they demand detailed evidence, then proving procurement criminality will be even more difficult as it already is and will quite frequently end up in failure. Therefore, giving prosecutors a simple legal framework with elements of crimes, demanding only what realistically can be proven is a key factor for success.

Originality/value

Only with such a simple legal framework can the prosecutor’s fight against procurement criminality bring urgent, positive results.
Tax evasion in the media: a comparison of Southern vs Central and Northern Italy
Authors: Mangani Andrea
Published: January 2019

Purpose

The representation of economic and financial crimes in the mass media can have a significant impact on readers’ and citizens’ perceptions of illegality and on a firm’s propensity to invest in different areas of the country in question. This paper aims to study the possible geographical media bias regarding tax evasion in Italy.

Design/methodology/approach

The empirical analysis considers 618 articles on tax evasion published between 2012 and 2016 in two top Italian newspapers, La Repubblica (based in Rome) and Il Corriere della Sera (based in Milan).

Findings

Excluding Insular Italy (Sicily and Sardinia), the articles on tax evasion in Southern Italy are systematically shorter. A further analysis shows that La Repubblica is largely responsible for this bias. This result holds after controlling for other events (bank robberies) and for the identity of journalists.

Originality/value

Previous studies considered the possible media bias regarding particularly dramatic criminal events, for example, terrorism acts or murders. This paper considers a less dramatic though more pervasive crime. In addition, an assessment of media attitude towards tax evasion is more complex, because the news reports both the crime and the successful actions that combat it.
Determinants of sales misconduct in Indian retail banking services
Authors: Mittal Suman , Garg Krishan K.
Published: January 2019

Purpose

The purpose of this paper is to demonstrate those factors which are responsible for the sales misconduct in Retail banking services across the world and try to find out the determinants which majorly affect the Indian Retail banking industry. The authors also try to find out whether the sales approach leads to malpractices in sales and how does it affect the different categories of the customers.

Design/methodology/approach

Primary data have been collected from the bank account holders having account in various private and public sector banks operating in India.

Findings

The authors have come out with finding that sales misconduct is majorly affected by misrepresentation of facts, complexity of products, lack of disclosure norms and more. They also found that push sales approach is adopted by banks, particularly by private banks to majorly tap the class customers to sell the financial products without their requirement and achieve the revenue targets.

Practical implications

Banking regulators can keep a close supervision on sales mal practices in banking sector and implement stringent norms to reduce these kinds of practices.

Originality/value

Very few studies have been conducted on the basis of the class of the customer, and how sales approach leads the malpractices in sales and how it affects the class of the customers.