bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macitentan in pulmonary hypertension due to left ventricular dysfunction
Authors: Vachiéry Jean-Luc , Delcroix Marion , Al-Hiti Hikmet , Efficace Michela , Hutyra Martin , Lack Gabriela , Papadakis Kelly , Rubin Lewis J. 
Published: February 2018

The MELODY-1 study evaluated macitentan for pulmonary hypertension because of left heart disease (PH-LHD) in patients with combined post- and pre-capillary PH.63 patients with PH-LHD and diastolic pressure gradient ≥7 mmHg and pulmonary vascular resistance (PVR) >3WU were randomised to macitentan 10 mg (n=31) or placebo (n=32) for 12 weeks. The main end-point assessed a composite of significant fluid retention (weight gain ≥5% or ≥5 kg because of fluid overload or parenteral diuretic administration) or worsening in New York Heart Association functional class from baseline to end of treatment. Exploratory end-points included changes in N-terminal pro-brain natriuretic peptide (NT-proBNP) and haemodynamics at week 12.Seven macitentan-treated and four placebo-treated patients experienced significant fluid retention/worsening functional class; treatment difference, 10.08% (95% CI −15.07–33.26; p=0.34). The difference, driven by the fluid retention component, was apparent within the first month. At week 12,versusplacebo, the macitentan group showed no change in PVR, mean right atrial pressure or pulmonary arterial wedge pressure; a non-significant increase in cardiac index (treatment effect 0.4 (95% CI 0.1–0.7) L·min−1·m−2) and decrease in NT-proBNP (0.77 (0.55–1.08)) was observed. Adverse events and serious adverse events were numerically more frequent with macitentanversusplacebo.Macitentan-treated patients were quantitatively more likely to experience significant fluid retentionversusplacebo. Macitentan resulted in no significant changes in any exploratory end-points.
Neurogenic differentiation by hippocampal neural stem and progenitor cells is biased by NFIX expression
Authors: Harris Lachlan , Zalucki Oressia , Clément Olivier , Fraser James , Matuzelski Elise , Oishi Sabrina , Harvey Tracey J. , Burne Thomas H. J. , Heng Julian Ik-Tsen , Gronostajski Richard M. , Piper Michael 
Published: February 2018

ABSTRACT
Our understanding of the transcriptional programme underpinning adult hippocampal neurogenesis is incomplete. In mice, under basal conditions, adult hippocampal neural stem cells (AH-NSCs) generate neurons and astrocytes, but not oligodendrocytes. The factors limiting oligodendrocyte production, however, remain unclear. Here, we reveal that the transcription factor NFIX plays a key role in this process. NFIX is expressed by AH-NSCs, and its expression is sharply upregulated in adult hippocampal neuroblasts. Conditional ablation of Nfix from AH-NSCs, coupled with lineage tracing, transcriptomic sequencing and behavioural studies collectively reveal that NFIX is cell-autonomously required for neuroblast maturation and survival. Moreover, a small number of AH-NSCs also develop into oligodendrocytes following Nfix deletion. Remarkably, when Nfix is deleted specifically from intermediate progenitor cells and neuroblasts using a Dcx-creERT2 driver, these cells also display elevated signatures of oligodendrocyte gene expression. Together, these results demonstrate the central role played by NFIX in neuroblasts within the adult hippocampal stem cell neurogenic niche in promoting the maturation and survival of these cells, while concomitantly repressing oligodendrocyte gene expression signatures.
A genetically encoded fluorescent probe for imaging of oxygenation gradients in living Drosophila
Authors: Lidsky Peter V. , Lukyanov Konstantin A. , Misra Tvisha , Handke Björn , Mishin Alexander S. , Lehner Christian F. 
Published: February 2018

ABSTRACT
Oxygen concentrations vary between tissues of multicellular organisms and change under certain physiological or pathological conditions. Multiple methods have been developed for measuring oxygenation of biological samples in vitro and in vivo. However, most require complex equipment, are laborious and have significant limitations. Here we report that oxygen concentration determines the choice between two maturation pathways of DsRed FT (Timer). At high oxygen levels, this DsRed derivate matures predominantly into a red fluorescent isoform. By contrast, a green fluorescent isoform is favored by low oxygen levels. Ratiometric analysis of green and red fluorescence after a pulse of Timer expression in Drosophila larvae provides a record of the history of tissue oxygenation during a subsequent chase period, for the whole animal with single-cell precision. Tissue spreads revealed fine differences in oxygen exposure among different cells of the same organ. We expect that the simplicity and robustness of our approach will greatly impact hypoxia research, especially in small animal models.
ES cell-derived presomitic mesoderm-like tissues for analysis of synchronized oscillations in the segmentation clock
Authors: Matsumiya Marina , Tomita Takehito , Yoshioka-Kobayashi Kumiko , Isomura Akihiro , Kageyama Ryoichiro 
Published: February 2018

ABSTRACT
Somites are periodically formed by segmentation of the anterior parts of the presomitic mesoderm (PSM). In the mouse embryo, this periodicity is controlled by the segmentation clock gene Hes7, which exhibits wave-like oscillatory expression in the PSM. Despite intensive studies, the exact mechanism of such synchronous oscillatory dynamics of Hes7 expression still remains to be analyzed. Detailed analysis of the segmentation clock has been hampered because it requires the use of live embryos, and establishment of an in vitro culture system would facilitate such analyses. Here, we established a simple and efficient method to generate mouse ES cell-derived PSM-like tissues, in which Hes7 expression oscillates like traveling waves. In these tissues, Hes7 oscillation is synchronized between neighboring cells, and the posterior-anterior axis is self-organized as the central-peripheral axis. This method is applicable to chemical-library screening and will facilitate the analysis of the molecular nature of the segmentation clock.
The ELMO-MBC complex and RhoGAP19D couple Rho family GTPases during mesenchymal-to-epithelial-like transitions
Authors: Toret Christopher P. , Shivakumar Pruthvi C. , Lenne Pierre-François , Le Bivic Andre 
Published: February 2018

ABSTRACT
Many metazoan developmental processes require cells to transition between migratory mesenchymal- and adherent epithelial-like states. These transitions require Rho GTPase-mediated actin rearrangements downstream of integrin and cadherin pathways. A regulatory toolbox of GEF and GAP proteins precisely coordinates Rho protein activities, yet defining the involvement of specific regulators within a cellular context remains a challenge due to overlapping and coupled activities. Here, we demonstrate that Drosophila dorsal closure is a powerful model for Rho GTPase regulation during transitions from leading edges to cadherin contacts. During these transitions, a Rac GEF ELMO-MBC complex regulates both lamellipodia and Rho1-dependent, actomyosin-mediated tension at initial cadherin contacts. Moreover, the Rho GAP RhoGAP19D controls Rac and Rho GTPases during the same processes and genetically regulates the ELMO-MBC complex. This study presents a fresh framework with which to understand the inter-relationship between GEF and GAP proteins that tether Rac and Rho cycles during developmental processes.
Face morphogenesis is promoted by Pbx-dependent EMT via regulation of Snail1 during frontonasal prominence fusion
Authors: Losa Marta , Risolino Maurizio , Li Bingsi , Hart James , Quintana Laura , Grishina Irina , Yang Hui , Choi Irene F. , Lewicki Patrick , Khan Sameer , Aho Robert , Feenstra Jennifer , Vincent C. Theresa , Brown Anthony M. C. , Ferretti Elisabetta , Williams Trevor , Selleri Licia 
Published: February 2018

ABSTRACT
Human cleft lip with or without cleft palate (CL/P) is a common craniofacial abnormality caused by impaired fusion of the facial prominences. We have previously reported that, in the mouse embryo, epithelial apoptosis mediates fusion at the seam where the prominences coalesce. Here, we show that apoptosis alone is not sufficient to remove the epithelial layers. We observed morphological changes in the seam epithelia, intermingling of cells of epithelial descent into the mesenchyme and molecular signatures of epithelial-mesenchymal transition (EMT). Utilizing mouse lines with cephalic epithelium-specific Pbx loss exhibiting CL/P, we demonstrate that these cellular behaviors are Pbx dependent, as is the transcriptional regulation of the EMT driver Snail1. Furthermore, in the embryo, the majority of epithelial cells expressing high levels of Snail1 do not undergo apoptosis. Pbx1 loss- and gain-of-function in a tractable epithelial culture system revealed that Pbx1 is both necessary and sufficient for EMT induction. This study establishes that Pbx-dependent EMT programs mediate murine upper lip/primary palate morphogenesis and fusion via regulation of Snail1. Of note, the EMT signatures observed in the embryo are mirrored in the epithelial culture system.
Mesenchymal Wnt/β-catenin signaling limits tooth number
Authors: Järvinen Elina , Shimomura-Kuroki Junko , Balic Anamaria , Jussila Maria , Thesleff Irma 
Published: February 2018

ABSTRACT
Tooth agenesis is one of the predominant developmental anomalies in humans, usually affecting the permanent dentition generated by sequential tooth formation and, in most cases, caused by mutations perturbing epithelial Wnt/β-catenin signaling. In addition, loss-of-function mutations in the Wnt feedback inhibitor AXIN2 lead to human tooth agenesis. We have investigated the functions of Wnt/β-catenin signaling during sequential formation of molar teeth using mouse models. Continuous initiation of new teeth, which is observed after genetic activation of Wnt/β-catenin signaling in the oral epithelium, was accompanied by enhanced expression of Wnt antagonists and a downregulation of Wnt/β-catenin signaling in the dental mesenchyme. Genetic and pharmacological activation of mesenchymal Wnt/β-catenin signaling negatively regulated sequential tooth formation, an effect partly mediated by Bmp4. Runx2, a gene whose loss-of-function mutations result in sequential formation of supernumerary teeth in the human cleidocranial dysplasia syndrome, suppressed the expression of Wnt inhibitors Axin2 and Drapc1 in dental mesenchyme. Our data indicate that increased mesenchymal Wnt signaling inhibits the sequential formation of teeth, and suggest that Axin2/Runx2 antagonistic interactions modulate the level of mesenchymal Wnt/β-catenin signaling, underlying the contrasting dental phenotypes caused by human AXIN2 and RUNX2 mutations.
Lsd1 interacts with cMyb to demethylate repressive histone marks and maintain inner ear progenitor identity
Authors: Ahmed Mohi , Streit Andrea 
Published: February 2018

ABSTRACT
During development, multipotent progenitor cells must maintain their identity while retaining the competence to respond to new signalling cues that drive cell fate decisions. This depends on both DNA-bound transcription factors and surrounding histone modifications. Here, we identify the histone demethylase Lsd1 as a crucial component of the molecular machinery that preserves progenitor identity in the developing ear prior to lineage commitment. Although Lsd1 is mainly associated with repressive complexes, we show that, in ear precursors, it is required to maintain active transcription of otic genes. We reveal a novel interaction between Lsd1 and the transcription factor cMyb, which in turn recruits Lsd1 to the promoters of key ear transcription factors. Here, Lsd1 prevents the accumulation of repressive H3K9me2, while allowing H3K9 acetylation. Loss of Lsd1 function causes rapid silencing of active promoters and loss of ear progenitor genes, and shuts down the entire ear developmental programme. Our data suggest that Lsd1-cMyb acts as a co-activator complex that maintains a regulatory module at the top of the inner ear gene network.
F-box proteins Pof3 and Pof1 regulate Wee1 degradation and mitotic entry in fission yeast
Authors: Qiu Cui , Yi Yuan-yuan , Lucena Rafael , Wu Meng-juan , Sun Jia-hao , Wang Xi , Jin Quan-wen , Wang Yamei 
Published: February 2018

ABSTRACT
The key cyclin-dependent kinase Cdk1 (Cdc2) promotes irreversible mitotic entry, mainly by activating the phosphatase Cdc25 while suppressing the tyrosine kinase Wee1. Wee1 needs to be downregulated at the onset of mitosis to ensure rapid activation of Cdk1. In human somatic cells, one mechanism of suppressing Wee1 activity is mediated by ubiquitylation-dependent proteolysis through the Skp1/Cul1/F-box protein (SCF) ubiquitin E3 ligase complex. This mechanism is believed to be conserved from yeasts to humans. So far, the best-characterized human F-box proteins involved in recognition of Wee1 are β-TrCP (BTRCP) and Tome-1 (CDCA3). Although fission yeast Wee1 was the first identified member of its conserved kinase family, the F-box proteins involved in recognition and ubiquitylation of Wee1 have not been identified in this organism. In this study, our screen using Wee1–Renilla luciferase as the reporter revealed that two F-box proteins, Pof1 and Pof3, are required for downregulating Wee1 and are possibly responsible for recruiting Wee1 to SCF. Our genetic analyses supported a functional relevance between Pof1 and Pof3 and the rate of mitotic entry, and Pof3 might play a major role in this process.
Non-equivalence of nuclear import among nuclei in multinucleated skeletal muscle cells
Authors: Cutler Alicia A. , Jackson Jennifer B. , Corbett Anita H. , Pavlath Grace K. 
Published: February 2018

ABSTRACT
Skeletal muscle is primarily composed of large myofibers containing thousands of post-mitotic nuclei distributed throughout a common cytoplasm. Protein production and localization in specialized myofiber regions is crucial for muscle function. Myonuclei differ in transcriptional activity and protein accumulation, but how these differences among nuclei sharing a cytoplasm are achieved is unknown. Regulated nuclear import of proteins is one potential mechanism for regulating transcription spatially and temporally in individual myonuclei. The best-characterized nuclear localization signal (NLS) in proteins is the classical NLS (cNLS), but many other NLS motifs exist. We examined cNLS and non-cNLS reporter protein import using multinucleated muscle cells generated in vitro, revealing that cNLS and non-cNLS nuclear import differs among nuclei in the same cell. Investigation of cNLS nuclear import rates in isolated myofibers ex vivo confirmed differences in nuclear import rates among myonuclei. Analyzing nuclear import throughout myogenesis revealed that cNLS and non-cNLS import varies during differentiation. Taken together, our results suggest that both spatial and temporal regulation of nuclear import pathways are important in muscle cell differentiation and protein regionalization in myofibers.
Tight junctions negatively regulate mechanical forces applied to adherens junctions in vertebrate epithelial tissue
Authors: Hatte Guillaume , Prigent Claude , Tassan Jean-Pierre 
Published: February 2018

ABSTRACT
Epithelia are layers of polarised cells tightly bound to each other by adhesive contacts. Epithelia act as barriers between an organism and its external environment. Understanding how epithelia maintain their essential integrity while remaining sufficiently plastic to allow events such as cytokinesis to take place is a key biological problem. In vertebrates, the remodelling and reinforcement of adherens junctions maintains epithelial integrity during cytokinesis. The involvement of tight junctions in cell division, however, has remained unexplored. Here, we examine the role of tight junctions during cytokinesis in the epithelium of the Xenopus laevis embryo. Depletion of the tight junction-associated proteins ZO-1 and GEF-H1 leads to altered cytokinesis duration and contractile ring geometry. Using a tension biosensor, we show that cytokinesis defects originate from misregulation of tensile forces applied to adherens junctions. Our results reveal that tight junctions regulate mechanical tension applied to adherens junctions, which in turn impacts cytokinesis.
This article has an associated First Person interview with the first author of the paper.
The ARF guanine nucleotide exchange factor GBF1 is targeted to Golgi membranes through a PIP-binding domain
Authors: Meissner Justyna M. , Bhatt Jay M. , Lee Eunjoo , Styers Melanie L. , Ivanova Anna A. , Kahn Richard A. , Sztul Elizabeth 
Published: February 2018

ABSTRACT
ADP-ribosylation factors (ARF) GTPases are activated by guanine nucleotide exchange factors (GEFs) to support cellular homeostasis. Key to understanding spatio-temporal regulation of ARF signaling is the mechanism of GEF recruitment to membranes. Small GEFs are recruited through phosphoinositide (PIP) binding by a pleckstrin homology (PH) domain downstream from the catalytic Sec7 domain (Sec7d). The large GEFs lack PH domains, and their recruitment mechanisms are poorly understood. We probed Golgi recruitment of GBF1, a GEF catalyzing ARF activation required for Golgi homeostasis. We show that the homology downstream of Sec7d-1 (HDS1) regulates Golgi recruitment of GBF1. We document that GBF1 binds phosphoinositides, preferentially PI3P, PI4P and PI(4,5)P2, and that lipid binding requires the HDS1 domain. Mutations within HDS1 that reduce GBF1 binding to specific PIPs in vitro inhibit GBF1 targeting to Golgi membranes in cells. Our data imply that HDS1 and PH domains are functionally analogous in that each uses lipid-based membrane information to regulate GEF recruitment. Lipid-based recruitment of GBF1 extends the paradigm of lipid regulation to small and large GEFs and suggests that lipid-based mechanisms evolved early during GEF diversification.
This article has an associated First Person interview with the first author of the paper.
Abscisic acid – an anti-angiogenic phytohormone that modulates the phenotypical plasticity of endothelial cells and macrophages
Authors: Chaqour Julienne , Lee Sangmi , Ravichandra Aashreya , Chaqour Brahim 
Published: February 2018

ABSTRACT
Abscisic acid (ABA) has shown anti-inflammatory and immunoregulatory properties in preclinical models of diabetes and inflammation. Herein, we studied the effects of ABA on angiogenesis, a strictly controlled process that, when dysregulated, leads to severe angiogenic disorders including vascular overgrowth, exudation, cellular inflammation and organ dysfunction. By using a 3D sprouting assay, we show that ABA effectively inhibits migration, growth and expansion of endothelial tubes without affecting cell viability. Analyses of the retinal vasculature in developing normoxic and hyperoxic mice challenged by oxygen toxicity reveal that exogenously administered ABA stunts the development and regeneration of blood vessels. In these models, ABA downregulates endothelial cell (EC)-specific growth and migratory genes, interferes with tip and stalk cell specification, and hinders the function of filopodial protrusions required for precise guidance of vascular sprouts. In addition, ABA skews macrophage polarization towards the M1 phenotype characterized by anti-angiogenic marker expression. In accordance with this, ABA treatment accelerates macrophage-induced programmed regression of fetal blood vessels. These findings reveal protective functions of ABA against neovascular growth through modulation of EC and macrophage plasticity, suggesting the potential utility of ABA as a treatment in vasoproliferative diseases.
Recent insights into the cellular and molecular determinants of aging
Authors: Ruan Linhao , Zhang Xi , Li Rong 
Published: February 2018

ABSTRACT
Aging is the gradual decline of physiological functions and organismal fitness, which leads to age-dependent fitness loss, diseases and eventually mortality. Understanding the cause of aging constitutes one of most intriguing areas of research in biology. On both the cellular and molecular levels, it has been hypothesized that there are aging determinants to control the onset and progression of aging, including the loss of beneficial components and accumulation of detrimental factors. This Review highlights the recent advance in identifying various factors that affect the aging process, focusing on how these determinants affect the lifespan and fitness of a cell or organism. With more and more aging determinants revealed, further understanding about their functions and interconnections could enable the development of specific intervention to extend healthy lifespan and reduce the risk of age-related diseases.
The importance of membrane microdomains for bile salt-dependent biliary lipid secretion
Authors: Eckstein Johannes , Holzhütter Hermann-Georg , Berndt Nikolaus 
Published: February 2018

ABSTRACT
Alternative models explaining the biliary lipid secretion at the canalicular membrane of hepatocytes exist: successive lipid extraction by preformed bile salt micelles, or budding of membrane fragments with formation of mixed micelles. To test the feasibility of the latter mechanism, we developed a mathematical model that describes the formation of lipid microdomains in the canalicular membrane. Bile salt monomers intercalate into the external hemileaflet of the canalicular membrane, to form a rim to liquid disordered domain patches that then pinch off to form nanometer-scale mixed micelles. Model simulations perfectly recapitulate the measured dependence of bile salt-dependent biliary lipid extraction rates upon modulation of the membrane cholesterol (lack or overexpression of the cholesterol transporter Abcg5–Abcg8) and phosphatidylcholine (lack of Mdr2, also known as Abcb4) content. The model reveals a strong dependence of the biliary secretion rate on the protein density of the membrane. Taken together, the proposed model is consistent with crucial experimental findings in the field and provides a consistent explanation of the central molecular processes involved in bile formation.
H2AFX and MDC1 promote maintenance of genomic integrity in male germ cells
Authors: Testa Erika , Nardozi Daniela , Antinozzi Cristina , Faieta Monica , Di Cecca Stefano , Caggiano Cinzia , Fukuda Tomoyuki , Bonanno Elena , Zhenkun Lou , Maldonado Andros , Roig Ignasi , Di Giacomo Monica , Barchi Marco 
Published: February 2018

ABSTRACT
In somatic cells, H2afx and Mdc1 are close functional partners in DNA repair and damage response. However, it is not known whether they are also involved in the maintenance of genome integrity in meiosis. By analyzing chromosome dynamics in H2afx−/− spermatocytes, we found that the synapsis of autosomes and X-Y chromosomes was impaired in a fraction of cells. Such defects correlated with an abnormal recombination profile. Conversely, Mdc1 was dispensable for the synapsis of the autosomes and played only a minor role in X-Y synapsis, compared with the action of H2afx. This suggested that those genes have non-overlapping functions in chromosome synapsis. However, we observed that both genes play a similar role in the assembly of MLH3 onto chromosomes, a key step in crossover formation. Moreover, we show that H2afx and Mdc1 cooperate in promoting the activation of the recombination-dependent checkpoint, a mechanism that restrains the differentiation of cells with unrepaired DSBs. This occurs by a mechanism that involves P53. Overall, our data show that, in male germ cells, H2afx and Mdc1 promote the maintenance of genome integrity.
This article has an associated First Person interview with the first author of the paper.