bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oncogenic G12D mutation alters local conformations and dynamics of K-Ras
Authors: Vatansever Sezen , Erman Burak , Gümüş Zeynep H. 
Published: August 2019

AbstractK-Ras is the most frequently mutated oncoprotein in human cancers, and G12D is its most prevalent mutation. To understand how G12D mutation impacts K-Ras function, we need to understand how it alters the regulation of its dynamics. Here, we present local changes in K-Ras structure, conformation and dynamics upon G12D mutation, from long-timescale Molecular Dynamics simulations of active (GTP-bound) and inactive (GDP-bound) forms of wild-type and mutant K-Ras, with an integrated investigation of atomistic-level changes, local conformational shifts and correlated residue motions. Our results reveal that the local changes in K-Ras are specific to bound nucleotide (GTP or GDP), and we provide a structural basis for this. Specifically, we show that G12D mutation causes a shift in the population of local conformational states of K-Ras, especially in Switch-II (SII) and α3-helix regions, in favor of a conformation that is associated with a catalytically impaired state through structural changes; it also causes SII motions to anti-correlate with other regions. This detailed picture of G12D mutation effects on the local dynamic characteristics of both active and inactive protein helps enhance our understanding of local K-Ras dynamics, and can inform studies on the development of direct inhibitors towards the treatment of K-RasG12D-driven cancers.
De novo regulation of RD3 synthesis in residual neuroblastoma cells after intensive multi-modal clinical therapy harmonizes disease evolution
Authors: Somasundaram Dinesh Babu , Subramanian Karthikeyan , Aravindan Sheeja , Yu Zhongxin , Natarajan Mohan , Herman Terence , Aravindan Natarajan 
Published: August 2019

AbstractMost high-risk neuroblastomas that initially respond to therapy will ultimately relapse. Currently, no curative treatment is available. Acquired genetic/molecular rearrangement in therapy-resistant cells contributes to tumor relapse. Recently, we identified significant RD3 loss in progressive disease (PD) and defined its association with advanced disease-stage and poor clinical outcomes. Here, we investigated whether RD3 loss is an acquired process in cells that survive intensive multi-modal clinical therapy (IMCT) and its significance in disease evolution. RD3 status (mRNA, protein) during diagnosis (Dx) and PD after IMCT was investigated in NB patient cohort (n = 106), stage-4 NB cell lines (n = 15) with known treatment status and validated with independent data from another set of 15 cell-lines. Loss of RD3 in metastatic disease was examined using a mouse model of PD and metastatic-site-derived aggressive cells (MSDACs) ex vivo. RD3 silencing/expression assessed changes in metastatic state. Influence of RD3 loss in therapy resistance was examined through independent in vitro and in vivo studies. A significant loss of RD3 mRNA and protein was observed in resistant cells derived from patients with PD after IMCT. This is true to the effect within and between patients. Results from the mouse model identified significant transcriptional/translational loss of RD3 in metastatic tumors and MSDACs. RD3 re-expression in MSDACs and silencing RD3 in parental cells defined the functional relevance of RD3-loss in PD pathogenesis. Analysis of independent studies with salvage therapeutic agents affirmed RD3 loss in surviving resistant cells and residual tumors. The profound reductions in RD3 transcription indicate the de novo regulation of RD3 synthesis in resistant cells after IMCT. Defining RD3 loss in PD and the benefit of targeted reinforcement could improve salvage therapy for progressive neuroblastoma.
Novel clinical and dual infection by Histoplasma capsulatum genotypes in HIV patients from Northeastern, Brazil
Authors: Damasceno Lisandra Serra , Teixeira Marcus de Melo , Barker Bridget Marie , Almeida Marcos Abreu , Muniz Mauro de Medeiros , Pizzini Cláudia Vera , Mesquita Jacó Ricarte Lima , Rodríguez-Arellanes Gabriela , Ramírez José Antonio , Vite-Garín Tania , Leitão Terezinha do Menino Jesus Silva , Taylor Maria Lucia , Almeida-Paes Rodrigo , Zancopé-Oliveira Rosely Maria 
Published: August 2019

AbstractHistoplasmosis is a worldwide-distributed deep mycosis that affects healthy and immunocompromised hosts. Severe and disseminated disease is especially common in HIV-infected patients. At least 11 phylogenetic species are recognized and the majority of diversity is found in Latin America. The northeastern region of Brazil has one of the highest HIV/AIDS prevalence in Latin America and Ceará State has one of the highest death rates due to histoplasmosis in the world, where the mortality rate varies between 33–42%. The phylogenetic distribution and population genetic structure of 51 clinical isolates from Northeast Brazil was studied. For that morphological characteristics, exoantigens profile, and fungal mating types were evaluated. The genotypes were deduced by a MSLT in order to define local population structure of this fungal pathogen. In addition, the relationships of H. capsulatum genotypes with clinically relevant phenotypes and clinical aspects were investigated. The results suggest two cryptic species, herein named population Northeast BR1 and population Northeast BR2. These populations are recombining, exhibit a high level of haplotype diversity, and contain different ratios of mating types MAT1-1 and MAT1-2. However, differences in phenotypes or clinical aspects were not observed within these new cryptic species. A HIV patient can be co-infected by two or more genotypes from Northeast BR1 and/or Northeast BR2, which may have significant impact on disease progression due to the impaired immune response. We hypothesize that co-infections could be the result of multiple exposure events and may indicate higher risk of disseminated histoplasmosis, especially in HIV infected patients.
Silver ions cause oscillation of bacterial length of Escherichia coli
Authors: Krishnamurthi Venkata Rao , Chen Jingyi , Wang Yong 
Published: August 2019

AbstractSilver (Ag) in various forms have recently gained broad interest and been revisited due to their promising antimicrobial effects. Here we report our study on the morphological dynamics of live bacteria when subjected to Ag+ ions. Using time-lapse microscopy, we observed oscillations of cell-length for a large fraction of bacteria exposed to 60 μM of Ag+ ions. In addition, we found that the responses of bacteria to Ag+ ions were heterogeneous. We quantified the oscillations of cell-length with power spectral density, which appeared different from that of bacteria growing in the absence of Ag+ ions. Furthermore, a model similar to the predator-prey argument was developed to understand the observed oscillations of cell-length upon exposure to Ag+ ions. This model not only successfully produced the oscillations but also explained the observed heterogeneity in the bacterial responses to Ag+ ions.
A new alvarezsaurian theropod from the Upper Jurassic Shishugou Formation of western China
Authors: Qin Zichuan , Clark James , Choiniere Jonah , Xu Xing 
Published: August 2019

AbstractAlvarezsaurian dinosaurs, a group of bizarre theropods with greatly shortened and modified forelimbs, are known mostly from the Cretaceous of Asia and South America. Here we report a new alvarezsaurian, Shishugounykus inexpectus gen. et sp. nov, based on a specimen recovered from the Middle–Upper Jurassic Shishugou Formation of the Junggar Basin, western China. Together with two other alvarezsaurians from this formation, i.e., Haplocheirus sollers and Aorun zhaoi, these Shishugou forms represent the only known Jurassic alvarezsaurians worldwide. Similar to the two other Shishugou alvarezsaurians, this new alvarezsaurian displays early stages in the development of the highly modified alvarezsaurian forelimb, but it possesses a number of manual features closer to the typical coelurosaurian theropod condition. Combining morphological and histological features, our analysis indicates that the earliest known alvarezsaurians are variable in size and other important morphological features, and in particular display a mosaic distribution of forelimb features.
Identification of plasticity and interactions of a highly conserved motif within a picornavirus capsid precursor required for virus infectivity
Authors: Kristensen Thea , Belsham Graham J. 
Published: August 2019

AbstractThe picornavirus family includes poliovirus (PV) (genus: enterovirus), human rhinoviruses (enterovirus) and foot-and-mouth disease virus (FMDV) (aphthovirus). These are responsible for important human and animal health concerns worldwide including poliomyelitis, the common cold and foot-and-mouth disease (FMD) respectively. In picornavirus particles, the positive-sense RNA genome (ca. 7–9 kb) is packaged within a protein shell (capsid) usually consisting of three surface exposed proteins, VP1, VP2 and VP3 plus the internal VP4, which are generated following cleavage of the capsid precursor by a virus-encoded protease. We have previously identified a motif near the C-terminus of FMDV VP1 that is required for capsid precursor processing. This motif is highly conserved among other picornaviruses, and is also likely to be important for their capsid precursor processing. We have now determined the plasticity of residues within this motif for virus infectivity and found an important interaction between FMDV residue VP1 R188 within this conserved motif and residue W129 in VP2 that is adjacent in the virus capsid. The FMDV (VP1 R188A) mutant virus has only been rescued with the secondary substitution VP2 W129R. This additional change compensates for the defect resulting from the VP1 R188A substitution and restored both capsid precursor processing and virus viability.
TNF-α promoter polymorphisms (G-238A and G-308A) are associated with susceptibility to Systemic Lupus Erythematosus (SLE) and P. falciparum malaria: a study in malaria endemic area
Authors: Mahto Harishankar , Tripathy Rina , Meher Biswa Ranjan , Prusty Birendra K. , Sharma Meenakshi , Deogharia Divya , Saha Anjana Kumari , Panda Aditya K. , Das Bidyut K. 
Published: August 2019

AbstractTumor necrosis factor-α (TNF-α) is a proinflammatory cytokine associated with autoimmune and infectious diseases. Importance of TNF-α inP.falciparummalaria and systemic lupus erythematosus (SLE) have been demonstrated. However, association of functional promoter variants with SLE and malaria is lacking in malaria endemic population. A total of 204 female SLE patients and 224 age and sex matched healthy controls were enrolled in the study. Three hundred fourteenP.falciparuminfected patients with different clinical phenotypes were included. TNF-α polymorphisms (G-238A & G-308A) were genotyped by PCR-RFLP. Plasma levels of TNF-α was quantified by ELISA. Heterozygous mutants and minor alleles of TNF-α (G-238A and G-308A) polymorphisms were significantly higher in SLE patients compared to healthy controls and associated with development of lupus nephritis. In addition, both promoter variants were associated with severeP.falciparum malaria. SLE patients demonstrated higher levels of plasma TNF-α compared to healthy controls. TNF-α (G-238A and G-308A) variants were associated with higher plasma TNF-α. In conclusion, TNF-α (G-238A & G-308A) variants are associated with higher plasma TNF-α levels in SLE patients residing in malaria endemic areas and could be a contributing factor in the development of SLE and susceptibility to severeP.falciparummalaria.
BMP-4 enhances epithelial mesenchymal transition and cancer stem cell properties of breast cancer cells via Notch signaling
Authors: Choi Sanghyuk , Yu Jinyeong , Park Aran , Dubon Maria Jose , Do Jungbeom , Kim Youngjae , Nam Donghyun , Noh Jinok , Park Ki-Sook 
Published: August 2019

AbstractBone morphogenetic protein (BMP) signaling and Notch signaling play important roles in tumorigenesis in various organs and tissues, including the breast. BMP-4 enhanced epithelial mesenchymal transition (EMT) and stem cell properties in both mammary epithelial cell line and breast carcinoma cell line. BMP-4 increased the expression of EMT biomarkers, such as fibronectin, laminin, N-cadherin, and Slug. BMP-4 also activated Notch signaling in these cells and increased the sphere forming efficiency of the non-transformed mammary epithelial cell line MCF-10A. In addition, BMP-4 upregulated the sphere forming efficiency, colony formation efficiency, and the expression of cancer stem cell markers, such as Nanog and CD44, in the breast carcinoma cell line MDA-MB-231. Inhibition of Notch signaling downregulated EMT and stem cell properties induced by BMP-4. Down-regulation of Smad4 using siRNA impaired the BMP-4-induced activation of Notch signaling, as well as the BMP-4-mediated EMT. These results suggest that EMT and stem cell properties are increased in mammary epithelial cells and breast cancer cells through the activation of Notch signaling in a Smad4-dependent manner in response to BMP-4.
Structure-based identification of a potential non-catalytic binding site for rational drug design in the fructose 1,6-biphosphate aldolase from Giardia lamblia
Authors: Méndez Sara-Teresa , Castillo-Villanueva Adriana , Martínez-Mayorga Karina , Reyes-Vivas Horacio , Oria-Hernández Jesús 
Published: August 2019

AbstractGiardia lamblia is the causal agent of giardiasis, one of the most prevalent parasitosis in the world. Even though effective pharmacotherapies against this parasite are available, the disadvantages associated with its use call for the development of new antigiardial compounds. Based on the Giardia dependence on glycolysis as a main energy source, glycolytic enzymes appear to be attractive targets with antiparasitic potential. Among these, fructose 1,6-biphosphate aldolase (GlFBPA) has been highlighted as a promising target for drug design. Current efforts are based on the design of competitive inhibitors of GlFBPA; however, in the kinetic context of metabolic pathways, competitive inhibitors seem to have low potential as therapeutic agents. In this work, we performed an experimental and in silico structure-based approach to propose a non-catalytic binding site which could be used as a hot spot for antigardial drug design. The druggability of the selected binding site was experimentally tested; the alteration of the selected region by site directed mutagenesis disturbs the catalytic properties and the stability of the enzyme. A computational automated search of binding sites supported the potential of this region as functionally relevant. A preliminary docking study was performed, in order to explore the feasibility and type of molecules to be able to accommodate in the proposed binding region. Altogether, the results validate the proposed region as a specific molecular binding site with pharmacological potential.
Rev-Erbα and Photoreceptor Outer Segments modulate the Circadian Clock in Retinal Pigment Epithelial Cells
Authors: Milićević Nemanja , Mazzaro Nadia , de Bruin Ivanka , Wils Esmée , ten Brink Jacoline , Asbroek Anneloor ten , Mendoza Jorge , Bergen Arthur , Felder-Schmittbuhl Marie-Paule 
Published: August 2019

AbstractRetinal photoreceptor outer segments (POS) are renewed daily through phagocytosis by the adjacent retinal pigment epithelial (RPE) monolayer. Phagocytosis is mainly driven by the RPE circadian clock but the underlying molecular mechanisms remain elusive. Using ARPE-19 (human RPE cell-line) dispersed and monolayer cell cultures, we investigated the influence of cellular organization on the RPE clock and phagocytosis genes. PCR analysis revealed rhythmic expression of clock and phagocytosis genes in all ARPE-19 cultures. Monolayers had a tendency for higher amplitudes of clock gene oscillations. In all conditions ARNTL, CRY1, PER1-2, REV-ERBα, ITGB5, LAMP1 and PROS1 were rhythmically expressed with REV-ERBα being among the clock genes whose expression showed most robust rhythms in ARPE-19 cells. Using RPE-choroid explant preparations of the mPer2Luc knock-in mice we found that Rev-Erbα deficiency induced significantly longer periods and earlier phases of PER2-bioluminescence oscillations. Furthermore, early phagocytosis factors β5-Integrin and FAK and the lysosomal marker LAMP1 protein levels are rhythmic. Finally, POS incubation affects clock and clock-controlled phagocytosis gene expression in RPE monolayers in a time-dependent manner suggesting that POS can reset the RPE clock. These results shed some light on the complex interplay between POS, the RPE clock and clock-controlled phagocytosis machinery which is modulated by Rev-Erbα.
Staphylococcus hominis subspecies can be identified by SDS-PAGE or MALDI-TOF MS profiles
Authors: Pereira Eliezer Menezes , de Mattos Claudio Simões , dos Santos Olinda Cabral , Ferreira Dennis Carvalho , de Oliveira Tamara Lopes Rocha , Laport Marinella Silva , de Oliveira Ferreira Eliane , dos Santos Katia Regina Netto 
Published: August 2019

AbstractStaphylococcus hominis is part of the normal human microbiome. Two subspecies, S. hominis hominis (Shh) and S. hominis novobiosepticus (Shn), have clinical significance. Forty-nine S. hominis isolates were analyzed by the MicroScan automated system, SDS-PAGE and MALDI-TOF methods, followed by partial sequencing of the 16S rDNA gene. The trehalose fermentation test, disk diffusion and broth microdilution tests were used to identify (novobiocin test) and access the susceptibility to oxacillin and vancomycin of isolates. The SCCmec elements and genomic diversity were evaluated by PCR and PFGE methods, respectively. Profiles of 28 (57%; 8 Shh and 20 Shn) isolates corroborated with the results found in all the applied methods of identification. The remaining 21 (43%) isolates were phenotypically identified as Shh by MicroScan; however, they were identified as Shn by SDS-PAGE and mass spectral, and confirmed by 16S rDNA sequencing. Among 41 isolates identified as Shn by the molecular and mass spectrometry methods, 19 (41%) were novobiocin-sensitive, and the trehalose test indicated 11 positive isolates, which are considered atypical phenotypic results for this subspecies. In addition, 92.7% of the isolates identified as Shn by these methods carried mecA gene, while only 12.5% of the Shh isolates were positive. Together, the results highlighted the SDS-PAGE and MALDI-TOF MS methods as promising tools for discriminating S. hominis subspecies.
In utero exposure to acetaminophen and ibuprofen leads to intergenerational accelerated reproductive aging in female mice
Authors: Rossitto Moïra , Ollivier Margot , Déjardin Stéphanie , Pruvost Alain , Brun Christine , Marchive Candice , Nguyen Anvi Laetitia , Ghettas Aurélie , Keime Céline , de Massy Bernard , Poulat Francis , Philibert Pascal , Boizet-Bonhoure Brigitte 
Published: August 2019

AbstractNonsteroidal anti-inflammatory drugs (NSAIDs) and analgesic drugs, such as acetaminophen (APAP), are frequently taken during pregnancy, even in combination. However, they can favour genital malformations in newborn boys and reproductive disorders in adults. Conversely, the consequences on postnatal ovarian development and female reproductive health after in utero exposure are unknown. Here, we found that in mice, in utero exposure to therapeutic doses of the APAP-ibuprofen combination during sex determination led to delayed meiosis entry and progression in female F1 embryonic germ cells. Consequently, follicular activation was reduced in postnatal ovaries through the AKT/FOXO3 pathway, leading in F2 animals to subfertility, accelerated ovarian aging with abnormal corpus luteum persistence, due to decreased apoptosis and increased AKT-mediated luteal cell survival. Our study suggests that administration of these drugs during the critical period of sex determination could lead in humans to adverse effects that might be passed to the offspring.
Paper Spray Ionization Mass Spectrometry in Forensic Chemistry
Authors: Allochio Filho João Francisco , de Jesus Macrino Clebson , Lacerda Valdemar , Rodrigues Marcella Ferreira , Vaz Boniek G. , Romão Wanderson 
Published: August 2019

The chemical identification and determination of any kind of forensic evidence are often required in illegality investigations or even in legal prosecutions, and represent the main goal of forensic chemistry. A variety of types, forms, and complexity of evidence are commonly analyzed in forensic chemistry by different analytical techniques, e.g., hair, blood, urine, saliva, drugs, food, beverages, documents, gunshot residue, explosives, fire residue, agrochemicals, among others. Paper spray ionization mass spectrometry (PSI-MS) is an ambient technique of ionization that provides results quickly with high accuracy, sensitivity and reproducibility, employing a simple, non-destructive, and low-cost sampling procedure, very relevant in analysis of evidence in the forensic chemistry field. In this chapter, the most important methodologies and applications of the PSI-MS will be presented and discussed involving the forensic chemistry analysis in illicit drugs such as marijuana, cocaine, hallucinogens and new psychoactive substances, among others; in addition, the evaluation of agrochemicals, food adulterants, documentoscopy, and explosives will be displayed.
Future Challenges and Point-of-view
Authors: Paixão Thiago R. L. C. , Salles Maiara O. , Coltro Wendell K. T. 
Published: August 2019

This book has shown several forensic analytical methods applied to all kinds of forensic samples. Ten different topics were addressed in this book: forensic sampling and sample preparation, Atomic Absorption Spectrometry (AAS), Laser-induced Breakdown Spectroscopy (LIBS), Nuclear Magnetic Resonance (NMR), electrochemical devices, Scanning Electron Microscopy (SEM), Infrared (FTIR and NIRS), paper spray ionization mass spectroscopy, point-of-need and portable miniaturized devices and epigenetics. All of these topics were presented with different applications giving the reader a broad notion on how these analytical techniques are applied to forensic analysis. Nevertheless, there are still challenges in this area that can be overcome by the development of new methods, as will be addressed in this chapter.