bluuebunny/crossref_metadata_2025_split huggingface dataset:
A review on the 40th anniversary of the first regulation of drinking water disinfection by‐products
Authors: DeMarini David M. 
Published: May 2020

AbstractWater disinfection, primarily by chlorination, is one of the greatest achievements of public health. However, more than half a century after its introduction, studies in the 1970s reported that (a) chlorine interacted with organic matter in the water to form disinfection by‐products (DBPs); (b) two DBPs, chloroform and bromoform, both trihalomethanes (THMs), were rodent carcinogens; (c) three brominated THMs were mutagenic; in six studies chlorinated drinking waters in the United States and Canada were mutagenic; and (d) in one epidemiological study there was an association between bladder cancer mortality and THM exposure. This led the U.S. Environmental Protection Agency to issue its first DBP regulation in 1979. Forty years later, >600 DBPs have been characterized, 20/22 have been shown to be rodent carcinogens, >100 have been shown to be genotoxic, and 1000s of water samples have been found to be mutagenic. Data support a hypothesis that long‐term dermal/inhalation exposure to certain levels of the three brominated THMs, as well as oral exposure to the haloacetic acids, combined with a specific genotype may increase the risk for bladder cancer for a small but significant population group. Improved water‐treatment methods and stricter regulations have likely reduced such risks over the years, and further reductions in potential risk are anticipated with the application of advanced water‐treatment methods and wider application of drinking water regulations. This 40‐year research effort is a remarkable example of sustained cooperation between academic and government scientists, along with public/private water companies, to find answers to a pressing public health question.
Serum‐free suspension cultured human cells can produce a high‐level of recombinant human erythropoietin
Authors: Costa e Silva Luciano , dos Santos Matheus Henrique , Heluy Tarik Reis , Biaggio Rafael Tagé , Ferreira Alexander Rodrigo , Milhomens Jonathan , Kashima Simone , El Nemer Wassim , El Hoss Sara , Picanço‐Castro Virgínia , Covas Dimas Tadeu , Swiech Kamilla 
Published: May 2020

AbstractCurrently, the majority of commercial recombinant therapeutic proteins are produced in nonhuman expression systems. Human cells are capable of producing recombinant proteins with post‐translational modifications that are more similar to native proteins which reduce immunogenicity. This article describes the potential of the human cell lines Sk‐Hep‐1, HKB‐11, and Huh‐7, cultured in serum‐free suspension conditions, to produce a complex recombinant glycoprotein, human erythropoietin (EPO). Recombinant cell lines were generated by lentiviral transduction and sorted by flow cytometry. All the recombinant cells presented high‐specific cell growth rates and a high level of rhEPO production. Maximum rhEPO concentrations achieved by Sk‐Hep‐1, HKB‐11, and Huh‐7 cells were 112.5 μg/mL, 112.7 μg/mL, and 571 μg/mL, respectively. The levels of rhEPO production by Huh‐7 cells were higher than the levels commonly reported in the literature for serum‐free suspension cultures. The rhEPO produced demonstrated biological activity measured through in vitro differentiation of CD34+ cells. In view of this, we demonstrate that Sk‐Hep‐1, HKB‐11, and Huh‐7 cell lines have good characteristics to be used as host cells for the production of complex recombinant glycoproteins, with special emphasis on Huh‐7 due to enhanced EPO production.
Efficacy and safety of perampanel monotherapy in patients with focal‐onset seizures with newly diagnosed epilepsy or recurrence of epilepsy after a period of remission: The open‐label Study 342 (FREEDOM Study)
Authors: Yamamoto Takamichi , Lim Sung Chul , Ninomiya Hirotomo , Kubota Yuichi , Shin Won Chul , Kim Dong Wook , Shin Dong Jin , Hoshida Tohru , Iida Koji , Ochiai Taku , Matsunaga Risa , Higashiyama Hiroyuki , Hiramatsu Hidetaka , Kim Ji Hyun 
Published: May 2020

AbstractObjectiveOur study assessed perampanel monotherapy in patients (aged ≥12 years) with focal‐onset seizures (FOS) with or without focal to bilateral tonic‐clonic seizures (FBTCS) in Japan and South Korea.MethodsStudy 342 (NCT03201900; FREEDOM) is a single‐arm, open‐label, Phase III study. Patients initially received perampanel in a 32‐week 4‐mg/d Treatment Phase (6‐week Titration; 26‐week Maintenance Periods). If they experienced a seizure during the 4‐mg/d Maintenance Period, they could be up‐titrated to 8 mg/d across an additional 30‐week Treatment Phase (4‐week Titration; 26‐week Maintenance Periods). Primary endpoint was the seizure‐freedom rate during the Maintenance Period (4 mg/d and last evaluated dose [4 or 8 mg/d]). Secondary endpoints included time to first seizure onset and to withdrawal during Maintenance. Treatment‐emergent adverse events (TEAEs) were monitored.ResultsAt data cutoff (February 28, 2019), 89 patients with FOS (84 [94.4%] with newly diagnosed epilepsy and 5 [5.6%] with recurrence of epilepsy after a period of remission) had received ≥1 perampanel dose; 16 patients discontinued during the 4‐mg/d Titration Period, meaning 73 patients entered the 4‐mg/d Maintenance Period and were included in the primary analysis set for efficacy. Seizure‐freedom rate in the 26‐week Maintenance Period was 46/73 (63.0%; 95% confidence interval [CI]: 50.9‐74.0) at 4 mg/d and 54/73 (74.0%; 95% CI: 62.4‐83.5) at 4 or 8 mg/d. Cumulative probability of seizure‐onset and withdrawal rates during Maintenance was 30.8% (95% CI: 21.5‐43.0) and 23.7% (95% CI: 15.4‐35.3) at 4 mg/d, and 18.2% (95% CI: 11.0‐29.3) and 23.3% (95% CI: 15.2‐34.8) at 4 or 8 mg/d. Perampanel was generally well tolerated, and the most common TEAE was dizziness.SignificancePerampanel monotherapy (4 to 8 mg/d) was efficacious and consistent with the known safety profile up to 26 weeks in patients (≥12 years) with primarily newly diagnosed FOS with or without FBTCS.
A study on genotype–environment interaction based on GGE biplot graphical method in sunflower genotypes (Helianthus annuus L.)
Authors: Ansarifard Isa , Mostafavi Khodadad , Khosroshahli Mahmood , Reza Bihamta Mohammad , Ramshini Hosein 
Published: May 2020

AbstractGGE biplot technique is one of the appropriate methods for investigating the genotype–environment interaction. An experiment was conducted to examine and evaluate the stability and adaptability of grain yield of 12 sunflower genotypes using the randomized complete block design (RCBD) with three replications in five regions including Karaj, Birjand, Firooz‐Abad, Kashmar, and Arak within two agricultural years. Analysis of variance indicated that the effect of location, year, location × year, genotype, and genotype × location was significant at 1% probability level. Results of biplot analysis showed that the first and second principle components accounted 50.6% and 22.8%, respectively, and in total 73.4% of grain yield variance. In this study, genotype, location, year, year × location, genotype × location, genotype × year, and genotype × year × location explained 2.75%, 17.36%, 5.47%, 17%, 10.8%, 1.04%, and 7.48% of total variance, respectively. Investigating the polygon view led to the identification of three top genotypes and also three mega‐environment. The first mega‐environment included Karaj, Birjand, and Kashmar. The second was Arak, and the third was Firooz‐Abad. To study the kernel yield and stability of genotypes simultaneously, average coordinate view of environments was used and it was determined that genotype Zaria with the highest grain yield has high yield stability also. Ranking the cultivars based on the ideal genotype introduced the genotype Zaria as the best genotype. The highest grain yield belonged to Zaria cultivar at 3.34 t/ha followed by Favorite with 3.23 t/ha. Results obtained from ranking the environments based on the ideal environment introduced Kashmar and Birjand regions as the best environments. Examining the biplot figure for testing environments correlation confirms the positive correlation among Karaj, Birjand, and Kashmar. Correlation between Karaj with Arak, Karaj with Firooz‐Abad, and Arak with Firooz‐Abad was negative. Arak and Firooz‐Abad were highly discriminating and representative and would be used to identification of superior genotypes.
Analysis of TP53 aflatoxin signature mutation in hepatocellular carcinomas from Guatemala: A cross‐sectional study (2016‐2017)
Authors: Alvarez Christian S. , Ortiz Jeremy , Bendfeldt‐Avila Giovanna , Xie Yi , Wang Mingyi , Wu Dongjing , Higson Herbert , Lee Elisa , Teshome Kedest , Barnoya Joaquin , Kleiner David E. , Groopman John D. , Orozco Roberto , McGlynn Katherine A. , Gharzouzi Eduardo , Dean Michael 
Published: May 2020

AbstractBackground and aimsGuatemala has the highest incidence of hepatocellular carcinoma (HCC) in the Western hemisphere. The major risk factors in Guatemala are not well characterized, but the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) appears to be low, while the prevalence of aflatoxin (AFB1) exposure appears to be high. To examine whether AFB1 may contribute to the elevated incidence of HCC in Guatemala, this study examined the frequency of the AFB1‐signature mutation in the TP53 gene (R249S) as well as other somatic mutations. In addition, we assessed whether the frequency of the TP53 mutation differed by sex.MethodsFormalin‐fixed, paraffin‐embedded (FFPE) HCC tissues were obtained from three hospitals in Guatemala City between 2016 and 2017. In addition, tumor tissues preserved in RNAlater were also obtained. Sociodemographic and clinical information including HBV and HCV status were collected. Targeted sequencing of TP53 was performed in the FFPE samples, and a panel of 253 cancer‐related genes was sequenced in the RNAlater samples.ResultsNinety‐one FFPE tissues were examined, from 52 men and 39 women. Median (IQR) age at diagnosis was 62 (51‐70). Among those with known HBV and HCV status, two were HBV+ and three were HCV+. Overall, 47% of the HCCs had a TP53 mutation. The AFB1‐signature R249S mutation was present in 24%. No overlap between the R249S mutation and HBV+ was observed in this cohort. Among 18 RNAlater samples examined, 44% had any TP53 mutation and 33% had the R249S mutation. Other somatic mutations were identified in known HCC driver genes.ConclusionsThe presence of the TP53 R249S mutation in the samples studied suggests that AFB1 may contribute to the high incidence of HCC in Guatemala. The proportion of HBV+ tumors was low, suggesting that AFB1 may be associated with HCC in the absence of concomitant HBV infection. Further investigation of AFB1 and other risk factors for HCC in Guatemala is warranted.
miR‐506‐3p alleviates uncontrolled osteoclastogenesis via repression of RANKL/NFATc1 signaling pathway
Authors: Dinesh Palani , Kalaiselvan Sowmiya , Sujitha Sali , Rasool Mahaboobkhan 
Published: May 2020

AbstractBone erosion is the major cause of deformities in autoimmune disease conditions such as osteoporosis and rheumatoid arthritis. Aberrant receptor activator of nuclear factor kappa B ligand (RANKL) secretion in bone disorders have been implicated to promote uncontrolled osteoclast differentiation through the regulation of nuclear factor of activated T cells 1 (NFATc1) transcription factor. This phenomenon is governed by several molecular factors including microRNAs, which are under‐expressed during disease progression. This report focuses on elucidating the molecular mechanism of miR‐506‐3p towards the RANKL/NFATc1 pathway. miR‐506‐3p showed high binding affinity towards NFATc1 (ΔG = −22.4 kcal/mol). Bone marrow‐derived macrophages (BMMs) isolated from rats stimulated with RANKL (100 ng/ml) showed active expression of NFATc1 which differentiated into mature osteoclasts. Moreover, NFATc1 activation resulted in downstream secretion of various bone resorptive enzymes (cathepsin K, carbonic anhydrase II, tartarate acid phosphatase, and matrix metalloproteinase 9) which lead to active bone resorption. However, transfection of miR‐506‐3p resulted in selective repression of NFATc1 inside the cells. This further resulted in the diminished release of bone resorptive enzymes that were essential for the degradation of the bone. Overall, we predict that miR‐506‐3p can be used as a molecular intervention for RANKL/NFATc1 mediated osteoclastogenesis.
Highly upregulated in liver cancer (HULC): An update on its role in carcinogenesis
Authors: Ghafouri‐Fard Soudeh , Esmaeili Mohammadhosein , Taheri Mohammad , Samsami Majid 
Published: May 2020

AbstractHighly upregulated in liver cancer (HULC) was initially recognized during the screening of a hepatocellular carcinoma (HCC)‐specific gene library. Further studies demonstrated its aberrant upregulation in several other tumor types. The oncogenic roles of this long noncoding RNA (lncRNA) have been verified through expression studies as well as functional studies. Moreover, the results of knockdown experiments have indicated diminished carcinogenic effects of cancer cell line in nude mice following HULC silencing. More recent studies have shown that expression levels of this lncRNA might be used as diagnostic biomarkers in cancer patients. Moreover, mechanistical studies have revealed associations between HULC and two HCC‐related viruses namely hepatitis B and C viruses. Taken together, HULC can be regarded as a therapeutic target not only for HCC but also for a variety of human malignancies. In the current review, we summarized the recent literature about the role of HULC in the carcinogenesis and its potential application in cancer diagnosis and prognosis.
Impaired actin filaments decrease cisplatin sensitivity via dysfunction of volume‐sensitive Cl− channels in human epidermoid carcinoma cells
Authors: Shimizu Takahiro , Fujii Takuto , Ohtake Hironao , Tomii Toshie , Takahashi Ryuta , Kawashima Kentaro , Sakai Hideki 
Published: May 2020

AbstractCisplatin is a widely used platinum‐based anticancer drug in the chemotherapy of numerous human cancers. However, cancer cells acquire resistance to cisplatin. So far, functional loss of volume‐sensitive outwardly rectifying (VSOR) Cl− channels has been reported to contribute to cisplatin resistance of cancer cells. Here, we analyzed protein expression patterns of human epidermoid carcinoma KB cells and its cisplatin‐resistant KCP‐4 cells. Intriguingly, KB cells exhibited higher β‐actin expression and clearer actin filaments than KCP‐4 cells. The β‐actin knockdown in KB cells decreased VSOR Cl− currents and inhibited the regulatory volume decrease (RVD) process after cell swelling. Consistently, KB cells treated with cytochalasin D, which depolymerizes actin filaments, showed smaller VSOR Cl− currents and slower RVD. Cytochalasin D also inhibited cisplatin‐triggered apoptosis in KB cells. These results suggest that the disruption of actin filaments cause the dysfunction of VSOR Cl− channels, which elicits resistance to cisplatin in human epidermoid carcinoma cells.
Finding any given 2‐factor in sparse pseudorandom graphs efficiently
Authors: Han Jie , Kohayakawa Yoshiharu , Morris Patrick , Person Yury 
Published: May 2020

AbstractGiven an ‐vertex pseudorandom graph and an ‐vertex graph with maximum degree at most two, we wish to find a copy of in , that is, an embedding so that for all . Particular instances of this problem include finding a triangle‐factor and finding a Hamilton cycle in . Here, we provide a deterministic polynomial time algorithm that finds a given in any suitably pseudorandom graph . The pseudorandom graphs we consider are ‐bijumbled graphs of minimum degree which is a constant proportion of the average degree, that is, . A ‐bijumbled graph is characterised through the discrepancy property: for any two sets of vertices and . Our condition on bijumbledness is within a log factor from being tight and provides a positive answer to a recent question of Nenadov. We combine novel variants of the absorption‐reservoir method, a powerful tool from extremal graph theory and random graphs. Our approach builds on our previous work, incorporating the work of Nenadov, together with additional ideas and simplifications.
Effect of the CXCR4 antagonist plerixafor on endogenous neutrophil dynamics in the bone marrow, lung and spleen
Authors: Pillay Janesh , Tregay Nicola , Juzenaite Goda , Carlin Leo M. , Pirillo Chiara , Gaboriau David C. A. , Farahi Neda , Summers Charlotte , Lo Celso Cristina , Chilvers Edwin R. , Rankin Sara , De Filippo Katia 
Published: May 2020

Abstract
Treatment with the CXCR4 antagonist, plerixafor (AMD3100), has been proposed for clinical use in patients with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome and in pulmonary fibrosis. However, there is controversy with respect to the impact of plerixafor on neutrophil dynamics in the lung, which may affect its safety profile. In this study, we investigated the kinetics of endogenous neutrophils by direct imaging, using confocal intravital microscopy in mouse bone marrow, spleen, and lungs. Neutrophils are observed increasing their velocity and exiting the bone marrow following plerixafor administration, with a concomitant increase in neutrophil numbers in the blood and spleen, while the marginated pool of neutrophils in the lung microvasculature remained unchanged in terms of numbers and cell velocity. Use of autologous radiolabeled neutrophils and SPECT/CT imaging in healthy volunteers showed that plerixafor did not affect GM-CSF-primed neutrophil entrapment or release in the lungs. Taken together, these data suggest that plerixafor causes neutrophil mobilization from the bone marrow but does not impact on lung marginated neutrophil dynamics and thus is unlikely to compromise respiratory host defense both in humans and mice.
Binding of the placental growth factor to VEGF receptor type 1 modulates human T cell functions
Authors: Leplina Olga , Smetanenko Ekaterina , Tikhonova Marina , Batorov Egor , Tyrinova Tamara , Pasman Natalya , Ostanin Alexander , Chernykh Elena 
Published: May 2020

Abstract
The immunosuppressive properties of vascular endothelial growth factors (VEGFs) suggest a new role of angiogenic factors in T cell modulation in cancer and pregnancy. Most of VEGF effects on T cells are mediated through the VEGF receptor type 2 (VEGFR-2). This study aims to investigate the role of placental growth factor (PlGF) as a selective VEGFR-1 ligand in the modulation of human T cells functions. For this, PBMCs from healthy donors were stimulated with anti-CD3 mAbs (a-CD3) or Concanavalin A (ConA) in the absence or presence of PlGF and assessed for T cell proliferation, IL-10 production, programmed cell death, and the expression of inhibitory receptors (PD-1, CTLA-4, TIM-3) using radiometric (3H-thymidine incorporation) and FACS analysis. We showed that most T cells in freshly isolated PBMCs lacked VEGFR-1. However, activation with a-CD3 or ConA strongly increased the percentages of VEGFR-1 expressing CD4+ and CD8+ T cells. PlGF in a wide dose range suppressed PBMC cell proliferation, inhibiting both CD4+ and CD8+ T cells. Blockade of VEGFR-1, but not VEGFR-2 with neutralizing Abs completely abolished the suppressive effect of PlGF. Furthermore, we found that treatment with PlGF up-regulated IL-10 production in CD4+ and CD8+ T cells, promoted CD8+ T cells apoptosis and enhanced the expression of inhibitory receptors (PD-1 and TIM-3) on activated T cells. Our in vitro findings suggest the involvement of PlGF/VEGFR-1 signaling in the modulation of T cell responses in a-CD3-stimulated PBMCs.
Differential activity and selectivity of N-terminal modified CXCL12 chemokines at the CXCR4 and ACKR3 receptors
Authors: Jaracz-Ros Agnieszka , Bernadat Guillaume , Cutolo Pasquale , Gallego Carmen , Gustavsson Martin , Cecon Erika , Baleux Françoise , Kufareva Irina , Handel Tracy M. , Bachelerie Françoise , Levoye Angélique 
Published: May 2020

Abstract
Chemokines play critical roles in numerous physiologic and pathologic processes through their action on seven-transmembrane (TM) receptors. The N-terminal domain of chemokines, which is a key determinant of signaling via its binding within a pocket formed by receptors’ TM helices, can be the target of proteolytic processing. An illustrative case of this regulatory mechanism is the natural processing of CXCL12 that generates chemokine variants lacking the first two N-terminal residues. Whereas such truncated variants behave as antagonists of CXCR4, the canonical G protein-coupled receptor of CXCL12, they are agonists of the atypical chemokine receptor 3 (ACKR3/CXCR7), suggesting the implication of different structural determinants in the complexes formed between CXCL12 and its two receptors. Recent analyses have suggested that the CXCL12 N-terminus first engages the TM helices of ACKR3 followed by the receptor N-terminus wrapping around the chemokine core. Here we investigated the first stage of ACKR3-CXCL12 interactions by comparing the activity of substituted or N-terminally truncated variants of CXCL12 toward CXCR4 and ACKR3. We showed that modification of the first two N-terminal residues of the chemokine (K1R or P2G) does not alter the ability of CXCL12 to activate ACKR3. Our results also identified the K1R variant as a G protein-biased agonist of CXCR4. Comparative molecular dynamics simulations of the complexes formed by ACKR3 either with CXCL12 or with the P2G variant identified interactions between the N-terminal 2–4 residues of CXCL12 and a pocket formed by receptor's TM helices 2, 6, and 7 as critical determinants for ACKR3 activation.
SARS‐CoV‐2: Structural diversity, phylogeny, and potential animal host identification of spike glycoprotein
Authors: Dabravolski Siarhei Alexander , Kavalionak Yury Kazimirovich 
Published: May 2020

AbstractTo investigate the evolutionary history of the current pandemic outbreak of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), a total of 137 genomes of coronavirus strains with release dates between January 2019 and 25 March 2020, were analyzed. To investigate the potential intermediate host of the SARS‐CoV‐2, we analyzed spike glycoprotein sequences from different animals, with particular emphasis on bats. We performed phylogenetic analysis and structural reconstruction of the spike glycoproteins with subsequent alignment and comparison. Our phylogenetic results revealed that SARS‐CoV‐2 was more similar to the bats' betacoronavirus isolates: HKU5‐related from Pipistrellus abramus and HKU4‐related from Tylonycteris pachypus. We also identified a yak betacoronavirus strain, YAK/HY24/CH/2017, as the closest match in the comparison of the structural models of spike glycoproteins. Interestingly, a set of unique features has been described for this particular strain of the yak betacoronavirus. Therefore, our results suggest that the human SARS‐CoV‐2, responsible for the current outbreak of COVID‐19, could also come from yak as an intermediate host.