bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel function of IMPA2, plays a tumor-promoting role in cervical cancer
Authors: Zhang Kan , Liu Lei , Wang Min , Yang Min , Li Xianping , Xia Xiaomeng , Tian Jingjing , Tan Shan , Luo Lingli 
Published: May 2020

AbstractDiscovery of genes and molecular mechanism involved in cervical cancer development would promote the prevention and treatment. By comparing gene expression profiles of cervical carcinoma in situ (CCIS) and adjacent normal tissues, we identified a potential cancer-promoting gene, IMPA2. This study aimed to elucidate the role of IMPA2 and underlying molecular mechanisms in cervical cancer progression. To do this expression of IMPA2 was compared between human cervical cancer and corresponding adjacent normal cervical tissues firstly. CCK-8 assay, clone formation assay, wound healing assay, transwell assay, and tumor formation in nude mice were performed to demonstrate the effect of IMPA2 in cervical cancer proliferation and metastasis. Further proteomic profiling and western blotting explored the molecular pathway involved in the IMPA2-regulating process. The results showed that IMPA2 gene expression was upregulated in cervical cancer. Consistently, silencing of IMPA2 suppressed tumor formation in BALB/c nude mice. Short hairpin RNA (shRNA)-mediated IMPA2 silencing significantly inhibited proliferation and colony-forming abilities of cervical cancer cells, while IMPA2 overexpression had little impact. Also, IMPA2 silencing suppressed cellular migration, but overexpression promoted migration. Proteomics analysis revealed the involvement of mitogen-activated protein kinase (MAPK) pathway in tumor-promoting action of IMPA2. Significantly, the inhibition of IMPA2 activated ERK phosphorylation, and its inhibitory effects can be restored by using selective ERK inhibitor, FR180204. In conclusion, IMPA2 acts as an oncogene in the proliferation and migration of cervical cancer. IMPA2 downregulated ERK phosphorylation to promote cervical cancer. These findings identify a new mechanism underlying cervical cancer and suggest a regulating effect of IMPA2 in MAPK signaling pathway.
Restoration of lysosomal function after damage is accompanied by recycling of lysosomal membrane proteins
Authors: Eriksson Ida , Wäster Petra , Öllinger Karin 
Published: May 2020

AbstractLysosomes are central organelles for cellular degradation and energy homeostasis. In addition, lysosomal membrane permeabilization (LMP) and subsequent release of lysosomal content to the cytosol can initiate programmed cell death. The extent of LMP and available repair mechanisms determine the cell fate after lysosomal damage. In this study, we aimed to investigate the premises for lysosomal membrane repair after LMP and found that lysosomal membrane damage initiated by l-leucyl-l-leucine methyl ester (LLOMe) caused caspase-dependent apoptosis in almost 50% of the cells, while the rest recovered. Immediately after LLOMe addition, lysosomal proteases were detected in the cytosol and the ESCRT-components ALIX and CHMP4B were recruited to the lysosomal membrane. Next, lysophagic clearance of damaged lysosomes was evident and a concentration-dependent translocation of several lysosomal membrane proteins, including LAMP2, to the cytosol was found. LAMP2 was present in small vesicles with the N-terminal protein chain facing the lumen of the vesicle. We conclude that lysophagic clearance of damaged lysosomes results in generation of lysosomal membrane protein complexes, which constitute small membrane enclosed units, possibly for recycling of lysosomal membrane proteins. These lysosomal membrane complexes enable an efficient regeneration of lysosomes to regain cell functionality.
Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response
Authors: Dufey Estefanie , Bravo-San Pedro José Manuel , Eggers Cristian , González-Quiroz Matías , Urra Hery , Sagredo Alfredo I. , Sepulveda Denisse , Pihán Philippe , Carreras-Sureda Amado , Hazari Younis , Sagredo Eduardo A. , Gutierrez Daniela , Valls Cristian , Papaioannou Alexandra , Acosta-Alvear Diego , Campos Gisela , Domingos Pedro M. , Pedeux Rémy , Chevet Eric , Alvarez Alejandra , Godoy Patricio , Walter Peter , Glavic Alvaro , Kroemer Guido , Hetz Claudio 
Published: May 2020

AbstractThe molecular connections between homeostatic systems that maintain both genome integrity and proteostasis are poorly understood. Here we identify the selective activation of the unfolded protein response transducer IRE1α under genotoxic stress to modulate repair programs and sustain cell survival. DNA damage engages IRE1α signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1α-dependent decay (RIDD) without activating its canonical output mediated by the transcription factor XBP1. IRE1α endoribonuclease activity controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The activation of the c-Abl kinase by DNA damage triggers the oligomerization of IRE1α to catalyze RIDD. The protective role of IRE1α under genotoxic stress is conserved in fly and mouse. Altogether, our results uncover an important intersection between the molecular pathways that sustain genome stability and proteostasis.
Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures
Authors: Vander Velde Robert , Yoon Nara , Marusyk Viktoriya , Durmaz Arda , Dhawan Andrew , Miroshnychenko Daria , Lozano-Peral Diego , Desai Bina , Balynska Olena , Poleszhuk Jan , Kenian Liu , Teng Mingxiang , Abazeed Mohamed , Mian Omar , Tan Aik Choon , Haura Eric , Scott Jacob , Marusyk Andriy 
Published: May 2020

ABSTRACTDespite high initial efficacy, targeted therapies eventually fail in advanced cancers, as tumors develop resistance and relapse. In contrast to the substantial body of research on the molecular mechanisms of resistance, understanding of how resistance evolves remains limited. Using an experimental model of ALK positive NSCLC, we explored the evolution of resistance to different clinical ALK inhibitors. We found that resistance can originate from heterogeneous, weakly resistant subpopulations with variable sensitivity to different ALK inhibitors. Instead of the commonly assumed stochastic single hit (epi) mutational transition, or drug-induced reprogramming, we found evidence for a hybrid scenario involving the gradual, multifactorial adaptation to the inhibitors through acquisition of multiple cooperating genetic and epigenetic adaptive changes. Additionally, we found that during this adaptation tumor cells might present unique, temporally restricted collateral sensitivities, absent in therapy naïve or fully resistant cells, suggesting the potential for new therapeutic interventions, directed against evolving resistance.
Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response
Authors: Szewczyk Magdalena M. , Ishikawa Yoshinori , Organ Shawna , Sakai Nozomu , Li Fengling , Halabelian Levon , Ackloo Suzanne , Couzens Amber L. , Eram Mohammad , Dilworth David , Fukushi Hideto , Harding Rachel , dela Seña Carlo C. , Sugo Tsukasa , Hayashi Kozo , McLeod David , Zepeda Carlos , Aman Ahmed , Sánchez-Osuna Maria , Bonneil Eric , Takagi Shinji , Al-Awar Rima , Tyers Mike , Richard Stephane , Takizawa Masayuki , Gingras Anne-Claude , Arrowsmith Cheryl H. , Vedadi Masoud , Brown Peter J. , Nara Hiroshi , Barsyte-Lovejoy Dalia 
Published: May 2020

AbstractProtein arginine methyltransferases (PRMTs) regulate diverse biological processes and are increasingly being recognized for their potential as drug targets. Here we report the discovery of a potent, selective, and cell-active chemical probe for PRMT7. SGC3027 is a cell permeable prodrug, which in cells is converted to SGC8158, a potent, SAM-competitive PRMT7 inhibitor. Inhibition or knockout of cellular PRMT7 results in drastically reduced levels of arginine monomethylated HSP70 family stress-associated proteins. Structural and biochemical analyses reveal that PRMT7-driven in vitro methylation of HSP70 at R469 requires an ATP-bound, open conformation of HSP70. In cells, SGC3027 inhibits methylation of both constitutive and inducible forms of HSP70, and leads to decreased tolerance for perturbations of proteostasis including heat shock and proteasome inhibitors. These results demonstrate a role for PRMT7 and arginine methylation in stress response.
Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice
Authors: Alexopoulos Stephanie J. , Chen Sing-Young , Brandon Amanda E. , Salamoun Joseph M. , Byrne Frances L. , Garcia Christopher J. , Beretta Martina , Olzomer Ellen M. , Shah Divya P. , Philp Ashleigh M. , Hargett Stefan R. , Lawrence Robert T. , Lee Brendan , Sligar James , Carrive Pascal , Tucker Simon P. , Philp Andrew , Lackner Carolin , Turner Nigel , Cooney Gregory J. , Santos Webster L. , Hoehn Kyle L. 
Published: May 2020

AbstractObesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity. BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic clamp studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake.
BICORN: An R package for integrative inference of de novo cis-regulatory modules
Authors: Chen Xi , Gu Jinghua , Neuwald Andrew F. , Hilakivi-Clarke Leena , Clarke Robert , Xuan Jianhua 
Published: May 2020

AbstractGenome-wide transcription factor (TF) binding signal analyses reveal co-localization of TF binding sites, based on which cis-regulatory modules (CRMs) can be inferred. CRMs play a key role in understanding the cooperation of multiple TFs under specific conditions. However, the functions of CRMs and their effects on nearby gene transcription are highly dynamic and context-specific and therefore are challenging to characterize. BICORN (Bayesian Inference of COoperative Regulatory Network) builds a hierarchical Bayesian model and infers context-specific CRMs based on TF-gene binding events and gene expression data for a particular cell type. BICORN automatically searches for a list of candidate CRMs based on the input TF bindings at regulatory regions associated with genes of interest. Applying Gibbs sampling, BICORN iteratively estimates model parameters of CRMs, TF activities, and corresponding regulation on gene transcription, which it models as a sparse network of functional CRMs regulating target genes. The BICORN package is implemented in R (version 3.4 or later) and is publicly available on the CRAN server at https://cran.r-project.org/web/packages/BICORN/index.html.
Snapshots of human anatomy, locomotion, and behavior from Late Pleistocene footprints at Engare Sero, Tanzania
Authors: Hatala Kevin G. , Harcourt-Smith William E. H. , Gordon Adam D. , Zimmer Brian W. , Richmond Brian G. , Pobiner Briana L. , Green David J. , Metallo Adam , Rossi Vince , Liutkus-Pierce Cynthia M. 
Published: May 2020

AbstractFossil hominin footprints preserve data on a remarkably short time scale compared to most other fossil evidence, offering snapshots of organisms in their immediate ecological and behavioral contexts. Here, we report on our excavations and analyses of more than 400 Late Pleistocene human footprints from Engare Sero, Tanzania. The site represents the largest assemblage of footprints currently known from the human fossil record in Africa. Speed estimates show that the trackways reflect both walking and running behaviors. Estimates of group composition suggest that these footprints were made by a mixed-sex and mixed-age group, but one that consisted of mostly adult females. One group of similarly-oriented trackways was attributed to 14 adult females who walked together at the same pace, with only two adult males and one juvenile accompanying them. In the context of modern ethnographic data, we suggest that these trackways may capture a unique snapshot of cooperative and sexually divided foraging behavior in Late Pleistocene humans.
Endocrine disrupter chemicals affect the humoral antimicrobial activities of gilthead seabream males even upon the cease of the exposure
Authors: Valero Yulema , López-Cánovas Amanda E. , Rodenas M. Carmen , Cabas Isabel , García-Hernández Pilar , Arizcun Marta , García-Ayala Alfonsa , Chaves-Pozo Elena 
Published: May 2020

Abstract17α-ethynilestradiol (EE2) and tamoxifen (Tmx) are pollutants world-wide distributed in aquatic environments. Gilthead seabream, Sparus aurata L., is highlighted as a species model of intensively culture in anthropogenic disturbed environments. The effects of these pollutants on gilthead seabream reproduction and some immune responses have been described but, the humoral innate antimicrobial activities have never received attention. In this work we analysed the latest in the plasma of gilthead seabream males of different ages and reproductive stages treated with 0, 2.5, 5 or 50 μg EE2 or 100 μg Tmx g−1 food during different times of exposure and of reverting to commercial diet (recovery). The peroxidase and protease activities decreased as the spermatogenesis of the first reproductive cycle (RC) proceeded in control fish. However, only protease and antiprotease activities showed different level at different stages of the second RC in control fish, but showed scarce disruption in fish treated with EE2 or Tmx. Peroxidase and bactericide activities are more sensitive to EE2, than to Tmx. The effects induced by EE2 varied depending on the activity analyzed, the dose and the time of exposure and the reproductive stage and the age of the specimens.
Complexity and ultrastructure of infectious extracellular vesicles from cells infected by non-enveloped virus
Authors: Yang Jie E. , Rossignol Evan D. , Chang Deborah , Zaia Joseph , Forrester Isaac , Raja Kiran , Winbigler Holly , Nicastro Daniela , Jackson William T. , Bullitt Esther 
Published: May 2020

AbstractEnteroviruses support cell-to-cell viral transmission prior to their canonical lytic spread of virus. Poliovirus (PV), a prototype for human pathogenic positive-sense RNA enteroviruses, and picornaviruses in general, transport multiple virions en bloc via infectious extracellular vesicles, 100~1000 nm in diameter, secreted from host cells. Using biochemical and biophysical methods we identify multiple components in secreted microvesicles, including mature PV virions; positive-sense genomic and negative-sense replicative, template viral RNA; essential viral replication proteins; and cellular proteins. Using cryo-electron tomography, we visualize the near-native three-dimensional architecture of secreted infectious microvesicles containing both virions and a unique morphological component that we describe as a mat-like structure. While the composition of these mat-like structures is not yet known, based on our biochemical data they are expected to be comprised of unencapsidated RNA and proteins. In addition to infectious microvesicles, CD9-positive exosomes released from PV-infected cells are also infectious and transport virions. Thus, our data show that, prior to cell lysis, non-enveloped viruses are secreted within infectious vesicles that also transport viral unencapsidated RNAs, viral and host proteins. Understanding the structure and function of these infectious particles helps elucidate the mechanism by which extracellular vesicles contribute to the spread of non-enveloped virus infection.
A Micromorphic Beam Theory for Beams with Elongated Microstructures
Authors: Shaat M. , Ghavanloo E. , Emam S. 
Published: May 2020

AbstractA novel micromorphic beam theory that considers the exact shape and size of the beam’s microstructure is developed. The new theory complements the beam theories that are based on the classical mechanics by modeling the shape and size of the beam’s microstructure. This theory models the beam with a microstructure that has shape and size and exhibits microstrains that are independent of the beam’s macroscopic strains. This theory postulates six independent degrees of freedom to describe the axial and transverse displacements and the axial and shear microstrains of the beam. The detailed variational formulation of the beam theory is provided based on the reduced micromorphic model. For the first time, the displacement and microstrain fields of beams with elongated microstructures are developed. In addition, six material constants are defined to fully describe the beam’s microscopic and macroscopic stiffnesses, and two length scale parameters are used to capture the beam size effect. A case study of clamped-clamped beams is analytically solved to show the influence of the beam’s microstructural stiffness and size on its mechanical deformation. The developed micromorphic beam theory would find many important applications including the mechanics of advanced beams such as meta-, phononic, and photonic beams.
rTgOWP1-f, a specific biomarker for Toxoplasma gondii oocysts
Authors: Sousa Susana , Almeida André , Delgado Lurdes , Conceição Antónia , Marques Cláudia , da Costa José Manuel Correia , Castro António 
Published: May 2020

AbstractToxoplasma gondii oocyst wall protein 1 (TgOWP1) integrates a family of seven proteins, consensually assumed as specific antigens of Toxoplasma gondii oocyst stage, located in the outer layer of the oocyst wall. Herein, we notice the expression of a recombinant antigen, rTgOWP1-f, derived from a fragment selected on basis of its structural homology with Plasmodium MSP1–19. Rabbit polyclonal antibodies anti-rTgOWP1-f evidence ability for specific identification of environmental T. gondii oocysts. We assume, rTgOWP1-f, as a possible biomarker of oocysts. In addition, we present findings supporting this vision, including the development of an immunodetection method for T. gondii oocysts identification.
A novel peroxidase from Ziziphus jujuba fruit: purification, thermodynamics and biochemical characterization properties
Authors: Zeyadi Mustafa , Almulaiky Yaaser Q. 
Published: May 2020

AbstractIn this study, peroxidase from Ziziphus jujuba was purified using ion exchange, and gel filtration chromatography resulting in an 18.9-fold enhancement of activity with a recovery of 20%. The molecular weight of Z. jujuba peroxidase was 56 kDa, as estimated by Sephacryl S-200. The purity was evaluated by SDS, which showed a single prominent band. The optimal activity of the peroxidase was achieved at pH 7.5 and 50 °C. Z. jujuba peroxidase showed catalytic efficiency (Kcat/Km) values of 25 and 43 for guaiacol and H2O2, respectively. It was completely inactivated when incubated with β-mercaptoethanol for 15 min. Hg2+, Zn2+, Cd2+, and NaN3 (5 mM) were effective peroxidase inhibitors, whereas Cu2+ and Ca2+ enhanced the peroxidase activity. The activation energy (Ea) for substrate hydrolysis was 43.89 kJ mol−1, while the Z value and temperature quotient (Q10) were found to be 17.3 °C and 2, respectively. The half-life of the peroxidase was between 117.46 and 14.15 min. For denaturation of the peroxidase, the activation energy for irreversible inactivation Ea*(d) was 120.9 kJmol−1. Thermodynamic experiments suggested a non-spontaneous (∆G*d > 0) and endothermic reaction phase. Other thermodynamic parameters of the irreversible inactivation of the purified enzyme, such as ∆H* and ∆S*, were also studied. Based on these results, the purified peroxidase has a potential role in some industrial applications.
Neural network interpolation of exchange-correlation functional
Authors: Ryabov Alexander , Akhatov Iskander , Zhilyaev Petr 
Published: May 2020

AbstractDensity functional theory (DFT) is one of the most widely used tools to solve the many-body Schrodinger equation. The core uncertainty inside DFT theory is the exchange-correlation (XC) functional, the exact form of which is still unknown. Therefore, the essential part of DFT success is based on the progress in the development of XC approximations. Traditionally, they are built upon analytic solutions in low- and high-density limits and result from quantum Monte Carlo numerical calculations. However, there is no consistent and general scheme of XC interpolation and functional representation. Many different developed parametrizations mainly utilize a number of phenomenological rules to construct a specific XC functional. In contrast, the neural network (NN) approach can provide a general way to parametrize an XC functional without any a priori knowledge of its functional form. In this work, we develop NN XC functionals and prove their applicability to 3-dimensional physical systems. We show that both the local density approximation (LDA) and generalized gradient approximation (GGA) are well reproduced by the NN approach. It is demonstrated that the local environment can be easily considered by changing only the number of neurons in the first layer of the NN. The developed NN XC functionals show good results when applied to systems that are not presented in the training/test data. The generalizability of the formulated NN XC framework leads us to believe that it could give superior results in comparison with traditional XC schemes provided training data from high-level theories such as the quantum Monte Carlo and post-Hartree-Fock methods.
Bright light improves sleep in patients with Parkinson’s disease: possible role of circadian restoration
Authors: Endo Takuyuki , Matsumura Ritsuko , Tokuda Isao T. , Yoshikawa Tomoko , Shigeyoshi Yasufumi , Node Koichi , Sakoda Saburo , Akashi Makoto 
Published: May 2020

AbstractParkinson’s disease (PD) is one of the most common neurodegenerative disorders. Among the most common manifestations of PD are sleep problems, which are coupled with the adverse effects of dopaminergic therapies (DT). A non-pharmacological solution for these sleep problems has been sought to avoid additional pharmacological intervention. Here, we show that bright light therapy (BLT) is effective for improving sleep in Japanese PD patients receiving DT. Furthermore, experimental evaluation of peripheral clock gene expression rhythms revealed that most PD patients receiving DT who experienced improved sleep following BLT showed a circadian phase shift, indicating the existence of a correlation between circadian modulation and sleep improvement. Conversely, this result indicates that sleep problems in PD patients receiving DT may arise at least in part as a result of circadian dysfunction. Indeed, we found that chronic dopaminergic stimulation induced a rapid attenuation of autonomous oscillations of clock gene expression in ex vivo cultured mouse suprachiasmatic nucleus (SCN) at the single neuron level. In conclusion, BLT is a promising medical treatment for improving sleep in PD patients receiving DT. This BLT-induced improvement may be due to the restoration of circadian function.