bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct and Complementary Functions of Rho kinase isoforms ROCK1 and ROCK2 in Prefrontal Cortex Structural Plasticity
Authors: Greathouse Kelsey M. , Boros Benjamin D. , Deslauriers Josue F. , Henderson Benjamin W. , Curtis Kendall A. , Gentry Erik G. , Herskowitz Jeremy H. 
Published: March 2018

AbstractTwenty-nine protein kinase inhibitors have been used to treat human diseases. Out of these, two are Rho-associated protein kinase (ROCK) 1 and 2 inhibitors. ROCKs are attractive drug targets for a range of neurologic disorders; however a critical barrier to ROCK-based therapeutics is ambiguity over whether there are isoform-specific roles for ROCKs in neuronal structural plasticity. Here, we used a genetics approach to address this long-standing question. Both male and female adult ROCK1+/− and ROCK2+/− mice exhibited anxiety-like behaviors compared to littermate controls. Individual pyramidal neurons in the medial prefrontal cortex (mPFC) were targeted for iontophoretic microinjection of fluorescent dye, followed by high-resolution confocal microscopy and neuronal 3D reconstructions for morphometry analysis. Increased apical and basolateral dendritic length and intersections were observed in ROCK1+/− but not ROCK2+/− mice. Although dendritic spine densities were comparable among genotypes, apical spine extent was decreased in ROCK1+/− but increased in ROCK2+/− mice. Spine head and neck diameter were reduced similarly in ROCK1+/− and ROCK2+/− mice; however certain spine morphologic subclasses were more affected than others in a genotype-dependent manner. Biochemical analyses of ROCK substrates revealed that phosphorylation of LIM kinase was reduced in synaptic fractions from ROCK1+/− or ROCK2+/− mice, correlating to overlapping spine morphology phenotypes. Collectively, these observations implicate ROCK1 as a novel regulatory factor of neuronal dendritic structure and detail distinct and complementary roles of ROCKs in mPFC dendritic spine structural plasticity. This study provides a fundamental basis for current and future development of isoform-selective ROCK inhibitors to treat neurologic disorders.Significance StatementThe Rho-associated protein kinases (ROCK) 1 and 2 heavily influence neuronal architecture and synaptic plasticity. ROCKs are exciting drug targets and pan-ROCK inhibitors are clinically approved to treat hypertension, heart failure, glaucoma, spinal cord injury, and stroke. However development of isoform-specific ROCK inhibitors is hampered due to ambiguity over ROCK1- or ROCK2-specific functions in the brain. Our study begins to address this critical barrier and demonstrates that ROCK1 can mediate the dendritic arbor of neurons while both ROCK1 and ROCK2 heavily influence dendritic spine morphology. This study highlights distinct and complementary roles for ROCK1 and ROCK1 in prefrontal cortex structural plasticity and provides a fundamental basis for future development of isoform-selective ROCK inhibitors to treat neurologic disorders.
The IMMUNE-ASSOCIATED NUCLEOTIDE-BINDING 9 protein is a regulator of basal immunity in Arabidopsis thaliana
Authors: Wang Yuanzheng , Li Yansha , Rosas-Diaz Tabata , Caceres-Moreno Carlos , Lozano-Duran Rosa , Macho Alberto P. 
Published: March 2018

AbstractA robust regulation of plant immune responses requires multitude of positive and negative regulators that act in concert. The immune-associated nucleotide-binding (IAN) gene family members are associated with immunity in different organisms, although no characterization of their function has been carried out to date in plants. In this work, we analyzed the expression patterns of IAN genes and found that IAN9 is repressed upon pathogen infection or treatment with immune elicitors. IAN9 encodes a plasma membrane-localized protein that genetically behaves as a negative regulator of immunity. A novel ian9 mutant generated by CRISPR/Cas9 shows increased resistance to Pseudomonas syringae, while transgenic plants overexpressing IAN9 show a slight increase in susceptibility. In vivo immunoprecipitation of IAN9-GFP followed by mass spectrometry analysis revealed that IAN9 associates with a previously uncharacterized C3HC4-type RING finger domain-containing protein that we named IAP1, for IAN9-associated protein 1, which also acts as a negative regulator of basal immunity. Interestingly, neither ian9 or iap1 mutant plants show any obvious developmental phenotype, suggesting that they display enhanced inducible immunity rather than constitutive immune responses. Since both IAN9 and IAP1 have orthologs in important crop species, they could be suitable targets to generate plants more resistant to diseases caused by bacterial pathogens without yield penalty.
Inactivation of NUPR1 promotes cell death by coupling ER-stress responses with necrosis
Authors: Santofimia-Castaño Patricia , Lan Wenjun , Bintz Jennifer , Gayet Odile , Carrier Alice , Lomberk Gwen , Neira José Luis , González Antonio , Urrutia Raul , Soubeyran Philippe , Iovanna Juan 
Published: March 2018

AbstractGenetic inhibition of NUPR1 induces tumor growth arrest. Inactivation of NUPR1 expression in pancreatic cancer cells results in lower ATP production, higher consumption of glucose with a significant switch from OXPHOS to glycolysis followed by necrotic cell death. Importantly, induction of necrosis is independent of the caspase activity. We demonstrated that NUPR1 inactivation triggers a massive release of Ca2+from the endoplasmic reticulum (ER) to the cytosol and a strong increase in ROS production by mitochondria with a concomitant relocalization of mitochondria to the vicinity of the ER. In addition, transcriptomic analysis of NUPR1-deficient cells shows the induction of an ER stress which is associated to a decrease in the expression of some ER stress response-associated genes. Indeed, during ER stress induced by the treatment with thapsigargin, brefeldin A or tunicamycin, an increase in the mitochondrial malfunction with higher induction of necrosis was observed in NUPR1-defficent cells. Finally, activation of NUPR1 during acute pancreatitis protects acinar cells of necrosis in mice. Altogether, these data enable us to describe a model in which inactivation of NUPR1 in pancreatic cancer cells results in an ER stress that induces a mitochondrial malfunction, a deficient ATP production and, as consequence, the cell death by necrosis.HighlightsNUPR1 expression promotes pancreatic cancer development and progressionNUPR1-depletion is a promising therapeutic strategy to be used for treating cancersNUPR1-depletion induces ER stress, mitochondrial malfunction and a significant switch from OXPHOS to glycolysis followed by necrotic cell deathInactivation of NUPR1 antagonizes cell growth by coupling a defective ER-stress response and a caspase-independent necrosis.
mTORC1 controls glycogen synthase kinase 3β nuclear localization and function
Authors: Bautista Stephen J. , Boras Ivan , Vissa Adriano , Mecica Noa , Yip Christopher M. , Kim Peter K. , Antonescu Costin N. 
Published: March 2018

AbstractGlycogen synthase kinase 3β (GSK3β) phosphorylates and regulates a wide range of substrates involved in diverse cellular functions. Some GSK3β substrates, such as c-myc and snail, are nuclear-resident transcription factors, suggesting possible control of GSK3β function by regulation of its nuclear localization. Inhibition of mechanistic target of rapamycin (mTORC1) led to partial redistribution of GSK3β from the cytosol to the nucleus, and GSK3β-dependent reduction of the expression of c-myc and snail. mTORC1 is controlled by metabolic cues, such as by AMP-activated protein kinase (AMPK) or amino acid abundance. Indeed AMPK activation or amino acid deprivation promoted GSK3β nuclear localization in an mTORC1-dependent manner. GSK3β was detected in several distinct endomembrane compartments, including lysosomes. Consistently, disruption of late endosomes/lysosomes through perturbation of Rab7 resulted in loss of GSK3β from lysosomes, and enhanced GSK3β nuclear localization as well as GSK3β-dependent reduction of c-myc levels. This indicates that GSK3β nuclear localization and function is suppressed by mTORC1, and suggests a new link between metabolic conditions sensed by mTORC1 and GSK3β-dependent regulation of transcriptional networks controlling biomass production.Summary statement (15-30 words)GSK3β nuclear localization and function is negatively regulated by the metabolic and mitogenic sensor mTORC1. mTORC1 control of GSK3β localization requires Rab7 and lysosomal membrane traffic.
Analysis of novel domain-specific mutations in the zebrafishndr2/cyclopsgene generated using CRISPR-Cas9 RNPs
Authors: Turner Ashley N. , Andersen Reagan S. , Bookout Ivy E. , Brashear Lauren N. , Davis James C. , Gahan David M. , Gotham John P. , Hijaz Baraa A. , Kaushik Ashish S. , McGill Jordan B , Miller Victoria L. , Moseley Zachariah P. , Nowell Cerissa L. , Patel Riddhi K. , Rodgers Mia C. , Shihab Yazen A. , Walker Austin P. , Glover Sarah R. , Foster Samantha D. , Challa Anil K. 
Published: March 2018

AbstractNodal-related protein (ndr2) is a member of the transforming growth factor type β superfamily of factors and is required for ventral midline patterning of the embryonic central nervous system in zebrafish. In humans, mutations in the gene encoding nodal cause holoprosencephaly and heterotaxy. Mutations in thendr2gene in the zebrafish (Danio rerio) lead to similar phenotypes, including loss of the medial floor plate, severe deficits in ventral forebrain development, and cyclopia. Alleles of thendr2gene have been useful in studying patterning of ventral structures of the central nervous system. Fifteen differentndr2alleles have been reported in zebrafish, of which eight were generated using chemical mutagenesis, four were radiation-induced, and the remaining alleles were obtained via random insertion, gene targeting (TALEN), or unknown methods. Therefore, most mutation sites were random and could not be predicteda priori. Using the CRISPR-Cas9 system fromStreptococcus pyogenes, we targeted distinct regions in all three exons of zebrafishndr2and observed cyclopia in the injected (G0) embryos. We show that the use of sgRNA-Cas9 ribonucleoprotein (RNP) complexes can cause penetrant cyclopic phenotypes in injected (G0) embryos. Targeted PCR amplicon analysis using Sanger sequencing showed that most of the alleles had small indels resulting in frameshifts. The sequence information correlates with the loss of ndr2 activity. In this study, we validate multiple CRISPR targets using anin vitronuclease assay andin vivoanalysis using embryos. We describe one specific mutant allele resulting in loss of conserved terminal cysteine-coding sequences. This study is another demonstration of the utility of the CRISPR-Cas9 system in generating domain- specific mutations and provides further insights into the structure-function of thendr2gene.
Xchromosome and autosomal recombination are differentially sensitive to disruptions in SC maintenance
Authors: Billmyre Katherine Kretovich , Cahoon Cori K. , Heenan G. Matthew , Wesley Emily , Yu Zulin , Unruh Jay R. , Takeo Satomi , Hawley R. Scott 
Published: March 2018

AbstractThe synaptonemal complex (SC) is a conserved meiotic structure that regulates the repair of double strand breaks (DSBs) into crossovers or gene conversions. The removal of any central region SC component, such as theDrosophila melanogastertransverse filament protein C(3)G, causes a complete loss of SC structure and crossovers. To better understand the role of the SC in meiosis, we used CRISPR/Cas9 to construct three in-frame deletions within the predicted coiled-coil region of the C(3)G protein. These three deletion mutants disrupt SC maintenance at different times during pachytene and exhibit distinct defects in key meiotic processes, allowing us to define the stages of pachytene when the SC is necessary for homolog pairing and recombination. Our studies demonstrate that theXchromosome and the autosomes display substantially different defects in pairing and recombination when SC structure is disrupted, suggesting that theXchromosome is potentially regulated differently than the autosomes.
A novel GATA-binding protein 4 gene variation associated with familial atrial septal defect
Authors: Yang Yongchao , Xia Yu , Wu Yueheng , Huang Shufang , Teng Yun , Liu Xiaobing , Li Ping , Chen Jimei , Zhuang Jian 
Published: March 2018

AbstractAtrial septal defect (ASD) is the most common congenital heart defect. Part of ASD exhibits familial predisposition, but the genetic mechanism remains largely unknown. In the current study, we use multiple methods to identify and confirm the gene associated with a familial ASD. Chromosomal microarray analyses, whole exome sequencing, Sanger sequencing, multiple bioinformatics programs, in silico protein structure modeling and molecular dynamics simulation were performed to predict the pathogenic of the variant gene. Dual-Luciferase reporter gene assay was performed to evaluate the influence of downstream target gene of the target variation. A novel, heterozygous, missense variant GATA-binding protein 4 (GATA4):c.958C>T, p.R320W was identified. An autosomal dominant inheritance pattern with incomplete penetrance was observed in the family. Multiple prediction indicate the variant in GATA4 to be deleterious. Molecular dynamics simulation further revealed that the variation of p.R320W could prevent the zinc finger of GATA4 from interacting with the DNA. Dual-Luciferase reporter assay demonstrated a significant decrease in transcriptional activity (0.90±0.099 vs 1.50±0.079, p = 0.001) of the variant GATA4 compared with the wild type. We believe the novel variation of GATA4 (c.958C>T, p.R320W) with a pattern of incomplete inheritance that may be highly associated with this familial ASD. The finding enriched our knowledge of variations that may associated with ASD.
Action for increasing energy-saving behaviour in student residences at Rhodes University, South Africa
Authors: Bulunga Angel Ancha Lindelwa , Thondhlana Gladman 
Published: March 2018

Purpose
In response to increasing energy demand and financial constraints to invest in green infrastructure, behaviour change energy-saving interventions are increasingly being considered as a tool for encouraging pro-environmental behaviour in campus residences. This paper aims to report on a pilot programme aimed at reducing energy consumption via behaviour change interventions, variably applied in residences at Rhodes University, South Africa.

Design/methodology/approach
Data were collected via structured questionnaires, energy consumption records and post-intervention programme focus group discussions.

Findings
Participant residences that received a mix of different interventions in the forms of pamphlets, face-to-face discussions, incentives and feedback recorded more energy reductions of up to 9 per cent than residences that received a single or no intervention. In post-experiment discussions, students cited personal, institutional and structural barriers to pro-environmental energy-use behaviour.

Practical implications
Overall, the results of this study suggest that information provision of energy-saving tips combined with regular feedback and incentives can result in energy-use reductions in university residences, which may yield environmental and economic benefits for universities, but addressing barriers to pro-environmental behaviour might maximise the results.

Originality/value
Given the lack of literature on energy conservation in the global South universities, this study provides the basis for discussing the potential for using behavioural interventions in universities for stirring pathways towards sustainability.
Finite element investigation on mode I crack tip characteristics in residually stressed glare
Authors: Bhat Sunil , Narayanan S. 
Published: March 2018

Purpose
Behavior of mode I crack tip in fiber metal laminate (FML) differs from that in homogeneous or plain specimen made of metal used in the laminate due to the load transfer effect in the laminate caused by property mismatch between dissimilar material layers. The purpose of this paper is to present a finite element investigation on the characteristics of crack tip in monotonically loaded and residually stressed FML.

Design/methodology/approach
Crack tip characteristics are assessed by: the sizes of various zones that form at the tip; and crack tip energy release rates. The same are found by modeling two types of Glare laminates under monotonic tension with different crack orientations in SSY regime – Type I and Type II. Residual stresses are externally introduced in the models. Delaminations are modeled by cohesive elements. Crack tip zone sizes are measured from finite element solutions. Values of J integrals are computed over cyclic paths near the crack tips. Identically cracked and loaded plain aluminum alloy specimens are also modeled for comparison.

Findings
The sizes of crack tip zones in Glare laminates are found to be different than those in plain specimens. Process zone is observed to form at crack tip in Type I laminate whereas it does not develop in Type II laminate, the reverse being true in plain specimens. Values of J integrals near crack tips are also found to deviate from those in plain specimens, higher in Type I laminate due to crack tip stress amplification and lower in Type II laminate due to stress reduction. Crack orientation decides the amplification or shielding effect in the laminate.

Research limitations/implications
There is scope for validating the numerical results reported in the paper by theoretical models.

Practical implications
The method to quantify crack tip shielding and amplification is presented that shall be useful in checking the structural integrity/safety of the laminate during actual service conditions.

Originality/value
Shielding and amplification effects are explicitly described and illustrated in the paper. Suitability of using J integrals over paths crossing non-homogeneous and property mismatched material layers is tested. Use of cohesive zone method that is readily applicable in finite element procedures and is relatively simple, fast and reasonably accurate is also demonstrated.
Social media research in the context of emerging markets
Authors: Tamilmani Kuttimani , Rana Nripendra P. , Alryalat Mohammad Abdallah Ali , Al-Khowaiter Wassan A.A. , Dwivedi Yogesh K. 
Published: March 2018

Purpose
Despite the potential of social media in emerging markets (EMs), only a few studies published in high-quality information systems (IS) journals that have addressed issues related to social media in the context of EMs. The purpose of this paper is to analyse existing research related to social media published in high-quality IS journals for exploring initial research trends, emerging themes, limitations and future research directions in the context of EMs.

Design/methodology/approach
This study conducted a systematic review of 22 articles on social media, which were published in the “Senior Scholars Basket of IS Journals and Information Systems Frontiers” from 1997 to 2017. Manual literature search approach (i.e. screening through the table of contents of each journal) was employed to identify relevant articles. The content of relevant articles was systematically analysed and synthesised along with keyword analysis to understand research trends on social media related issues in the EMs context.

Findings
The study identified four major themes from existing research on the social media in the context of EMs, namely: social media frameworks; social media and consumers; social media and organisations; and social media and society with the majority of the studies focussing on consumers. A single subject was found as the major limitation with studies analysed focussing on single platform/country/domain hindering the generalisability whereas including a new exogenous variable to improve the validity of existing studies emerged as main future research direction.

Originality/value
This study conducted literature review on social media in EMs, which have not been undertaken yet. Moreover, it employed manual search (an effort and time-intensive approach) to overcome the shortcomings of keyword search to identify, locate, select and analyse the social media literature in the context of EMs.
Asset misappropriation in small businesses
Authors: Kennedy Jay P. 
Published: March 2018

Purpose
This paper aims to increase the understanding of the types of insider financial frauds that occur within small businesses by focusing on a sample of businesses that have not employed a certified fraud examiner (CFE) in response to employee theft.

Design/methodology/approach
The survey data analyzed come from 102 small businesses (100 employees or fewer) in a midsized Midwestern city in the USA, and reflect 125 reported employee thefts.

Findings
The study results indicate that small businesses that do not hire a CFE report certain thefts with greater and lower frequencies as compared to small businesses that do hire a CFE. For particular types of frauds, CFEs may be no more useful than the efforts of business owners or managers, and other employees.

Practical implications
There may be important organizational differences between businesses that hire CFEs and those that do not, differences related to the ways in which business finances are maintained, the ways in which specific controls are used and the ability of employees to access business resources. These factors may create business-based opportunity structures that make particular types of insider financial frauds more or less likely to occur within a particular business.

Originality/value
Existing research on insider financial frauds may not appropriately account for small businesses that cannot afford, or are unwilling, to hire a CFE. The findings discussed in this paper contribute to a more complete picture of the types of frauds that small businesses experience, as well as how these businesses deal with insider theft.