bluuebunny/crossref_metadata_2025_split huggingface dataset:
CCN3 and DLL1 co-regulate osteogenic differentiation of mouse embryonic fibroblasts in a Hey1-dependent manner
Authors: Su Xin , Wei Yalin , Cao Junjie , Wu Xiulin , Mou Daiyong , Luo Jinyong , Li Aifang , Zuo Guo-Wei , Tang Min 
Published: December 2018

AbstractNotch signaling pathway is one of the most important pathways to regulate intercellular signal transduction and is crucial in the regulation of bone regeneration. Nephroblastoma overexpressed (NOV or CCN3) serves as a non-canonical secreted ligand of Notch signaling pathway and its role in the process of osteogenic differentiation of mesenchymal stem cells (MSCs) was undefined. Here we conducted a comprehensive study on this issue. In vivo and in vitro studies have shown that CCN3 significantly inhibited the early and late osteogenic differentiation of mouse embryonic fibroblasts (MEFs), the expression of osteogenesis-related factors, and the subcutaneous ectopic osteogenesis of MEFs in nude mice. In mechanism studies, we found that CCN3 significantly inhibited the expression of BMP9 and the activation of BMP/Smad and BMP/MAPK signaling pathways. There was also a mutual inhibition between CCN3 and DLL1, one of the classic membrane protein ligands of Notch signaling pathway. Additionally, we further found that Hey1, the target gene shared by BMP and Notch signaling pathways, partially reversed the inhibitory effect of CCN3 on osteoblastic differentiation of MEFs. In summary, our findings suggested that CCN3 significantly inhibited the osteogenic differentiation of MEFs. The inhibitory effect of CCN3 was mainly through the inhibition of BMP signaling and the mutual inhibition with DLL1, so as to inhibit the expression of Hey1, the target gene shared by BMP and Notch signaling pathways.
Therapeutic effect of hepatocyte growth factor-overexpressing bone marrow-derived mesenchymal stem cells on CCl4-induced hepatocirrhosis.
Authors: Zhang Yichi , Li Ruini , Rong Weiwei , Han Mingzi , Cui Chenghu , Feng Zhenning , Sun Xiaoli , Jin Shizhu 
Published: December 2018

AbstractHepatocirrhosis is one of the most severe complications of chronic hepatic disease in terms of medical intervention, and the available therapies are limited and not very successful. In this study, bone marrow-derived mesenchymal stem cells (BM-MSCs) from host rats were transduced with an adenoviral vector labelled with green fluorescent protein (EGFP) to overexpress hepatocyte growth factor (HGF). The therapeutic effect of these modified stem cells (HGF-BM-MSC group) transplanted intravenously into hepatocirrhosis model rats treated with CCl4 was evaluated using serological, biochemical and histological approaches. We compared the rats in the HGF-BM-MSC group with those in the other groups (rats treated with BM-MSCs, rats treated with HGF and untreated rats (Controls)) in detail. The localisation of EGFP-tagged BM-MSCs in the injured liver was evaluated using a microscope, and the cells co-expressed hepatocyte nuclear factor 4α, albumin and cytokeratin 18. After treatment for 4 weeks, the HGF-BM-MSC, BM-MSC and HGF groups exhibited increased protein and mRNA levels of hepatocyte nuclear factor 4α, albumin and cytokeratin 18, but decreased levels of aspartate aminotransferase, alanine aminotransferase and total bilirubin. These findings indicate that BM-MSC transplantation and HGF application have great potential for the treatment of hepatocirrhosis.
Polymer morphology and interfacial charge transfer dominate over energy-dependent scattering in organic-inorganic thermoelectrics
Authors: Kumar Pawan , Zaia Edmond W. , Yildirim Erol , Repaka D. V. Maheswar , Yang Shuo-Wang , Urban Jeffrey J. , Hippalgaonkar Kedar 
Published: December 2018

AbstractHybrid (organic-inorganic) materials have emerged as a promising class of thermoelectric materials, achieving power factors (S2σ) exceeding those of either constituent. The mechanism of this enhancement is still under debate, and pinpointing the underlying physics has proven difficult. In this work, we combine transport measurements with theoretical simulations and first principles calculations on a prototypical PEDOT:PSS-Te(Cux) nanowire hybrid material system to understand the effect of templating and charge redistribution on the thermoelectric performance. Further, we apply the recently developed Kang-Snyder charge transport model to show that scattering of holes in the hybrid system, defined by the energy-dependent scattering parameter, remains the same as in the host polymer matrix; performance is instead dictated by polymer morphology manifested in an energy-independent transport coefficient. We build upon this language to explain thermoelectric behavior in a variety of PEDOT and P3HT based hybrids acting as a guide for future work in multiphase materials.
Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia
Authors: Tron Adriana E. , Belmonte Matthew A. , Adam Ammar , Aquila Brian M. , Boise Lawrence H. , Chiarparin Elisabetta , Cidado Justin , Embrey Kevin J. , Gangl Eric , Gibbons Francis D. , Gregory Gareth P. , Hargreaves David , Hendricks J. Adam , Johannes Jeffrey W. , Johnstone Ricky W. , Kazmirski Steven L. , Kettle Jason G. , Lamb Michelle L. , Matulis Shannon M. , Nooka Ajay K. , Packer Martin J. , Peng Bo , Rawlins Philip B. , Robbins Daniel W. , Schuller Alwin G. , Su Nancy , Yang Wenzhan , Ye Qing , Zheng Xiaolan , Secrist J. Paul , Clark Edwin A. , Wilson David M. , Fawell Stephen E. , Hird Alexander W. 
Published: December 2018

AbstractMcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683).
Escherichia coli can survive stress by noisy growth modulation
Authors: Patange Om , Schwall Christian , Jones Matt , Villava Casandra , Griffith Douglas A. , Phillips Andrew , Locke James C. W. 
Published: December 2018

AbstractGene expression can be noisy, as can the growth of single cells. Such cell-to-cell variation has been implicated in survival strategies for bacterial populations. However, it remains unclear how single cells couple gene expression with growth to implement these strategies. Here, we show how noisy expression of a key stress-response regulator, RpoS, allows E. coli to modulate its growth dynamics to survive future adverse environments. We reveal a dynamic positive feedback loop between RpoS and growth rate that produces multi-generation RpoS pulses. We do so experimentally using single-cell, time-lapse microscopy and microfluidics and theoretically with a stochastic model. Next, we demonstrate that E. coli prepares for sudden stress by entering prolonged periods of slow growth mediated by RpoS. This dynamic phenotype is captured by the RpoS-growth feedback model. Our synthesis of noisy gene expression, growth, and survival paves the way for further exploration of functional phenotypic variability.
JunB regulates homeostasis and suppressive functions of effector regulatory T cells
Authors: Koizumi Shin-ichi , Sasaki Daiki , Hsieh Tsung-Han , Taira Naoyuki , Arakaki Nana , Yamasaki Shinichi , Wang Ke , Sarkar Shukla , Shirahata Hiroki , Miyagi Mio , Ishikawa Hiroki 
Published: December 2018

AbstractFoxp3-expressing CD4+ regulatory T (Treg) cells need to differentiate into effector Treg (eTreg) cells to maintain immune homeostasis. T-cell receptor (TCR)-dependent induction of the transcription factor IRF4 is essential for eTreg differentiation, but how IRF4 activity is regulated in Treg cells is still unclear. Here we show that the AP-1 transcription factor, JunB, is expressed in eTreg cells and promotes an IRF4-dependent transcription program. Mice lacking JunB in Treg cells develop multi-organ autoimmunity, concomitant with aberrant activation of T helper cells. JunB promotes expression of Treg effector molecules, such as ICOS and CTLA4, in BATF-dependent and BATF-independent manners, and is also required for homeostasis and suppressive functions of eTreg. Mechanistically, JunB facilitates the accumulation of IRF4 at a subset of IRF4 target sites, including those located near Icos and Ctla4. Thus, JunB is a critical regulator of IRF4-dependent Treg effector programs, highlighting important functions for AP-1 in Treg-mediated immune homeostasis.
Differentiation of primate primordial germ cell-like cells following transplantation into the adult gonadal niche
Authors: Sosa Enrique , Chen Di , Rojas Ernesto J. , Hennebold Jon D. , Peters Karen A. , Wu Zhuang , Lam Truong N. , Mitchell Jennifer M. , Sukhwani Meena , Tailor Ramesh C. , Meistrich Marvin L. , Orwig Kyle E. , Shetty Gunapala , Clark Amander T. 
Published: December 2018

AbstractA major challenge in stem cell differentiation is the availability of bioassays to prove cell types generated in vitro are equivalent to cells in vivo. In the mouse, differentiation of primordial germ cell-like cells (PGCLCs) from pluripotent cells was validated by transplantation, leading to the generation of spermatogenesis and to the birth of offspring. Here we report the use of xenotransplantation (monkey to mouse) and homologous transplantation (monkey to monkey) to validate our in vitro protocol for differentiating male rhesus (r) macaque PGCLCs (rPGCLCs) from induced pluripotent stem cells (riPSCs). Specifically, transplantation of aggregates containing rPGCLCs into mouse and nonhuman primate testicles overcomes a major bottleneck in rPGCLC differentiation. These findings suggest that immature rPGCLCs once transplanted into an adult gonadal niche commit to differentiate towards late rPGCs that initiate epigenetic reprogramming but do not complete the conversion into ENO2-positive spermatogonia.
Lysosomal protease deficiency or substrate overload induces an oxidative-stress mediated STAT3-dependent pathway of lysosomal homeostasis
Authors: Martínez-Fábregas Jonathan , Prescott Alan , van Kasteren Sander , Pedrioli Deena Leslie , McLean Irwin , Moles Anna , Reinheckel Thomas , Poli Valeria , Watts Colin 
Published: December 2018

AbstractDiverse cellular processes depend on the lysosomal protease system but how cells regulate lysosomal proteolytic capacity is only partly understood. We show here that cells can respond to protease/substrate imbalance in this compartment by de novo expression of multiple lysosomal hydrolases. This response, exemplified here either by loss of asparagine endopeptidase (AEP) or other lysosomal cysteine proteases, or by increased endocytic substrate load, is not dependent on the transcription factor EB (TFEB) but rather is triggered by STAT3 activation downstream of lysosomal oxidative stress. Similar lysosomal adaptations are seen in mice and cells expressing a constitutively active form of STAT3. Our results reveal how cells can increase lysosomal protease capacity under ‘fed’ rather than ‘starved’ conditions that activate the TFEB system. In addition, STAT3 activation due to lysosomal stress likely explains the hyperproliferative kidney disease and splenomegaly observed in AEP-deficient mice.
Stabilization of cytokine mRNAs in iNKT cells requires the serine-threonine kinase IRE1alpha
Authors: Govindarajan Srinath , Gaublomme Djoere , Van der Cruyssen Renée , Verheugen Eveline , Van Gassen Sofie , Saeys Yvan , Tavernier Simon , Iwawaki Takao , Bloch Yehudi , Savvides Savvas. N. , Lambrecht Bart N. , Janssens Sophie , Elewaut Dirk , Drennan Michael B. 
Published: December 2018

AbstractActivated invariant natural killer T (iNKT) cells rapidly produce large amounts of cytokines, but how cytokine mRNAs are induced, stabilized and mobilized following iNKT activation is still unclear. Here we show that an endoplasmic reticulum stress sensor, inositol-requiring enzyme 1α (IRE1α), links key cellular processes required for iNKT cell effector functions in specific iNKT subsets, in which TCR-dependent activation of IRE1α is associated with downstream activation of p38 MAPK and the stabilization of preformed cytokine mRNAs. Importantly, genetic deletion of IRE1α in iNKT cells reduces cytokine production and protects mice from oxazolone colitis. We therefore propose that an IRE1α-dependent signaling cascade couples constitutive cytokine mRNA expression to the rapid induction of cytokine secretion and effector functions in activated iNKT cells.
Local and global chromatin interactions are altered by large genomic deletions associated with human brain development
Authors: Zhang Xianglong , Zhang Ying , Zhu Xiaowei , Purmann Carolin , Haney Michael S. , Ward Thomas , Khechaduri Arineh , Yao Jie , Weissman Sherman M. , Urban Alexander E. 
Published: December 2018

AbstractLarge copy number variants (CNVs) in the human genome are strongly associated with common neurodevelopmental, neuropsychiatric disorders such as schizophrenia and autism. Here we report on the epigenomic effects of the prominent large deletion CNVs on chromosome 22q11.2 and on chromosome 1q21.1. We use Hi-C analysis of long-range chromosome interactions, including haplotype-specific Hi-C analysis, ChIP-Seq analysis of regulatory histone marks, and RNA-Seq analysis of gene expression patterns. We observe changes on all the levels of analysis, within the deletion boundaries, in the deletion flanking regions, along chromosome 22q, and genome wide. We detect gene expression changes as well as pronounced and multilayered effects on chromatin states, chromosome folding and on the topological domains of the chromatin, that emanate from the large CNV locus. These findings suggest basic principles of how such large genomic deletions can alter nuclear organization and affect genomic molecular activity.
A rapid and robust method for single cell chromatin accessibility profiling
Authors: Chen Xi , Miragaia Ricardo J. , Natarajan Kedar Nath , Teichmann Sarah A. 
Published: December 2018

AbstractThe assay for transposase-accessible chromatin using sequencing (ATAC-seq) is widely used to identify regulatory regions throughout the genome. However, very few studies have been performed at the single cell level (scATAC-seq) due to technical challenges. Here we developed a simple and robust plate-based scATAC-seq method, combining upfront bulk Tn5 tagging with single-nuclei sorting. We demonstrate that our method works robustly across various systems, including fresh and cryopreserved cells from primary tissues. By profiling over 3000 splenocytes, we identify distinct immune cell types and reveal cell type-specific regulatory regions and related transcription factors.
Genomic insights into multidrug-resistance, mating and virulence in Candida auris and related emerging species
Authors: Muñoz José F. , Gade Lalitha , Chow Nancy A. , Loparev Vladimir N. , Juieng Phalasy , Berkow Elizabeth L. , Farrer Rhys A. , Litvintseva Anastasia P. , Cuomo Christina A. 
Published: December 2018

AbstractCandida auris is an emergent multidrug-resistant fungal pathogen causing increasing reports of outbreaks. While distantly related to C. albicans and C. glabrata, C. auris is closely related to rarely observed and often multidrug-resistant species from the C. haemulonii clade. Here, we analyze near complete genome assemblies for the four C. auris clades and three related species, and map intra- and inter-species rearrangements across the seven chromosomes. Using RNA-Seq-guided gene predictions, we find that most mating and meiosis genes are conserved and that clades contain either the MTLa or MTLα mating loci. Comparing the genomes of these emerging species to those of other Candida species identifies genes linked to drug resistance and virulence, including expanded families of transporters and lipases, as well as mutations and copy number variants in ERG11. Gene expression analysis identifies transporters and metabolic regulators specific to C. auris and those conserved with related species which may contribute to differences in drug response in this emerging fungal clade.
Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis
Authors: Ponath Gerald , Lincoln Matthew R. , Levine-Ritterman Maya , Park Calvin , Dahlawi Somiah , Mubarak Mayyan , Sumida Tomokazu , Airas Laura , Zhang Shun , Isitan Cigdem , Nguyen Thanh D. , Raine Cedric S. , Hafler David A. , Pitt David 
Published: December 2018

AbstractEpigenetic annotation studies of genetic risk variants for multiple sclerosis (MS) implicate dysfunctional lymphocytes in MS susceptibility; however, the role of central nervous system (CNS) cells remains unclear. We investigated the effect of the risk variant, rs7665090G, located near NFKB1, on astrocytes. We demonstrated that chromatin is accessible at the risk locus, a prerequisite for its impact on astroglial function. The risk variant was associated with increased NF-κB signaling and target gene expression, driving lymphocyte recruitment, in cultured human astrocytes and astrocytes within MS lesions, and with increased lesional lymphocytic infiltrates and lesion sizes. Thus, our study establishes a link between genetic risk for MS (rs7665090G) and dysfunctional astrocyte responses associated with increased CNS access for peripheral immune cells. MS may therefore result from variant-driven dysregulation of the peripheral immune system and of the CNS, where perturbed CNS cell function aids in establishing local autoimmune inflammation.
Structural basis of meiotic telomere attachment to the nuclear envelope by MAJIN-TERB2-TERB1
Authors: Dunce James M. , Milburn Amy E. , Gurusaran Manickam , da Cruz Irene , Sen Lee T. , Benavente Ricardo , Davies Owen R. 
Published: December 2018

AbstractMeiotic chromosomes undergo rapid prophase movements, which are thought to facilitate the formation of inter-homologue recombination intermediates that underlie synapsis, crossing over and segregation. The meiotic telomere complex (MAJIN, TERB1, TERB2) tethers telomere ends to the nuclear envelope and transmits cytoskeletal forces via the LINC complex to drive these rapid movements. Here, we report the molecular architecture of the meiotic telomere complex through the crystal structure of MAJIN-TERB2, together with light and X-ray scattering studies of wider complexes. The MAJIN-TERB2 2:2 hetero-tetramer binds strongly to DNA and is tethered through long flexible linkers to the inner nuclear membrane and two TRF1-binding 1:1 TERB2-TERB1 complexes. Our complementary structured illumination microscopy studies and biochemical findings reveal a telomere attachment mechanism in which MAJIN-TERB2-TERB1 recruits telomere-bound TRF1, which is then displaced during pachytene, allowing MAJIN-TERB2-TERB1 to bind telomeric DNA and form a mature attachment plate.
Kinase-dead ATR differs from ATR loss by limiting the dynamic exchange of ATR and RPA
Authors: Menolfi Demis , Jiang Wenxia , Lee Brian J. , Moiseeva Tatiana , Shao Zhengping , Estes Verna , Frattini Mark G. , Bakkenist Christopher J. , Zha Shan 
Published: December 2018

AbstractATR kinase is activated by RPA-coated single-stranded DNA (ssDNA) to orchestrate DNA damage responses. Here we show that ATR inhibition differs from ATR loss. Mouse model expressing kinase-dead ATR (Atr+/KD), but not loss of ATR (Atr+/−), displays ssDNA-dependent defects at the non-homologous region of X-Y chromosomes during male meiosis leading to sterility, and at telomeres, rDNA, and fragile sites during mitosis leading to lymphocytopenia. Mechanistically, we find that ATR kinase activity is necessary for the rapid exchange of ATR at DNA-damage-sites, which in turn promotes CHK1-phosphorylation. ATR-KD, but not loss of ATR, traps a subset of ATR and RPA on chromatin, where RPA is hyper-phosphorylated by ATM/DNA-PKcs and prevents downstream repair. Consequently, Atr+/KD cells have shorter inter-origin distances and are vulnerable to induced fork collapses, genome instability and mitotic catastrophe. These results reveal mechanistic differences between ATR inhibition and ATR loss, with implications for ATR signaling and cancer therapy.
Overcoming efficiency and stability limits in water-processing nanoparticular organic photovoltaics by minimizing microstructure defects
Authors: Xie Chen , Heumüller Thomas , Gruber Wolfgang , Tang Xiaofeng , Classen Andrej , Schuldes Isabel , Bidwell Matthew , Späth Andreas , Fink Rainer H. , Unruh Tobias , McCulloch Iain , Li Ning , Brabec Christoph J. 
Published: December 2018

AbstractThere is a strong market driven need for processing organic photovoltaics from eco-friendly solvents. Water-dispersed organic semiconducting nanoparticles (NPs) satisfy these premises convincingly. However, the necessity of surfactants, which are inevitable for stabilizing NPs, is a major obstacle towards realizing competitive power conversion efficiencies for water-processed devices. Here, we report on a concept for minimizing the adverse impact of surfactants on solar cell performance. A poloxamer facilitates the purification of organic semiconducting NPs through stripping excess surfactants from aqueous dispersion. The use of surfactant-stripped NPs based on poly(3-hexylthiophene) / non-fullerene acceptor leads to a device efficiency and stability comparable to the one from devices processed by halogenated solvents. A record efficiency of 7.5% is achieved for NP devices based on a low-band gap polymer system. This elegant approach opens an avenue that future organic photovoltaics processing may be indeed based on non-toxic water-based nanoparticle inks.