bluuebunny/crossref_metadata_2025_split huggingface dataset:
The desmosomal cadherin Desmogon is necessary for the structural integrity of the Medaka notochord
Authors: Seleit Ali , Gross Karen , Woelk Michaela , Autorino Camilla , Onistschenko Jasmin , Centanin Lazaro 
Published: April 2019

AbstractThe notochord is an embryonic tissue that acts as a precursor to the spine. It is composed of outer sheath cells and inner vacuolated cells. Together they ensure the ability of the notochord to act as a hydrostatic skeleton until ossification begins. To date, there is still a paucity in our understanding of how the notochord cell types are specified and the molecular players controlling both their formation and maintenance remain poorly understood. Here we report thatdesmogon, a desmosomal cadherin, is essential for proper vacuolated cell shape and therefore correct notochord morphology. We tracedesmogon+precursors and uncover an early developmental heterogeneity that dictates the balance of vacuolated and sheath cell formation. We demonstrate that the growth of vacuolated cells occurs asynchronously and reveal the presence of distinct injury sensing mechanisms in the notochord. Additionally, using a small-scale F0 CRISPR screen we implicate uncharacterized genes in notochordal integrity.
Dual delivery of nucleic acids and PEGylated-bisphosphonates via calcium phosphate nanoparticles
Authors: Bisso Sofia , Mura Simona , Castagner Bastien , Couvreur Patrick , Leroux Jean-Christophe 
Published: April 2019

AbstractDespite many years of research and a few success stories with gene therapeutics, efficient and safe DNA delivery remains a major bottleneck for the clinical translation of gene-based therapies. Gene transfection with calcium phosphate (CaP) nanoparticles brings the advantages of low toxicity, high DNA entrapment efficiency and good endosomal escape properties. The macroscale aggregation of CaP nanoparticles can be easily prevented through surface coating with bisphosphonate conjugates. Bisphosphonates, such as alendronate, recently showed promising anticancer effects. However, their poor cellular permeability and preferential bone accumulation hamper their full application in chemotherapy. Here, we investigated the dual delivery of plasmid DNA and alendronate using CaP nanoparticles, with the goal to facilitate cellular internalization of both compounds and potentially achieve a combined pharmacological effect on the same or different cell lines. A pH-sensitive poly(ethylene glycol)-alendronate conjugate was synthetized and used to formulate stable plasmid DNA-loaded CaP nanoparticles. These particles displayed good transfection efficiency in cancer cells and a strong cytotoxic effect on macrophages. The in vivo transfection efficiency, however, remained low, calling for an improvement of the system, possibly with respect to the extent of particle uptake and their physical stability.Graphical abstract
Adaptive substitutions underlying cardiac glycoside insensitivity in insects exhibit epistasis in vivo
Authors: Taverner Andrew M. , Yang Lu , Barile Zackery J. , Lin Becky , Peng Julie , Pinharanda Ana , Rao Arya , Roland Bartholomew P. , Talsma Aaron D. , Wei Daniel , Petschenka Georg , Palladino Michael J. , Andolfatto Peter 
Published: April 2019

AbstractPredicting how species will respond to selection pressures requires understanding the factors that constrain their evolution. We use genome engineering of Drosophila to investigate constraints on the repeated evolution of unrelated herbivorous insects to toxic cardiac glycosides, which primarily occurs via a small subset of possible functionally-relevant substitutions to Na+,K+-ATPase. Surprisingly, we find that frequently observed adaptive substitutions at two sites, 111 and 122, are lethal when homozygous and adult heterozygotes exhibit dominant neural dysfunction. We identify a phylogenetically correlated substitution, A119S, that partially ameliorates the deleterious effects of substitutions at 111 and 122. Despite contributing little to cardiac glycoside-insensitivity in vitro, A119S, like substitutions at 111 and 122, substantially increases adult survivorship upon cardiac glycoside exposure. Our results demonstrate the importance of epistasis in constraining adaptive paths. Moreover, by revealing distinct effects of substitutions in vitro and in vivo, our results underscore the importance of evaluating the fitness of adaptive substitutions and their interactions in whole organisms.
Memory for Individual Items is Related to Non-Reinforced Preference Change
Authors: Botvinik-Nezer Rotem , Bakkour Akram , Salomon Tom , Shohamy Daphna , Schonberg Tom 
Published: April 2019

AbstractIt is commonly assumed that memories contribute to value-based decisions. Nevertheless, most theories of value-based decision-making do not account for memory influences on choice. Recently, new interest has emerged in the interactions between these two fundamental processes, mainly using reinforcement-based paradigms. Here, we aimed to study the role memory processes play in preference change following the non-reinforced cue-approach training (CAT) paradigm. In CAT, the mere association of cued items with a speeded motor response influences choices. Previous studies with this paradigm showed that a single training session induces a long-lasting effect of enhanced preferences for high-value trained stimuli, that is maintained for several months. We hypothesized that CAT influences memory accessibility for trained items, leading to enhanced accessibility of their positive associative memories and in turn to preference changes. In two pre-registered experiments, we tested whether memory for trained items was enhanced following CAT, in the short and in the long-term, and whether memory modifications were related to choices. We found that memory was enhanced for trained items and that better memory was correlated with enhanced preferences at the individual item level, both immediately and one month following CAT. Our findings show that memory plays a central role in value-based decision-making following CAT, even in the absence of external reinforcements. These findings contribute to new theories relating memory and value-based decision-making and set the groundwork for the implementation of novel behavioral interventions that lead to long-lasting behavioral change.
Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling
Authors: Segura-Bayona Sandra , Villamor-Payà Marina , Attolini Camille Stephan-Otto , Stracker Travis H. 
Published: April 2019

AbstractThe Tousled like kinases 1 and 2 (TLK1/2) control histone deposition through the ASF1 histone chaperones and are regulated by the DNA damage response. Depletion of TLK activity caused replication stress, increased chromosomal instability and cell arrest or death. Here, we show that stalled forks in TLK depleted cells are processed by BLM, SAMHD1 and the MRE11 nuclease to generate ssDNA and activate checkpoint signaling. TLK depletion also impaired heterochromatin maintenance, inducing features of alternative lengthening of telomeres and increasing spurious expression of other repetitive elements, associated with impaired deposition of the histone variant H3.3. TLK depletion culminated in a BLM-dependent, STING-mediated innate immune response. In many human cancers, TLK1/2 expression correlated with signatures of chromosomal instability and anti-correlated with STING and innate and adaptive immune response signatures. Together, our results show that TLK activity protects replication forks from active processing, contributes to chromatin silencing and suppresses innate immune responses, suggesting that TLK amplification may protect chromosomally unstable cancers from immune detection.
Inhibition of RNA Polymerase I Transcription Activates Targeted DNA Damage Response and Enhances the Efficacy of PARP Inhibitors in High-Grade Serous Ovarian Cancer
Authors: Sanij Elaine , Hannan Katherine M. , Yan Shunfei , Xuan Jiachen , Ahern Jessica E. , Chan Keefe T. , Son Jinbae , Kondrashova Olga , Lieschke Elizabeth , Wakefield Matthew J. , Trigos Anna S. , Frank Daniel , Ellis Sarah , Cullinane Carleen , Kang Jian , Poortinga Gretchen , Nag Purba , Khanna Kum Kum , Mileshkin Linda , McArthur Grant A. , Soong John , Berns Els M.J.J. , Hannan Ross D , Scott Clare L. , Sheppard Karen E , Pearson Richard B 
Published: April 2019

AbstractHigh-grade serous ovarian cancer (HGSOC) accounts for the majority of ovarian cancer and has a dismal prognosis. PARP inhibitors (PARPi) have revolutionized disease management of patients with homologous recombination (HR) DNA repair-deficient HGSOC. However, acquired resistance to PARPi by complex mechanisms including HR restoration and stabilisation of replication forks is a major challenge in the clinic. Here, we demonstrate CX-5461, an inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress at rDNA leading to activation of DNA damage response and DNA damage involving MRE11-dependent degradation of replication forks. CX-5461 cooperates with PARPi in exacerbating DNA damage and enhances synthetic lethal interactions of PARPi with HR deficiency in HGSOC-patient-derived xenograft (PDX)in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi and destabilises replication forks irrespective of HR pathway status, overcoming two well-known mechanisms of resistance to PARPi. Importantly, CX-5461 exhibits single agent efficacy in PARPi-resistant HGSOC-PDX. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. Therefore, CX-5461 is a promising therapy alone and in combination therapy with PARPi in HR-deficient HGSOC. CX-5461 is also an exciting treatment option for patients with relapsed HGSOC tumors that have poor clinical outcome.
Female mice are resilient to age-related decline of substantia nigra dopamine neuron firing parameters
Authors: Howell Rebecca D. , Dominguez-Lopez Sergio , Ocañas Sarah , Freeman Willard M. , Beckstead Michael J. 
Published: April 2019

SUMMARYThe degeneration of substantia nigra (SN) dopamine neurons is a central feature in the pathology associated with Parkinson’s disease, which is characterized by progressive loss of motor and cognitive functions. The largest risk factors for Parkinson’s disease are age and sex; most cases occur after age 60 and males have nearly twice the incidence as females. While much research in Parkinson’s has focused on the mechanisms underlying dopamine neuron degeneration, very little work has considered the influence of these two risk factors to disease risk and presentation. In this work, we performed whole cell patch clamp recordings in brain slices to study the alterations in intrinsic firing properties of single dopamine neurons in C57BL/6 mice across ages and between sexes. We observed a progressive decline in dopamine neuron firing activity in males by 18 months of age, while dopamine neurons from females remained largely unaffected. A semiquantitative analysis of midbrain dopamine neuron populations revealed a slight decrease only in substantia nigra dopamine neurons in males, while females did not change. This was also accompanied by increases in the expression of genes that have been linked to Parkinson’s including PTEN-induced kinase 1 (PINK1) in both males and females, and the ubiquitin ligase parkin, primarily in the substantia nigra of males. These impairments in dopamine neuron function in males may represent a vulnerability to further insults that could predispose these cells to neurodegenerative diseases such as in Parkinson’s.
Systematic determination of in vitro phenotypic resistance to HIV-1 integrase strand transfer inhibitors from clinical samples
Authors: Shahid Aniqa , Zhang Wendy W. , Montoya Vincent , Cheung Peter K. , Oliveira Natalia , Sidhu Manraj S. , Woods Conan K. , Robbins Marjorie A. , Brumme Chanson J. , Harrigan P. Richard 
Published: April 2019

ABSTRACTPhenotypic resistance data is relatively sparse for the newest HIV-1 integrase strand transfer inhibitors (INSTIs), dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB). In this study, we report the phenotypic susceptibility of a large panel of oligo-clonal patient-derived HIV-1 integrase viruses. Representative clinical samples (N=141) were selected from a large database (N=17,197) of clinically-derived HIV integrase sequences, based on the presence of permutations of substitutions at 27 pre-defined positions in integrase (N=288). HIV-1 RNA was extracted from patient samples and diluted to approximately 500 HIV RNA copies/mL. Using an “oligo-clonal” amplification approach to achieve single-copy amplification, these dilutions were subjected to 12 parallel RT-PCR reactions to amplify integrase. Confirmed clonal amplicons were co-transfected with linearized pNL4.3∆int into CEM-GXR cells. In total, 162 HIV-1 viruses that carried no mixtures and had a unique sequence were harvested, and phenotyped in MT4-LTR-EGFP cells subsequently. Variants with the highest fold change (FC) had G140S and Q148R/H and resistant to all five drugs; R263K was the only single variant conferring >3-FC to DTG, BIC and CAB. There was extensive cross-resistance between DTG, BIC, and CAB and phenotypic resistance values for all the three INSTIs were almost collinear. The greatest exceptions were variants with N155H/G163E or L74I/T97M/F121C/V151I/E157Q/G163K, where both had >70-FC for CAB, while <3-FC for DTG and BIC. While site-directed mutagenesis is invaluable; the systematic selection of representative mutational patterns observedin vivoprovides an efficient way to identify clinically relevant drug resistance.
Investigating Coronary Artery Disease methylome through targeted bisulfite sequencing
Authors: Ghose Subhoshree , Ghosh Sourav , Tanwar Vinay Singh , Tolani Priya , Sharma Anju , Bhardwaj Nitin , Shamsudheen KV , Verma Ankit , Jayarajan Rijith , Sivasubbu Sridhar , Scaria Vinod , Seth Sandeep , Sengupta Shantanu 
Published: April 2019

AbstractBackgroundGene environment interactions leading to epigenetic alterations play pivotal role in the pathogenesis of Coronary Artery Disease (CAD). Altered DNA methylation is one such epigenetic factor that could lead to altered disease etiology. In this study, we comprehensively identified methylation sites in several genes that have been previously associated with young CAD patients.MethodsThe study population consisted of 42 healthy controls and 33 young CAD patients (age group < 50 years). We performed targeted bisulfite sequencing of promoter as well as genic regions of several genes in various pathways like cholesterol synthesis and metabolism, endothelial dysfunction, apoptosis, which are implicated in the development of CAD.ResultsWe observed that the genes likeGALNT2, HMGCRwere hypermethylated in the promoter whereasLDLRgene promoter was hypomethylated indicating that intracellular LDL uptake was higher in CAD patients. AlthoughAPOA1did not show significant change in methylation butAPOC3andAPOA5showed variation in methylation in promoter and exonic regions. Glucokinase (GCK) and endothelial nitric oxide synthase 3(NOS3)were hyper methylated in the promoter. Genes involved in apoptosis(BAX/BCL2/AKT2)and inflammation (PHACTR1/LCK) also showed differential methylation between controls and CAD patients.ConclusionsThis study is unique because it highlights important gene methylation alterations which might predict the risk of young CAD in Indian population. Large scale studies in different populations would be important for validating our findings and understanding the epigenetic events associated with CAD.
Critical length in long read resequencing
Authors: Wouter De Coster , Mojca Strazisar , Peter De Rijk 
Published: April 2019

AbstractLong read sequencing has a substantial advantage for structural variant discovery and phasing of variants compared to short-read technologies, but the required and optimal read length has not been assessed. In this work, we used simulated long reads and evaluated structural variant discovery and variant phasing using current best practice bioinformatics methods. We determined that optimal discovery of structural variants from human genomes can be obtained with reads of minimally 15 kbp. Haplotyping genes entirely only reaches its optimum from reads of 100 kbp. These findings are important for the design of future long read sequencing projects.
Novel feeding and mating behaviors of a population of nautiluses, Nautilus belauensis, in Palau
Authors: Barord Gregory J. , Swanson Rebecca L. , Ward Peter D. 
Published: April 2019

AbstractThe nautiloid lineage extends back nearly 500 million years but today, is represented by only two living genera, Nautilus and Allonautilus. Behavioral observations of these living nautiluses have improved our understanding of how nautiloids, and ammonoids, behaved and interacted in their environment. These behaviors may also help to inform conservation practices. Here, we describe feeding and mating behaviors in wild nautiluses not reported from any other population. In Palau, Nautilus belauensis was observed actively preying on a large, living crab (Chaceon sp.) and performing courtship-like behaviors prior to mating. These behaviors occurred across multiple nights and from different nautiluses, suggesting that the behaviors are characteristic of at least a subset of the population, if not the entire population. Perhaps the behaviors exhibited by the Palauan nautiluses are an outlier and simply a localized characteristic of a far-removed population. Or, perhaps these apparent abnormal behaviors of Palauan nautiluses are what all nautiluses across the Indo-Pacific should be exhibiting. If the latter explanation is correct, we can start to address the potential causes of the behavioral differences, such as population size, habitat type, and prey availability. In either case, this apparent behavioral plasticity may have also been a reason that the nautiloid lineage has been able to survive throughout millions of years of environmental changes. Today, these behavioral observations could prove to be a valuable conservation tool to protect species and environments, especially in the deep-sea ecosystem the nautiluses inhabit.
Dot sensitivity analysis of ferromagnetic materials for topology optimization in an axi-symmetric magnetostatic system
Authors: Hong SeungGeon , Lee Kang Hyouk , Park Il Han 
Published: April 2019

Purpose
The purpose of this paper is to propose dot sensitivity analysis of ferromagnetic materials for topology optimization in an axi-symmetric magnetostatic system.

Design/methodology/approach
The dot sensitivity formula for the axi-symmetric system is derived as a closed form using the continuum shape sensitivity formula. The dot sensitivity method is combined with the level set method to perform topology optimization.

Findings
Derived dot sensitivity analysis can generate a ferromagnetic ring torus in a vacant region. Thus, an initial design is not needed for the design material. Two design problems are tested to demonstrate the usefulness of dot sensitivity.

Originality/value
By simultaneously using the shape sensitivity and dot sensitivity, in axi-symmetric magnetic system, the design space is expanded and it includes the interface and the inside of the vacant region. This property can reduce the possibility of local optimum convergence.
Effects of authentic leadership on work–family balance in China
Authors: Lyu Yijing , Wang Minmin , Le Jiaqi , Kwan Ho Kwong 
Published: April 2019

PurposeThe purpose of this paper is to examine the effects of authentic leadership on the work–family balance (WFB) of followers by focusing on the mediating roles of leader–member exchange (LMX) and work-to-family enrichment (WFE) and the moderating role of traditionality in China.Design/methodology/approachData were collected using field survey research design. Participants included 206 employees in a pharmaceutical company in China.FindingsThe results indicate that LMX and WFE sequentially mediated the positive relationship between authentic leadership and WFB. In addition, traditionality strengthened the relationship between authentic leadership and LMX.Research limitations/implicationsThis study contributes to the integration of authentic leadership literature and the WFB model. This research also indicates that authentic leadership is a source of enhancing employees’ WFB. However, data are correlational and cross-sectional, which limits the ability to draw causal relationships.Practical implicationsThe findings reveal that authentic leadership is effective in inducing followers’ WFB. The value of traditionality can strengthen the effect of authentic leadership.Originality/valueThis study addresses unexplored theoretical predictions and provides new directions for authentic leadership and work–family research.
Audit committee effectiveness and family firms: impact on performance
Authors: Al-Okaily Jihad , Naueihed Salma 
Published: April 2019

Purpose
The purpose of this paper is to empirically examine the relationship between audit committee characteristics and firm performance, and whether family ownership and involvement moderate the latter relationship.

Design/methodology/approach
Following Anderson and Reeb (2003), this paper estimates a two-way fixed effects model. A sub-sample analysis is used by first examining the impact of audit committee effectiveness on firm performance only in non-family firms and then only in family firms. A fully interacted model was also analyzed in the robustness tests.

Findings
This paper finds that the audit committee characteristics of size, expertise and meeting frequency are positively and significantly related to non-family firm performance, while insignificantly related to family firm performance.

Research limitations/implications
The evidence reported in this paper may be of use for regulators and policy makers pondering corporate governance reforms, as well as for investors, managers and minority shareholders concerned with firm performance and valuation.

Originality/value
To the best of the authors’ knowledge, this is the first study of its kind to examine the moderating effect of family control and involvement on the relationship between firm performance and audit committee effectiveness in terms of size, expertise and meeting frequency.