bluuebunny/crossref_metadata_2025_split huggingface dataset:
FOXM1 contributes to taxane resistance by regulating UHRF1-controlled cancer cell stemness
Authors: Yuan Bowen , Liu Youhong , Yu Xiaohui , Yin Linglong , Peng Yuchong , Gao Yingxue , Zhu Qianling , Cao Tuoyu , Yang Yinke , Fan Xuegong , Li Xiong 
Published: May 2018

AbstractTherapy-induced expansion of cancer stem cells (CSCs) has been identified as one of the most critical factors contributing to therapeutic resistance, but the mechanisms of this adaptation are not fully understood. UHRF1 is a key epigenetic regulator responsible for therapeutic resistance, and controls the self-renewal of stem cells. In the present study, taxane-resistant cancer cells were established and stem-like cancer cells were expanded. UHRF1 was overexpressed in the taxane-resistant cancer cells, which maintained CSC characteristics. UHRF1 depletion overcame taxane resistance in vitro and in vivo. Additionally, FOXM1 has been reported to play a role in therapeutic resistance and the self-renewal of CSCs. FOXM1 and UHRF1 are highly correlated in prostate cancer tissues and cells, FOXM1 regulates CSCs by regulating uhrf1 gene transcription in an E2F-independent manner, and FOXM1 protein directly binds to the FKH motifs at the uhrf1 gene promoter. This present study clarified a novel mechanism by which FOXM1 controls CSCs and taxane resistance through a UHRF1-mediated signaling pathway, and validated FOXM1 and UHRF1 as two potential therapeutic targets to overcome taxane resistance.
Caspase-mediated cleavage of the centrosomal proteins during apoptosis
Authors: Seo Mi Young , Rhee Kunsoo 
Published: May 2018

AbstractThe centrosome is the major microtubule-organizing center and plays important roles in intracellular transport, cellular morphology, and motility. In mitotic cells, centrosomes function as spindle poles to pull a set of chromosomes into daughter cells. In quiescent cells, primary cilia are originated from the centrosomes. Given its involvement in various cellular processes, it is little surprising that the organelle would also participate in apoptotic events. However, it remains elusive how the centrosome changes in structure and organization during apoptosis. Apoptosis, a programmed cell death, is required for homeostatic tissue maintenance, embryonic development, stress responses, etc. Activation of caspases generates a cascade of apoptotic pathways, explaining much of what happens during apoptosis. Here, we report the proteolytic cleavage of selected centrosomal proteins in apoptotic cells. SAS-6, a cartwheel component of centrioles, was specifically cleaved at the border of the coiled-coil domain and the disordered C-terminus. Pericentrin, a scaffold of pericentriolar material, was also cleaved during apoptosis. These cleavages were efficiently blocked by the caspase inhibitors. We propose that the caspase-dependent proteolysis of the centrosomal proteins may destabilize the configuration of a centrosome. Loss of centrosomes may be required for the formation of apoptotic microtubule networks, which are essential for apoptotic fragmentation. This work demonstrates the first centrosomal targets by caspases during apoptosis.
Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment
Authors: Ashraf Shazia , Kudo Hiroki , Rao Jia , Kikuchi Atsuo , Widmeier Eugen , Lawson Jennifer A. , Tan Weizhen , Hermle Tobias , Warejko Jillian K. , Shril Shirlee , Airik Merlin , Jobst-Schwan Tilman , Lovric Svjetlana , Braun Daniela A. , Gee Heon Yung , Schapiro David , Majmundar Amar J. , Sadowski Carolin E. , Pabst Werner L. , Daga Ankana , van der Ven Amelie T. , Schmidt Johanna M. , Low Boon Chuan , Gupta Anjali Bansal , Tripathi Brajendra K. , Wong Jenny , Campbell Kirk , Metcalfe Kay , Schanze Denny , Niihori Tetsuya , Kaito Hiroshi , Nozu Kandai , Tsukaguchi Hiroyasu , Tanaka Ryojiro , Hamahira Kiyoshi , Kobayashi Yasuko , Takizawa Takumi , Funayama Ryo , Nakayama Keiko , Aoki Yoko , Kumagai Naonori , Iijima Kazumoto , Fehrenbach Henry , Kari Jameela A. , El Desoky Sherif , Jalalah Sawsan , Bogdanovic Radovan , Stajić Nataša , Zappel Hildegard , Rakhmetova Assel , Wassmer Sharon-Rose , Jungraithmayr Therese , Strehlau Juergen , Kumar Aravind Selvin , Bagga Arvind , Soliman Neveen A. , Mane Shrikant M. , Kaufman Lewis , Lowy Douglas R. , Jairajpuri Mohamad A. , Lifton Richard P. , Pei York , Zenker Martin , Kure Shigeo , Hildebrandt Friedhelm 
Published: May 2018

AbstractNo efficient treatment exists for nephrotic syndrome (NS), a frequent cause of chronic kidney disease. Here we show mutations in six different genes (MAGI2, TNS2, DLC1, CDK20, ITSN1, ITSN2) as causing NS in 17 families with partially treatment-sensitive NS (pTSNS). These proteins interact and we delineate their roles in Rho-like small GTPase (RLSG) activity, and demonstrate deficiency for mutants of pTSNS patients. We find that CDK20 regulates DLC1. Knockdown of MAGI2, DLC1, or CDK20 in cultured podocytes reduces migration rate. Treatment with dexamethasone abolishes RhoA activation by knockdown of DLC1 or CDK20 indicating that steroid treatment in patients with pTSNS and mutations in these genes is mediated by this RLSG module. Furthermore, we discover ITSN1 and ITSN2 as podocytic guanine nucleotide exchange factors for Cdc42. We generate Itsn2-L knockout mice that recapitulate the mild NS phenotype. We, thus, define a functional network of RhoA regulation, thereby revealing potential therapeutic targets.
A novel small molecule chaperone of rod opsin and its potential therapy for retinal degeneration
Authors: Chen Yuanyuan , Chen Yu , Jastrzebska Beata , Golczak Marcin , Gulati Sahil , Tang Hong , Seibel William , Li Xiaoyu , Jin Hui , Han Yong , Gao Songqi , Zhang Jianye , Liu Xujie , Heidari-Torkabadi Hossein , Stewart Phoebe L. , Harte William E. , Tochtrop Gregory P. , Palczewski Krzysztof 
Published: May 2018

AbstractRhodopsin homeostasis is tightly coupled to rod photoreceptor cell survival and vision. Mutations resulting in the misfolding of rhodopsin can lead to autosomal dominant retinitis pigmentosa (adRP), a progressive retinal degeneration that currently is untreatable. Using a cell-based high-throughput screen (HTS) to identify small molecules that can stabilize the P23H-opsin mutant, which causes most cases of adRP, we identified a novel pharmacological chaperone of rod photoreceptor opsin, YC-001. As a non-retinoid molecule, YC-001 demonstrates micromolar potency and efficacy greater than 9-cis-retinal with lower cytotoxicity. YC-001 binds to bovine rod opsin with an EC50 similar to 9-cis-retinal. The chaperone activity of YC-001 is evidenced by its ability to rescue the transport of multiple rod opsin mutants in mammalian cells. YC-001 is also an inverse agonist that non-competitively antagonizes rod opsin signaling. Significantly, a single dose of YC-001 protects Abca4
−/−
Rdh8
−/−
mice from bright light-induced retinal degeneration, suggesting its broad therapeutic potential.
Probing femtosecond lattice displacement upon photo-carrier generation in lead halide perovskite
Authors: Batignani Giovanni , Fumero Giuseppe , Srimath Kandada Ajay Ram , Cerullo Giulio , Gandini Marina , Ferrante Carino , Petrozza Annamaria , Scopigno Tullio 
Published: May 2018

AbstractElectronic properties and lattice vibrations are expected to be strongly correlated in metal-halide perovskites, due to the soft fluctuating nature of their crystal lattice. Thus, unveiling electron–phonon coupling dynamics upon ultrafast photoexcitation is necessary for understanding the optoelectronic behavior of the semiconductor. Here, we use impulsive vibrational spectroscopy to reveal vibrational modes of methylammonium lead-bromide perovskite under electronically resonant and non-resonant conditions. We identify two excited state coherent phonons at 89 and 106 cm−1, whose phases reveal a shift of the potential energy minimum upon ultrafast photocarrier generation. This indicates the transition to a new geometry, reached after approximately 90 fs, and fully equilibrated within the phonons lifetime of about 1 ps. Our results unambiguously prove that these modes drive the crystalline distortion occurring upon photo-excitation, demonstrating the presence of polaronic effects.
Distinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes
Authors: Lomberk Gwen , Blum Yuna , Nicolle Rémy , Nair Asha , Gaonkar Krutika Satish , Marisa Laetitia , Mathison Angela , Sun Zhifu , Yan Huihuang , Elarouci Nabila , Armenoult Lucile , Ayadi Mira , Ordog Tamas , Lee Jeong-Heon , Oliver Gavin , Klee Eric , Moutardier Vincent , Gayet Odile , Bian Benjamin , Duconseil Pauline , Gilabert Marine , Bigonnet Martin , Garcia Stephane , Turrini Olivier , Delpero Jean-Robert , Giovannini Marc , Grandval Philippe , Gasmi Mohamed , Secq Veronique , De Reyniès Aurélien , Dusetti Nelson , Iovanna Juan , Urrutia Raul 
Published: May 2018

AbstractRecent studies have offered ample insight into genome-wide expression patterns to define pancreatic ductal adenocarcinoma (PDAC) subtypes, although there remains a lack of knowledge regarding the underlying epigenomics of PDAC. Here we perform multi-parametric integrative analyses of chromatin immunoprecipitation-sequencing (ChIP-seq) on multiple histone modifications, RNA-sequencing (RNA-seq), and DNA methylation to define epigenomic landscapes for PDAC subtypes, which can predict their relative aggressiveness and survival. Moreover, we describe the state of promoters, enhancers, super-enhancers, euchromatic, and heterochromatic regions for each subtype. Further analyses indicate that the distinct epigenomic landscapes are regulated by different membrane-to-nucleus pathways. Inactivation of a basal-specific super-enhancer associated pathway reveals the existence of plasticity between subtypes. Thus, our study provides new insight into the epigenetic landscapes associated with the heterogeneity of PDAC, thereby increasing our mechanistic understanding of this disease, as well as offering potential new markers and therapeutic targets.
Elucidating the genetic architecture of reproductive ageing in the Japanese population
Authors: Horikoshi Momoko , Day Felix R. , Akiyama Masato , Hirata Makoto , Kamatani Yoichiro , Matsuda Koichi , Ishigaki Kazuyoshi , Kanai Masahiro , Wright Hollis , Toro Carlos A. , Ojeda Sergio R. , Lomniczi Alejandro , Kubo Michiaki , Ong Ken K. , Perry John. R. B. 
Published: May 2018

AbstractPopulation studies elucidating the genetic architecture of reproductive ageing have been largely limited to European ancestries, restricting the generalizability of the findings and overlooking possible key genes poorly captured by common European genetic variation. Here, we report 26 loci (all P < 5 × 10–8) for reproductive ageing, i.e. puberty timing or age at menopause, in a non-European population (up to 67,029 women of Japanese ancestry). Highlighted genes for menopause include GNRH1, which supports a primary, rather than passive, role for hypothalamic-pituitary GnRH signalling in the timing of menopause. For puberty timing, we demonstrate an aetiological role for receptor-like protein tyrosine phosphatases by combining evidence across population genetics and pre- and peri-pubertal changes in hypothalamic gene expression in rodent and primate models. Furthermore, our findings demonstrate widespread differences in allele frequencies and effect estimates between Japanese and European associated variants, highlighting the benefits and challenges of large-scale trans-ethnic approaches.
CD4+ T cells are activated in regional lymph nodes and migrate to skin to initiate lymphedema
Authors: García Nores Gabriela D. , Ly Catherine L. , Cuzzone Daniel A. , Kataru Raghu P. , Hespe Geoffrey E. , Torrisi Jeremy S. , Huang Jung Ju , Gardenier Jason C. , Savetsky Ira L. , Nitti Matthew D. , Yu Jessie Z. , Rehal Sonia , Mehrara Babak J. 
Published: May 2018

AbstractT cell-mediated responses have been implicated in the development of fibrosis, impaired lymphangiogenesis, and lymphatic dysfunction in secondary lymphedema. Here we show that CD4+ T cells are necessary for lymphedema pathogenesis by utilizing adoptive transfer techniques in CD4 knockout mice that have undergone tail skin and lymphatic excision or popliteal lymph node dissection. We also demonstrate that T cell activation following lymphatic injury occurs in regional skin-draining lymph nodes after interaction with antigen-presenting cells such as dendritic cells. CD4+ T cell activation is associated with differentiation into a mixed T helper type 1 and 2 phenotype, as well as upregulation of adhesion molecules and chemokines that promote migration to the skin. Most importantly, we find that blocking T cell release from lymph nodes using a sphingosine-1-phosphate receptor modulator prevents lymphedema, suggesting that this approach may have clinical utility.
IgG-single-chain TRAIL fusion proteins for tumour therapy
Authors: Siegemund Martin , Schneider Felix , Hutt Meike , Seifert Oliver , Müller Ines , Kulms Dagmar , Pfizenmaier Klaus , Kontermann Roland E. 
Published: May 2018

AbstractSingle-chain formats of TNF-related apoptosis inducing ligand (scTRAIL) can serve as effector components of tumour-associated antigen-targeted as well as non-targeted fusion proteins, being characterized by high tumour cell-specific induction of apoptosis through death receptor activation. We studied the suitability of immunoglobulin G as a scaffold for oligovalent and bispecific TRAIL fusion proteins. Thus, we developed novel targeted hexa- and dodecavalent IgG-scTRAIL molecules by fusing scTRAIL to the C-terminus of either light (LC-scTRAIL) or heavy immunoglobulin chain (HC-scTRAIL), or to both ends (LC/HC-scTRAIL) of the anti-EGFR IgG antibody hu225. The binding specificity to EGFR and death receptors was retained in all IgG-scTRAIL formats and translated into high antigen-specific bioactivity on EGFR-positive Colo205, HCT116 and WM1366 tumour cell lines, with or without sensitization to apoptosis by bortezomib. In vivo, therapeutic potential was assessed for one of the targeted variants, HC-scTRAIL, compared to the non-targeted Fc-scTRAIL. Both molecules showed a significant reduction of tumour volume and synergism with a Smac mimetic in a Colo205 xenograft tumour model. The IgG-scTRAIL format allows directing a defined, highly bioactive form of TRAIL to a wide variety of tumour antigens, enabling customized solutions for a patient-specific targeted cancer therapy with a reduced risk of side effects.
Layer-by-layer siRNA/poly(L-lysine) Multilayers on Polydopamine-coated Surface for Efficient Cell Adhesion and Gene Silencing
Authors: Hong Cheol Am , Son Ho Yeon , Nam Yoon Sung 
Published: May 2018

AbstractFor tissue engineering applications, small interfering RNA (siRNA) is an attractive agent for controlling cellular functions and differentiation. Although polyionic condensation of nucleic acids with polycations has been widely used for gene delivery, siRNA is not strongly associated with cationic carriers due to its low charge density and rigid molecular structures. The use of an excess amount of cationic carriers is often used for siRNA condensation, though they can induce severe cytotoxicity. Here we introduce the self-assembly of siRNA with mild polyelectrolytes into multilayers for efficient gene silencing during cell proliferation. The multilayers were prepared through the sequential layer-by-layer deposition of siRNA and poly-L-lysine (PLL) on a polydopamine-coated substrate. The cells, grown on the siRNA/PLL multilayers, exhibited a remarkable inhibition of the expression of target genes as compared to the use of scrambled siRNA. The gene silencing efficiency depends on the number of siRNA layers within a multilayer. This result indicates that siRNA/PLL multilayers can be potentially utilized for efficient surface-mediated siRNA delivery.
Novel haloarchaeon Natrinema thermophila having the highest growth temperature among haloarchaea with a large genome size
Authors: Kim Yeon Bee , Kim Joon Yong , Song Hye Seon , Lee Changsu , Ahn Seung Woo , Lee Se Hee , Jung Min Young , Rhee Jin-Kyu , Kim Juseok , Hyun Dong-Wook , Bae Jin-Woo , Roh Seong Woon 
Published: May 2018

AbstractEnvironmental temperature is one of the most important factors for the growth and survival of microorganisms. Here we describe a novel extremely halophilic archaeon (haloarchaea) designated as strain CBA1119Tisolated from solar salt. Strain CBA1119Thad the highest maximum and optimal growth temperatures (66 °C and 55 °C, respectively) and one of the largest genome sizes among haloarchaea (5.1 Mb). It also had the largest number of strain-specific pan-genome orthologous groups and unique pathways among members of the genusNatrinemain the classHalobacteria. A dendrogram based on the presence/absence of genes and a phylogenetic tree constructed based on OrthoANI values highlighted the particularities of strain CBA1119Tas compared to otherNatrinemaspecies and other haloarchaea members. The large genome of strain CBA1119Tmay provide information on genes that confer tolerance to extreme environmental conditions, which may lead to the discovery of other thermophilic strains with potential applications in industrial biotechnology.
Sensory representation of an auditory cued tactile stimulus in the posterior parietal cortex of the mouse
Authors: Mohan Hemanth , Gallero-Salas Yasir , Carta Stefano , Sacramento João , Laurenczy Balazs , Sumanovski Lazar T. , de Kock Christiaan P. J. , Helmchen Fritjof , Sachidhanandam Shankar 
Published: May 2018

AbstractSensory association cortices receive diverse inputs with their role in representing and integrating multi-sensory content remaining unclear. Here we examined the neuronal correlates of an auditory-tactile stimulus sequence in the posterior parietal cortex (PPC) using 2-photon calcium imaging in awake mice. We find that neuronal subpopulations in layer 2/3 of PPC reliably represent texture-touch events, in addition to auditory cues that presage the incoming tactile stimulus. Notably, altering the flow of sensory events through omission of the cued texture touch elicited large responses in a subset of neurons hardly responsive to or even inhibited by the tactile stimuli. Hence, PPC neurons were able to discriminate not only tactile stimulus features (i.e., texture graininess) but also between the presence and omission of the texture stimulus. Whereas some of the neurons responsive to texture omission were driven by looming-like auditory sounds others became recruited only with tactile sensory experience. These findings indicate that layer 2/3 neuronal populations in PPC potentially encode correlates of expectancy in addition to auditory and tactile stimuli.
Embryonic POU5F1 is Required for Expanded Bovine Blastocyst Formation
Authors: Daigneault Bradford W. , Rajput Sandeep , Smith George W. , Ross Pablo J. 
Published: May 2018

AbstractPOU5F1 is a transcription factor and master regulator of cell pluripotency with indispensable roles in early embryo development and cell lineage specification. The role of embryonic POU5F1 in blastocyst formation and cell lineage specification differs between mammalian species but remains completely unknown in cattle. The CRISPR/Cas9 system was utilized for targeted disruption of the POU5F1 gene by direct injection into zygotes. Disruption of the bovine POU5F1 locus prevented blastocyst formation and was associated with embryonic arrest at the morula stage. POU5F1 knockout morulas developed at a similar rate as control embryos and presented a similar number of blastomeres by day 5 of development. Initiation of SOX2 expression by day 5 of development was not affected by lack of POU5F1. On the other hand, CDX2 expression was aberrant in embryos lacking POU5F1. Notably, the phenotype observed in bovine POU5F1 knockout embryos reveals conserved functions associated with loss of human embryonic POU5F1 that differ from Pou5f1- null mice. The similarity observed in transcriptional regulation of early embryo development between cattle and humans combined with highly efficient gene editing techniques make the bovine a valuable model for human embryo biology with expanded applications in agriculture and assisted reproductive technologies.
Consistent prediction of GO protein localization
Authors: Spetale Flavio E. , Arce Debora , Krsticevic Flavia , Bulacio Pilar , Tapia Elizabeth 
Published: May 2018

AbstractThe GO-Cellular Component (GO-CC) ontology provides a controlled vocabulary for the consistent description of the subcellular compartments or macromolecular complexes where proteins may act. Current machine learning-based methods used for the automated GO-CC annotation of proteins suffer from the inconsistency of individual GO-CC term predictions. Here, we present FGGA-CC+, a class of hierarchical graph-based classifiers for the consistent GO-CC annotation of protein coding genes at the subcellular compartment or macromolecular complex levels. Aiming to boost the accuracy of GO-CC predictions, we make use of the protein localization knowledge in the GO-Biological Process (GO-BP) annotations to boost the accuracy of GO-CC prediction. As a result, FGGA-CC+ classifiers are built from annotation data in both the GO-CC and GO-BP ontologies. Due to their graph-based design, FGGA-CC+ classifiers are fully interpretable and their predictions amenable to expert analysis. Promising results on protein annotation data from five model organisms were obtained. Additionally, successful validation results in the annotation of a challenging subset of tandem duplicated genes in the tomato non-model organism were accomplished. Overall, these results suggest that FGGA-CC+ classifiers can indeed be useful for satisfying the huge demand of GO-CC annotation arising from ubiquitous high throughout sequencing and proteomic projects.
Single Nucleotide Polymorphisms in the G-Protein Coupled Receptor Kinase 5 (GRK5) Gene are associated with Plasma LDL-Cholesterol Levels in Humans
Authors: Lutz Stefan Z. , Falcenberg Mathias , Machicao Fausto , Peter Andreas , Kächele Martin , Randrianarisoa Elko , Lehn-Stefan Angela , Wagner Robert , Machann Jürgen , Schick Fritz , Heni Martin , Ullrich Axel , Fritsche Andreas , Stefan Norbert , Häring Hans-Ulrich , Staiger Harald , Kantartzis Konstantinos 
Published: May 2018

AbstractGenetically modified mice models suggest an important role for G-protein-coupled receptor kinase 5 (GRK5) in the pathophysiology of obesity and related disorders. We investigated whether single nucleotide polymorphisms (SNPs) in the gene encoding GRK5 affect cardiometabolic traits in humans. We genotyped 3 common SNPs in intron 1 (rs1980030, rs10466210, rs9325562) and one SNP in intron 3 (rs10886471) of GRK5 in 2332 subjects at risk for type 2 diabetes. Total- and visceral fat mass were measured by magnetic resonance (MR) tomography and liver fat content by 1H-MR spectroscopy. Insulin secretion and sensitivity were estimated during an OGTT and measured during the euglycemic, hyperinsulinemic clamp (n = 498). Carriers of the minor allele of rs10466210 and rs1980030 had higher total- and LDL-cholesterol levels (p = 0.0018 and p = 0.0031, respectively, for rs10466210; p = 0.0035 and p = 0.0081, respectively, for rs1980030), independently of gender, age, BMI and lipid-lowering drugs. The effects of rs10466210 withstood Bonferroni correction. Similar associations were observed with apolipoprotein B levels (p = 0.0034 and p = 0.0122, respectively). Carriers of the minor allele of rs10466210 additionally displayed a trend for higher intima-media thickness of the carotid artery (p = 0.075). GRK5 may represent a novel target for strategies aiming at lowering LDL-cholesterol levels and at modifying cardiovascular risk.