bluuebunny/crossref_metadata_2025_split huggingface dataset:
On the enlargement of habitable zones around binary stars in hostile environments
Authors: Georgakarakos Nikolaos , Eggl Siegfried 
Published: June 2019

ABSTRACT
We investigate the hypothesis that the size of the habitable zone around hardened binaries in dense star-forming regions increases. Our results indicate that this hypothesis is essentially incorrect. Although certain binary star configurations permit extended habitable zones, such set-ups typically require all orbits in a system to be near-circular. In all other cases, planets can only remain habitable if they display an extraordinarily high climate inertia.
Tidal disruption event rates in galaxy merger remnants
Authors: Pfister Hugo , Bar-Or Ben , Volonteri Marta , Dubois Yohan , Capelo Pedro R 
Published: June 2019

ABSTRACT
The rate of tidal disruption events (TDEs) depends sensitively on the stellar properties of the central galactic regions. Simulations show that galaxy mergers cause gas inflows, triggering nuclear starbursts, increasing the central stellar density. Motivated by these numerical results, and by the observed overrepresentation of post-starburst galaxies among TDE hosts, we study the evolution of the TDE rate in high-resolution hydrodynamical simulations of a galaxy merger, in which we capture the evolution of the stellar density around the massive black holes (BHs). We apply analytical estimates of the loss-cone theory, using the stellar density profiles from simulations, to estimate the time evolution of the TDE rate. At the second pericentre, a nuclear starburst enhances the stellar density around the BH in the least massive galaxy, leading to an enhancement of the TDE rate around the secondary BH, although the magnitude and the duration of the increase depend on the stochasticity of star formation on very small scales. The central stellar density around the primary BH remains instead fairly constant, and so is its TDE rate. After the formation of the binary, the stellar density decreases, and so does the TDE rate.
The role of galectin-3 in spermatozoa-zona pellucida binding and its association with fertilization in vitro
Authors: Mei Si , Chen Panyu , Lee Cheuk-Lun , Zhao Weie , Wang Ying , Lam Kevin K W , Ho Pak-Chung , Yeung William S B , Fang Cong , Chiu Philip C N 
Published: June 2019

AbstractHuman spermatozoa can fertilize an oocyte only after post-testicular maturation and capacitation. These processes involve dynamic modification and reorganization of the sperm plasma membrane, which allow them to bind to the zona pellucida (ZP) of the oocyte. Defective sperm-ZP binding is one of the major causes of male subfertility. Galectin-3 is a secretory lectin in human seminal plasma well known for its action on cell adhesion. The aim of this study was to determine the role of galectin-3 in spermatozoa-ZP interaction and its association with fertilization rate in clinical assisted reproduction. Our studies revealed that the acrosomal region of ejaculated and capacitated spermatozoa possess strong galectin-3 immunoreactivity, which is much stronger than that of epididymal spermatozoa. Expression of galectin-3 can also be detected on seminal plasma-derived extracellular vesicles (EVs) and can be transferred to the sperm surface. Blocking of sperm surface galectin-3 function by antibody or carbohydrate substrate reduced the ZP-binding capacity of spermatozoa. Purified galectin-3 is capable of binding to ZP, indicating that galectin-3 may serve as a cross-linking bridge between ZP glycans and sperm surface glycoproteins. Galectin-3 levels in seminal plasma-derived EVs were positively associated with fertilization rates. These results suggest that galectin-3 in EVs is transferred to the sperm surface during post-testicular maturation and plays a crucial role in spermatozoa-ZP binding after capacitation. Reduced galectin-3 expression in seminal plasma-derived EVs may be a cause behind a low fertilization rate. Further studies with more clinical samples are required to confirm the relationship between galectin-3 levels and IVF outcomes.
A connection between reversible tyrosine phosphorylation and SNARE complex disassembly activity of N-ethylmaleimide-sensitive factor unveiled by the phosphomimetic mutant N-ethylmaleimide-sensitive factor-Y83E
Authors: Ruete María Celeste , Zarelli Valeria Eugenia Paola , Masone Diego , de Paola Matilde , Bustos Diego Martín , Tomes Claudia Nora 
Published: June 2019

Abstract
N-ethylmaleimide-sensitive factor (NSF) disassembles fusion-incompetent cis soluble-NSF attachment protein receptor (SNARE) complexes making monomeric SNAREs available for subsequent trans pairing and fusion. In most cells the activity of NSF is constitutive, but in Jurkat cells and sperm it is repressed by tyrosine phosphorylation; the phosphomimetic mutant NSF–Y83E inhibits secretion in the former. The questions addressed here are if and how the NSF mutant influences the configuration of the SNARE complex. Our model is human sperm, where the initiation of exocytosis (acrosome reaction (AR)) de-represses the activity of NSF through protein tyrosine phosphatase 1B (PTP1B)-mediated dephosphorylation. We developed a fluorescence microscopy-based method to show that capacitation increased, and challenging with an AR inducer decreased, the number of cells with tyrosine-phosphorylated PTP1B substrates in the acrosomal domain. Results from bioinformatic and biochemical approaches using purified recombinant proteins revealed that NSF–Y83E bound PTP1B and thereupon inhibited its catalytic activity. Mutant NSF introduced into streptolysin O-permeabilized sperm impaired cis SNARE complex disassembly, blocking the AR; subsequent addition of PTP1B rescued exocytosis. We propose that NSF–Y83E prevents endogenous PTP1B from dephosphorylating sperm NSF, thus maintaining NSF’s activity in a repressed mode and the SNARE complex unable to dissociate. The contribution of this paper to the sperm biology field is the detection of PTP1B substrates, one of them likely being NSF, whose tyrosine phosphorylation status varies during capacitation and the AR. The contribution of this paper to the membrane traffic field is to have generated direct evidence that explains the dominant-negative role of the phosphomimetic mutant NSF–Y83E.
Limits to a classic paradigm: most transcription factors in E. coli regulate genes involved in multiple biological processes
Authors: Ledezma-Tejeida Daniela , Altamirano-Pacheco Luis , Fajardo Vicente , Collado-Vides Julio 
Published: June 2019

AbstractTranscription factors (TFs) are important drivers of cellular decision-making. When bacteria encounter a change in the environment, TFs alter the expression of a defined set of genes in order to adequately respond. It is commonly assumed that genes regulated by the same TF are involved in the same biological process. Examples of this are methods that rely on coregulation to infer function of not-yet-annotated genes. We have previously shown that only 21% of TFs involved in metabolism regulate functionally homogeneous genes, based on the proximity of the gene products’ catalyzed reactions in the metabolic network. Here, we provide more evidence to support the claim that a 1-TF/1-process relationship is not a general property. We show that the observed functional heterogeneity of regulons is not a result of the quality of the annotation of regulatory interactions, nor the absence of protein–metabolite interactions, and that it is also present when function is defined by Gene Ontology terms. Furthermore, the observed functional heterogeneity is different from the one expected by chance, supporting the notion that it is a biological property. To further explore the relationship between transcriptional regulation and metabolism, we analyzed five other types of regulatory groups and identified complex regulons (i.e. genes regulated by the same combination of TFs) as the most functionally homogeneous, and this is supported by coexpression data. Whether higher levels of related functions exist beyond metabolism and current functional annotations remains an open question.
Infratentorial Supracerebellar Approach for Resection of Midbrain Cavernous Malformation: 3-Dimensional Operative Video
Authors: Patel Krunal , Budohoski Karol P , Olijnyk Leonardo Desessards , Bulstrode Harry , Santarius Thomas , Kirollos Ramez W , Trivedi Rikin A 
Published: June 2019

Abstract
Cavernous malformations (cavernomas) of the brain stem with recurrent hemorrhage may be amenable to microsurgical resection if they are present close to the surface. The risks of surgery need to be balanced with the natural history of the lesion and the accumulation of neurological deficits and risk to life with multiple hemorrhages. In this 3D operative video, we illustrate the technique for the resection of a dorsally located midbrain cavernous malformation.
Informed consent was obtained for this procedure. The cavernoma is accessed with the use of a supracerebellar infratentorial approach. The infratentorial craniotomy and coagulation of the superior vermian veins is shown. A description is provided of the use of hemosiderin staining and the intercollicular relative “safe zone”
1
as landmarks for the neurotomy. The technique of cavernoma dissection from the surrounding gliotic plane is shown and described.
In this case, the patient required prolonged rehabilitation but fully recovered without residual deficit 1 yr following surgery.
Financial Frictions and the Great Productivity Slowdown
Authors: Duval Romain , Hong Gee Hee , Timmer Yannick 
Published: June 2019

Abstract
We study the role of financial frictions for productivity. Using a rich cross-country firm-level data, we exploit variation in preexisting exposure to the 2008 global financial crisis to study the post-crisis productivity slowdown. Firms with weaker precrisis balance sheets experienced a highly persistent decline in post-crisis total factor productivity growth relative to their less vulnerable counterparts, accounting for about one-third of the within-firm productivity slowdown. This decline was larger for firms that faced a more severe tightening of credit conditions. Financially fragile firms cut back on innovation activities, one channel through which financial frictions weakened post-crisis productivity growth.
Domain-invariant features for mechanism of action prediction in a multi-cell-line drug screen
Authors: Boyd Joseph C. , Pinheiro Alice , Del Nery Elaine , Reyal Fabien , Walter Thomas 
Published: June 2019

AbstractHigh Content Screening is an important tool in drug discovery and characterisation. Often, high content drug screens are performed on one single cell line. Yet, a single cell line cannot be thought of as a perfect disease model. Many diseases feature an important molecular heterogeneity. Consequently, a drug may be effective against one molecular subtype of a disease, but less so against another. To characterise drugs with respect to their effect not only on one cell line but on a panel of cell lines is therefore a promising strategy to streamline the drug discovery process. The contribution of this paper is twofold. First, we investigate whether we can predict drug mechanism of action (MOA) at the molecular level without optimisation of the MOA classes to the screen specificities. To this end, we benchmark a set of algorithms within a conventional pipeline, and evaluate their MOA prediction performance according to a statistically rigorous framework. Second, we extend this conventional pipeline to the simultaneous analysis of multiple cell lines, each manifesting potentially different morphological baselines. For this, we propose multitask autoencoders, including a domain-adaptive model used to construct domain-invariant feature representations across cell lines. We apply these methods to a pilot screen of two triple negative breast cancer cell lines as models for two different molecular subtypes of the disease.
methylSCOPA and META-methylSCOPA: software for the analysis and aggregation of epigenome-wide association studies of multiple correlated phenotypes
Authors: Draisma Harmen , Liu Jun , Pupko Igor , Demirkan Ayşe , Balkhiyarova Zhanna , Morris Andrew P , Magi Reedik , Wielscher Matthias , Hassan Saqib , van Duijn Cornelia M. , Sebert Sylvain , Jarvelin Marjo-Riitta , Kaakinen Marika , Prokopenko Inga 
Published: June 2019

AbstractBackgroundMulti-phenotype genome-wide association studies (MP-GWAS) of correlated traits have greater power to detect genotype–phenotype associations than single-trait GWAS. However, no multi-phenotype analysis method exists for epigenome-wide association studies (EWAS).ResultsWe extended the SCOPA approach developed by us to “methylSCOPA” software in C++ by ‘reversely’ regressing DNA hyper/hypo-methylation information on a linear combination of phenotypes. We evaluated two models of association between DNA methylation and fasting glucose (FG) and insulin (FI) levels: Model 1, including FG, FI, and three measured potential confounders (body mass index [BMI], fasting serum triglyceride levels [TG], and waist/hip ratio [WHR]), and Model 2, including FG and FI corrected for the effects of BMI, TG, and WHR. Both models were additionally corrected for participant sex and smoking status (current/ever/never). We meta-analyzed the cohort-specific MP-EWAS results with our novel software META-methylSCOPA, mapped genomic locations to CGCh37/hg19, and adoptedP<1×10−7to denote epigenome-wide significance. We used the Illumina Infinium HumanMethylation450K BeadChip array data from the Northern Finland Birth Cohorts (NFBC) 1966/1986. We quality-controlled the data, regressed out the effects of measured potential confounders, and normalized the methylation signal intensity and FI data. The MP-EWAS included data for 643/457 individuals from NFBC1966 and NFBC1986, respectively (total N=1,100).In Model 1, we detected epigenome-wide significant association in the MP-EWAS meta-analysis at cg13708645 (chr12:121,974,305;P=1.2×10−8) withinKDM2Bgene. Single-trait effects withinKDM2Bwere on FI, BMI, and WHR. Model with effect on BMI and WHR showed the strongest association at this locus, while effect on FI in single-phenotype analysis was driven by the effect of adiposity. In Model 2, the strongest association was at cg05063096 (chr3:143,689,810;P=2.3×10−7) annotated toC3orf58with strongest effect on FI in single-trait analysis and multi-phenotype effect on FI and WHI within Model 1.We characterized the effects of established EWAS loci for diabetes and its risk factors and detected suggestive (p<0.01) associations at six markers includingPHGDH, TXNIP, SLC7A11, CPT1A, MYO5CandABCG1, through the dissection of the multi-phenotype effects in Model 1.ConclusionsWe implemented MP-EWAS in methylSCOPA and demonstrated its enhanced power over single-trait EWAS for correlated phenotypes in large-scale data.
Phenotypic plasticity as a mechanism of cave colonization and adaptation
Authors: Bilandžija Helena , Hollifield Breanna , Steck Mireille , Meng Guanliang , Ng Mandy , Koch Andrew D. , Gračan Romana , Ćetković Helena , Porter Megan L. , Renner Kenneth J. , Jeffery William R. 
Published: June 2019

ABSTRACTA widely accepted model for the evolution of cave animals posits colonization by surface ancestors followed by the acquisition of adaptations over many generations. However, the speed of cave adaptation in some species suggests mechanisms operating over shorter timescales. To address these mechanisms, we used Astyanax mexicanus, a teleost with ancestral surface morphs (surface fish, SF) and derived cave morphs (cavefish, CF). We exposed SF to completely dark conditions and identified numerous altered traits at both the gene expression and phenotypic levels. Remarkably, most of these alterations mimicked CF phenotypes. Our results indicate that cave-related traits can appear within a single generation by phenotypic plasticity. In the next generation, plasticity can be further refined. The initial plastic responses are random in adaptive outcome but may determine the subsequent course of evolution. Our study suggests that phenotypic plasticity contributes to the rapid evolution of cave-related traits in A. mexicanus.
Enhanced efficacy of vaccination with vaccinia virus in old versus young mice
Authors: Shmeleva Evgeniya V. , Smith Geoffrey L. , Ferguson Brian J. 
Published: June 2019

AbstractImmunosenescence is believed to be responsible for poor vaccine efficacy in the elderly. To overcome this difficulty, research into vaccination strategies and the mechanisms of immune responses to vaccination is required. By analyzing the innate and adaptive immune responses to vaccination with vaccinia virus (VACV) in mice of different age groups, we found that immune cell recruitment, production of cytokines/chemokines and control of viral replication at the site of intradermal vaccination were preserved in aged mice and were comparable with younger groups. Analysis of cervical draining lymph nodes (dLN) collected after vaccination showed that numbers of germinal center B cells and follicular T helper cells were similar across different age groups. The number of VACV-specific CD8 T cells in the spleen and the levels of serum neutralizing antibodies 1 month after vaccination were also comparable across all age groups. However, following intranasal challenge of vaccinated mice, body weight loss was lower and virus was cleared more rapidly in aged mice than in younger animals. In conclusion, vaccination with VACV can induce an effective immune response and stronger protection in elderly animals. Thus, the development of recombinant VACV-based vaccines against different infectious diseases should be considered as a strategy for improving vaccine immunogenicity and efficacy in the elderly.
Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis
Authors: Liu Xinquan , Ghosh Debadyuti 
Published: June 2019

AbstractThe RAS family of oncogenes (KRAS, HRAS, NRAS) are the most frequent mutations in cancers and regulate key signaling pathways that drive tumor progression. As a result, drug delivery targeting RAS-driven tumors has been a long-standing challenge in cancer therapy. Mutant RAS activates cancer cells to actively take up nutrients, including glucose, lipids, and albumin, via macropinocytosis to fulfill their energetic requirements to survive and proliferate. Here, we exploit this mechanism to deliver nanoparticles in cancer cells harboring activating KRAS mutations. We have synthesized stable albumin nanoparticles that demonstrate significantly greater uptake in cancer cells with activating mutations of KRAS than monomeric albumin (i.e. dissociated form of clinically-used nab-paclitaxel). From pharmacological inhibition and semi-quantitative fluorescent microscopy studies, these nanoparticles exhibit significantly increased uptake in mutant KRAS cancer cells than wild-type KRAS cells by macropinocytosis. Importantly, we demonstrate that their uptake is driven by KRAS. This nanoparticle-based strategy targeting RAS-driven macropinocytosis is a facile approach towards improved delivery into KRAS-driven cancers.
Reconsidering electrophysiological markers of response inhibition in light of trigger failures in the stop-signal task
Authors: Skippen P , Fulham W. R , Michie P.T , Matzke D , Heathcote A , Karayanidis F 
Published: June 2019

AbstractWe investigate the neural correlates underpinning response inhibition using a parametric ex-Gaussian model of stop-signal task performance, fit with hierarchical Bayesian methods, in a large healthy sample (N=156). The parametric model accounted for trigger failure (i.e., failures to initiate the inhibition process) and returned an SSRT estimate (SSRTEXG3) that was attenuated by ≈65ms compared to traditional non-parametric SSRT estimates (SSRTint). The amplitude and latency of the N1 and P3 event related potential components were derived for both stop-success and stop-failure trials and compared to behavioural estimates derived from traditional (SSRTint) and parametric (SSRTEXG3, trigger failure) models. Both the fronto-central N1 and P3 peaked earlier and were larger for stop-success than stop-failure trials. For stop-failure trials only, N1 peak latency correlated with both SSRT estimates as well as trigger failure and temporally coincided with SSRTEXG3, but not SSRTint. In contrast, P3 peak and onset latency were not associated with any behavioural estimates of inhibition for either trial type. While overall the N1 peaked earlier for stop-success than stop-failure trials, this effect was not found in poor task performers (i.e., high trigger failure/slow SSRT). These findings are consistent with attentional modulation of both the speed and reliability of the inhibition process, but not for poor performers. Together with the absence of any P3 onset latency effect, our findings suggest that attentional mechanisms are important in supporting speeded and reliable inhibition processes required in the stop-signal task.
Highly precise base editing with CC context-specificity using engineered human APOBEC3G-nCas9 fusions
Authors: Liu Zhiquan , Chen Siyu , Shan Huanhuan , Chen Mao , Song Yuning , Lai Liangxue , Li Zhanjun 
Published: June 2019

AbstractCytidine base editors, composed of a cytidine deaminase fused to Cas9 nickase, enable efficient C-to-T conversion in various organisms. However, current base editors can induce unwanted bystander C-to-T conversions when more than one C is present in the activity window of cytidine deaminase, which negatively affects the precision. Here, we develop a new base editor with CC context-specificity using rationally engineered human APOBEC3G, thus significantly reduce unwanted bystander activities. In addition, efficient C-to-T conversion that can further recognize relaxed NG PAMs is achieved by combining an engineered SpCas9-NG variant. These novel base editors with improved precision and targeting scope will expand the toolset for precise gene modification in organisms.
Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver
Authors: Wang Jianye , Hu Bian , Zhao Zhicong , Zhang Haiyan , Zhang He , Zhao Zhenjun , Ma Xiong , Shen Bin , Sun Beicheng , Huang Xingxu , Hou Jiajie , Xia Qiang 
Published: June 2019

AbstractEndoplasmic reticulum (ER) stress-associated cell death is prevalent in various liver diseases. However, the determinant mechanism how hepatocytes survive unresolved stress was still unclear. Interleukin-24 (IL-24) was previously found to promote ER stress-mediated cell death, and yet its expression and function in the liver remained elusive. Here we identified an anti-apoptotic role of IL-24, which transiently accumulated within ER-stressed hepatocytes in a X-box binding protein 1 (XBP1)-dependent manner. Disruption of IL-24 increased cell death in the CCL4- or APAP-challenged mouse liver or Tm-treated hepatocytes. In contrast, pharmaceutical blockade of eukaryotic initiation factor 2α (eIF2α) or genetical ablation of C/EBP homologous protein (CHOP) restored hepatocyte function in the absence of IL-24. In a clinical setting, patients with acute liver failure manifested a profound decrease of hepatic IL-24 expression, which was associated with disease progression. In conclusion, intrinsic hepatocyte IL-24 maintains ER homeostasis by restricting the eIF2α-CHOP pathway-mediated stress signal, which might be exploited as a bio-index for prognosis or therapeutic intervention in patients with liver injury.