bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vivo epigenetic editing of sema6a promoter reverses impaired transcallosal connectivity caused by C11orf46/ARL14EP neurodevelopmental risk gene
Authors: Peter Cyril J. , Saito Atsushi , Hasegawa Yuto , Tanaka Yuya , Perez Gabriel , Alway Emily , Espeso-gil Sergio , Fayyad Tariq , Ratner Chana , Dincer Aslihan , Gupta Achla , Devi Lakshmi , Pappas John G. , Lalonde François M. , Butman John A. , Han Joan C. , Akbarian Schahram , Kamiya Atsushi 
Published: December 2018

AbstractMany neuropsychiatric risk genes contribute to epigenetic regulation of gene expression but very little is known about specific chromatin-associated mechanisms governing the formation and maintenance of neuronal connectivity. Here we show that transcallosal connectivity is critically dependent on C11orf46 (also known as ARL14EP), a small nuclear protein encoded in the chromosome 11p13 Wilms Tumor, Aniridia, Genitourinary Abnormalities, intellectual disability (formerly referred to as Mental Retardation) (WAGR) risk locus. C11orf46 haploinsufficiency in WAGR microdeletion cases was associated with severe hypoplasia of the corpus callosum. In utero short hairpin RNA-mediated C11orf46 knockdown disrupted transcallosal projections of cortical pyramidal neurons, a phenotype that was rescued by wild type C11orf46 but not the C11orf46R236H mutant associated with autosomal recessive intellectual disability. Multiple genes encoding key regulators of axonal growth and differentiation, including Sema6A, were hyperexpressed in C11orf46-knockdown neurons. Importantly, RNA-guided epigenetic editing of neuronal Sema6a gene promoters via a dCas9 protein-conjugated SunTag scaffold with multimeric (10x) C11orf46 binding during early developmental periods, resulted in normalization of expression and rescue of transcallosal dysconnectivity via repressive chromatin remodeling, including up-regulated histone H3K9 methylation by the KAP1-SETDB1 repressor complex. Our study demonstrates that interhemispheric communication is highly sensitive to locus-specific remodeling of neuronal chromatin, revealing the therapeutic potential for shaping the brain’s connectome via gene-targeted designer activators and repressor proteins.
Regulation of Exocytosis and Mitochondrial Relocalization by Alpha-Synuclein in a Mammalian Cell Model
Authors: Ramezani Meraj , Wilkes Marcus M. , Das Tapojyoti , Holowka David , Eliezer David , Baird Barbara 
Published: December 2018

ABSTRACTWe characterized phenotypes in RBL-2H3 mast cells transfected with human alpha synuclein (a-syn) using stimulated exocytosis of recycling endosomes as a proxy for similar activities of synaptic vesicles in neurons. We found that low expression of a-syn inhibits stimulated exocytosis and that higher expression causes slight enhancement. NMR measurements of membrane interactions correlate with these functional effects: they are eliminated differentially by mutants that perturb helical structure in the helix 1 (A30P) or NAC/helix-2 (V70P) regions of membrane-bound a-syn, but not by other PD-associated mutants or C-terminal truncation. We further found that a-syn (but not A30P or V70P mutants) associates weakly with mitochondria, but this association increases markedly under conditions of cellular stress. These results highlight the importance of specific structural features of a-syn in regulating vesicle release, and point to a potential role for a-syn in perturbing mitochondrial function under pathological conditions.
Wd*-test: Robust Distance-Based Multivariate Analysis of Variance
Authors: Hamidi Bashir , Wallace Kristin , Vasu Chenthamarakshan , Alekseyenko Alexander V. 
Published: December 2018

AbstractBackgroundCommunity-wide analyses provide an essential means for evaluation of the effect of interventions or design variables on the composition of the microbiome. Applications of these analyses are omnipresent in microbiome literature, yet some of their statistical properties have not been tested for robustness towards common features of microbiome data. Recently, it has been reported that PERMANOVA can yield wrong results in the presence of heteroscedasticity and unbalanced sample sizes.FindingsWe develop a method for multivariate analysis of variance, , based on Welch MANOVA that is robust to heteroscedasticity in the data. We do so by extending a previously reported method that does the same for two-level independent factor variables. Our approach can accommodate multi-level factors, stratification, and multiple post hoc testing scenarios. An R language implementation of the method is available at https://github.com/alekseyenko/WdStar.ConclusionOur method resolves potential for confounding of location and dispersion effects in multivariate analyses by explicitly accounting for the differences in multivariate dispersion in the data tested. The methods based on have general applicability in microbiome and other ‘omics data analyses.
Niche adaptation limits bacteriophage predation of Vibrio cholerae in a nutrient-poor aquatic environment
Authors: Silva-Valenzuela Cecilia A. , Camilli Andrew 
Published: December 2018

AbstractVibrio cholerae, the causative agent of cholera, has reservoirs in fresh and brackish water where it interacts with virulent bacteriophages. Phages are the most abundant biological entity on earth and co-evolve with bacteria. It was reported that concentrations of phage and V. cholerae inversely correlate in aquatic reservoirs and in the human small intestine, and therefore that phages may quench cholera outbreaks. Although there is strong evidence for phage predation in cholera patients, evidence is lacking for phage predation of V. cholerae in aquatic environments. Here, we used three virulent phages, ICP1, ICP2, and ICP3, commonly shed by cholera patients in Bangladesh, as models to understand the predation dynamics in microcosms simulating aquatic environments. None of the phages were capable of predation in fresh water, and only ICP1 was able to prey on V. cholerae in estuarine water due to a requirement for salt. We conclude that ICP2 and ICP3 are better adapted for predation in a nutrient rich environment. Our results point to the evolution of niche-specific predation by V. cholerae-specific virulent phages, which complicates their use in predicting or monitoring cholera outbreaks as well as their potential use in reducing aquatic reservoirs of V. cholerae in endemic areas.Significance statementVirulent phages can reduce populations of bacteria and help shape bacterial evolution. Here, we used three virulent phages to understand their equilibrium with V. cholerae in nutrient-limiting aquatic microcosms. It has been proposed that phages quench cholera outbreaks, but no direct evidence of phage predation in aquatic environments had been established. Here we show that different phages possess varied abilities to infect in certain niches or stages of the host bacterial life cycle. Unveiling the phage/bacterial interactions in their natural setting is important to the understanding of cholera outbreaks and could be ultimately used to help develop a method for outbreak prediction and/or control.
Polysaccharide A-dependent opposing effects of mucosal and systemic exposures to human gut commensalBacteroides fragilisin type 1 diabetes
Authors: Sofi M. Hanief. , Johnson Benjamin M. , Gudi Radhika R. , Jolly Amy , Gaudreau Marie-Claude , Vasu Chenthamarakshan 
Published: December 2018

AbstractBacteroides fragilis(BF) is an integral component of the human colonic commensal microbiota. BF is also the most commonly isolated organism from clinical cases of intra-abdominal abscesses suggesting its potential to induce pro-inflammatory responses, upon accessing the systemic compartment. Hence, we examined the impact of mucosal and systemic exposures to BF on type 1 diabetes (T1D) incidence in non-obese diabetic (NOD) mice. The impact of intestinal exposure to BF under chemically-induced enhanced gut permeability condition, which permits microbial translocation, in T1D was also examined. While oral administration of pre-diabetic mice with heat-killed (HK) BF caused enhanced immune regulation and suppression of autoimmunity resulting in delayed hyperglycemia, mice that received HK BF by i.v. injection showed rapid disease progression. Importantly, polysaccharide-A deficient (ΔPSA) BF failed to produce these opposing effects upon oral and systemic deliveries. Further, BF induced modulation of disease progression was observed in WT, but not TLR2-deficient, NOD mice. Interestingly, oral administration of BF under enhanced gut permeability condition resulted in accelerated disease progression and rapid onset of hyperglycemia in NOD mice. Overall, these observations suggest that BF-like gut commensals can cause pro-inflammatory responses upon gaining access to systemic compartment and contribute to T1D in at-risk subjects.
Structure of a cytochrome-based bacterial nanowire
Authors: Filman David J. , Marino Stephen F. , Ward Joy E. , Yang Lu , Mester Zoltán , Bullitt Esther , Lovley Derek R. , Strauss Mike 
Published: December 2018

AbstractElectrically conductive pili from Geobacter species, termed bacterial “nanowires”, are intensely studied for their biological significance and potential in the development of new materials. We have characterized a unique nanowire from conductive G. sulfurreducens pili preparations by cryo-electron microscopy composed solely of the c-type cytochrome OmcS. We present here, at 3.4 Å resolution, a novel structure of a cytochrome-based filament and discuss its possible role in long-range biological electron transport.Summary sentenceCryo-electron microscopy reveals the remarkable assembly of a c-type cytochrome into filaments comprising a heme-based bacterial nanowire.
Quantification of microenvironmental metabolites in murine cancer models reveals determinants of tumor nutrient availability
Authors: Sullivan Mark R. , Danai Laura V. , Lewis Caroline A. , Chan Sze Ham , Gui Dan Y. , Kunchok Tenzin , Dennstedt Emily A. , Vander Heiden Matthew G. , Muir Alexander 
Published: December 2018

AbstractCancer cell metabolism is heavily influenced by microenvironmental factors, including nutrient availability. Therefore, knowledge of microenvironmental nutrient levels is essential to understand tumor metabolism. To measure the extracellular nutrient levels available to tumors, we developed a quantitative metabolomics method to measure the absolute concentrations of >118 metabolites in plasma and tumor interstitial fluid, the extracellular fluid that perfuses tumors. Comparison of nutrient levels in tumor interstitial fluid and plasma revealed that the nutrients available to tumors differ from those present in circulation. Further, by comparing interstitial fluid nutrient levels between autochthonous and transplant models of murine pancreatic and lung adenocarcinoma, we found that tumor type, anatomical location and animal diet affect local nutrient availability. These data provide a comprehensive characterization of the nutrients present in the tumor microenvironment of widely used models of lung and pancreatic cancer and identify factors that influence metabolite levels in tumors.Impact StatementNutrient availability is an important tumor microenvironmental factor that impacts cancer cell biology; we developed methods to measure nutrients available to tumor cells and characterized factors that influence tumor nutrient availability.
Identification of three sequence motifs in the transcription termination factor Sen1 that mediate direct interactions with Nrd1
Authors: Zhang Yinglu , Chun Yujin , Buratowski Stephen , Tong Liang 
Published: December 2018

AbstractThe Nrd1-Nab3-Sen1 (NNS) complex carries out the transcription termination of noncoding RNAs (ncRNAs) in yeast, although the detailed interactions among its subunits remain obscure. Here we have identified three sequence motifs in Sen1 that mediate direct interactions with the RNA polymerase II CTD interaction domain (CID) of Nrd1, determined the crystal structures of these Nrd1 interaction motifs (NIMs) bound to the CID, and characterized the interactionsin vitroand in yeast.
Consensus interpretation of the Met34Thr and Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel
Authors: Shen Jun , Oza Andrea M. , del Castillo Ignacio , Duzkale Hatice , Matsunaga Tatsuo , Pandya Arti , Kang Hyunseok P. , Mar-Heyming Rebecca , Guha Saurav , Moyer Krista , Lo Christine , Kenna Margaret , Alexander John , Zhang Yan , Hirsch Yoel , Luo Minjie , Cao Ye , Choy Kwong Wai , Cheng Yen-Fu , Avraham Karen B. , Hu Xinhua , Garrido Gema , Moreno-Pelayo Miguel A. , Greinwald John , Zhang Kejian , Zeng Yukun , Brownstein Zippora , Basel-Vanagaite Lina , Davidov Bella , Frydman Moshe , Weiden Tzvi , Nagan Narasimhan , Willis Alecia , Hemphill Sarah E. , Grant Andrew R. , Siegert Rebecca K. , DiStefano Marina T. , Amr Sami S. , Rehm Heidi L. , Tayoun Ahmad N. Abou ,   on behalf of the ClinGen Hearing Loss Working Group
Published: December 2018

ABSTRACTPURPOSEPathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants.METHODSThe ClinGen Hearing Loss Expert Panel (HL-EP) collected published data and shared unpublished information from participating laboratories regarding the two variants. Functional, computational, allelic, and segregation data were also obtained.RESULTSThe panel reviewed the synthesized information, and classified the Met34Thr and Val37Ile variants according to professional variant interpretation guidelines. We found that Met34Thr and Val37Ile are significantly overrepresented in hearing loss patients, compared to the general population. Met34Thr or Val37Ile homozygotes or compound heterozygotes typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for those two variants.CONCLUSIONResolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification rules, review evidence, and reach a consensus. The ClinGen HL-EP concluded that Met34Thr and Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and age-dependent penetrance.
Investigation of the spatial heterogeneity of soil microbial biomass carbon and nitrogen under long-term fertilizations in fluvo-aquic soil
Authors: Hong-ling YE 
Published: December 2018

AbstractSoils are heterogeneous and microbial spatial distribution can clearly indicate the spatial characteristics of the soil carbon and nitrogen cycle. However, it is not clear how long-term fertilization affects the spatial distribution of microbial biomass in fluvo-aquic soil. We collected fluvo-aquic soil samples (topsoil 0-7.5 cm and sub-topsoil 7.5-20 cm) using a spatially-explicit design within three 40.5 m2plots in each of four fertilization treatments. Fertilization treatments were: cropping without fertilizer inputs (CK); chemical nitrogen, phosphorus, and potassium fertilizer (NPK); chemical fertilizer with straw return (NPKS); and chemical fertilizer with animal manure (NPKM). Variables included soil microbial biomass carbon (MBC) and nitrogen (MBN), and MBC/MBN. For both soil layers, we hypothesized that: microbial biomass was lowest in CK but with the largest spatial heterogeneity; and microbial biomass was highest in NPKM and NPKS but with the lowest spatial heterogeneity. Results showed that: (1) Fertilization significantly increased MBC and MBN more in topsoil than sub-topsoil but had no MBC/MBN changes. (2) The coefficient of variation (CV) and Cochran’s C showed that variation was largest in CK in topsoil and NPK in sub-topsoil and that variation of topsoil was generally lower than in sub-topsoil. The sample size of the three variables was largest in CK in topsoil but had little variation among the other treatments. (3) The trend-surface model showed that within-plot heterogeneity varied substantially with fertilization (NPKM = NPK > NPKS > CK), but Moran’s I and the interpolation map showed that spatial variability with fertilization followed the order NPK > NPKS > CK = NPKM at a fine scale in topsoil. In sub-topsoil, the trend-surface model showed that within-plot heterogeneity followed the order NPKM = CK > NPK > NPKS and that the fine-scale pattern was NPKM>NPK=NPKS>CK. MBC had the highest spatial heterogeneity among the three variables in both soil layers. Our results indicate that the application of organic fertilizer (straw or manure) reduced the variation of MBC and MBN but increased the spatial variability of MBC and MBN. The spatial variation of the three variables was MBC > MBN > MBC/MBN regardless of whether variation was considered at the plot-scale or the fine-scale in both layers.
Determinants of banks’ profitability in Angola
Authors: Garcia Maria Teresa Medeiros , Trindade Maria José 
Published: December 2018

PurposeThe purpose of this paper is to analyze the factors that influence the profitability of 17 banks in Angola between 2010 and 2016, as low profitability weakens the ability and willingness of banks to finance the wider economy.Design/methodology/approachThe paper conducts panel data analysis, using two measures of profitability: the return on average assets and the return on average equity. Several control variables were included concerning both bank-specific and macroeconomic characteristics which have not been considered in previous studies.FindingsThe authors conclude that several independent variables have an impact which is different from expected, especially regarding ownership, which shows positive statistically significant effect on banks’ profitability.Originality/valueTo the best of the authors’ knowledge, this is the first attempt to examine determinants of banks’ profitability in Angola, both internal and external, which have not been considered in previous studies.
Regional crises and corruption: the eclipse of the quality of working life in Nigeria
Authors: Adisa Toyin Ajibade , Gbadamosi Gbolahan 
Published: December 2018

PurposeIn recent years, there has been a rapid decline in the quality of working life (QWL) of Nigerian workers at all levels. This phenomenon is cryptic and knowledge thereof is inadequate due to a dearth of compelling research on QWL in Nigeria. The purpose of this paper is to a deeper understanding of QWL among Nigerian workers by investigating the impact of corruption and regional crises on QWL in this non-western context. The study also examines what QWL means to Nigerian employees.Design/methodology/approachThe study employs qualitative data gleaned from semi-structured interviews.FindingsThe research reveals that corruption has a strongly negative effect on employees’ QWL, which in turn affects their motivation, attitude towards their job and the psychological contract between them and their employers. Furthermore, the findings revealed that regional crises (such as the heinous activities of the Boko Haram sect in the north–east, the continuing agitation of the secessionists (e.g. the Indigenous People of Biafra), in the south–east, and the tumultuous activities of the Niger Delta Avengers in the south–south) have combined to reduce employees’ QWL.Research limitations/implicationsThe extent to which the findings of this research can be generalised is constrained by the selected sample of the research (public sector employees).Originality/valueThese results and the practical implications thereof will be useful to the Nigerian Government, policymakers and organisations for creating and enhancing good QWL in Nigeria.
Traveler loyalty and its antecedents in the hotel industry
Authors: Han Heesup , Kiatkawsin Kiattipoom , Kim Wansoo 
Published: December 2018

PurposeThe purpose of this paper is to examine the intricate associations among the performance of ambient atmospherics, emotional experiences, overall image and guest satisfaction and test the influence of these relationships on loyalty intentions by considering the moderating impact of continuance commitment in the upscale hotel context.Design/methodology/approachA field survey was conducted to collect the data. A quantitative approach was used for data analysis. Structural equation modeling and a test for metric invariance were used to identify the impact of study variables.FindingsThe results of this paper indicated that the hypothesized relationships were in general significant, that the proposed theoretical framework satisfactorily predicted guests’ intentions to be loyal and that the role of satisfaction among study constructs was prominent. Findings from the test for metric invariance also showed that continuance commitment significantly affected the associations among emotional experiences, satisfaction and loyalty intentions. Moreover, emotional experiences, overall hotel image and guest satisfaction were found to play a significant mediating role in generating loyalty intentions.Practical implicationsThe findings of this paper inform hotel practitioners of the clear role of atmospherics, emotional experiences, image, satisfaction and continuous commitment in building loyalty. In addition, these findings can help hotel practitioners and researchers invent thorough and strategic methods for loyalty enhancement.Originality/valueThe existing hotel literature has provided a limited view regarding the impact of these research variables. The present paper filled this research gap through the successfully development of a robust framework for hotel guest loyalty.
Coercive management behaviour causes scale: validation and reliability
Authors: Doe Frederick , Puplampu Bill Buenar 
Published: December 2018

PurposeThe purpose of this study is to provide a link that will close the gap in the field in respect of the methods used to measure the causes of coercive management behaviour (CMB) in universities and analogous institutions. Second, cultural and geographical differences and absence of studies of the phenomenon in the African university context have instigated researchers’ decision to design new scales to identify and measure the causes of CMB in the workplace.Design/methodology/approachA total of 371 respondents were surveyed in a cross-sectional survey using a developed scale which had 20 items. The study adopted the latent variable approach to scale development.FindingsFollowing an exploratory factor analysis done, five factors were extracted for the measurement of causes of CMB. A Cronbach alpha for all five factors to measure causes of CMB revealed validity for the administrative, social, organisational, cultural and governance elements. The research therefore surmised that the instrument developed to measure causes of CMB proposed is valid.Research limitations/implicationsThe study provides a vital bridge in the gap between the occurrence of CMB and the identification and measurement of its causes in universities thus contributing to knowledge.Practical implicationsAs a nation that is heavily imbued with culture, there is need to push for modifications in culture at the national level and within the African setting so as to ensure curtailment or total eradication of CMB for the future.Originality/valueThe study brings to research attention hitherto unmarked causes of CMB by providing a validated instrument that can be used to measure causes of the phenomenon.