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https://www.readbyqxmd.com/read/28732309/zebularine-induces-replication-dependent-double-strand-breaks-which-are-preferentially-repaired-by-homologous-recombination
#1
Manuel Luis Orta, Nuria Pastor, Estefanía Burgos-Morón, Inmaculada Domínguez, José Manuel Calderón-Montaño, Carlos Huertas Castaño, Miguel López-Lázaro, Thomas Helleday, Santiago Mateos
Zebularine is a second-generation, highly stable hydrophilic inhibitor of DNA methylation with oral bioavailability that preferentially target cancer cells. It acts primarily as a trap for DNA methyl transferases (DNMTs) protein by forming covalent complexes between DNMT protein and zebularine-substrate DNA. It's well documented that replication-blocking DNA lesions can cause replication fork collapse and thereby to the formation of DNA double-strand breaks (DSB). DSB are dangerous lesions that can lead to potentially oncogenic genomic rearrangements or cell death...
July 12, 2017: DNA Repair
https://www.readbyqxmd.com/read/28731447/chromatin-bound-oxidized-%C3%AE-synuclein-causes-strand-breaks-in-neuronal-genomes-in-in-vitro-models-of-parkinson-s-disease
#2
Velmarini Vasquez, Joy Mitra, Pavana M Hegde, Arvind Pandey, Shiladitya Sengupta, Sankar Mitra, K S Rao, Muralidhar L Hegde
Alpha-synuclein (α-Syn) overexpression and misfolding/aggregation in degenerating dopaminergic neurons have long been implicated in Parkinson's disease (PD). The neurotoxicity of α-Syn is enhanced by iron (Fe) and other pro-oxidant metals, leading to generation of reactive oxygen species in PD brain. Although α-Syn is predominantly localized in presynaptic nerve terminals, a small fraction exists in neuronal nuclei. However, the functional and/or pathological role of nuclear α-Syn is unclear. Following up on our earlier report that α-Syn directly binds DNA in vitro, here we confirm the nuclear localization and chromatin association of α-Syn in neurons using proximity ligation and chromatin immunoprecipitation analysis...
July 17, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28729543/evaluation-of-atm-heterozygous-mutations-underlying-individual-differences-in-radiosensitivity-using-genome-editing-in-human-cultured-cells
#3
Ekaterina Royba, Tatsuo Miyamoto, Silvia Natsuko Akutsu, Kosuke Hosoba, Hiroshi Tauchi, Yoshiki Kudo, Satoshi Tashiro, Takashi Yamamoto, Shinya Matsuura
Ionizing radiation (IR) induces DNA double-strand breaks (DSBs), which are an initial step towards chromosomal aberrations and cell death. It has been suggested that there are individual differences in radiosensitivity within human populations, and that the variations in DNA repair genes might determine this heterogeneity. However, it is difficult to quantify the effect of genetic variants on the individual differences in radiosensitivity, since confounding factors such as smoking and the diverse genetic backgrounds within human populations affect radiosensitivity...
July 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28729158/fixed-dose-combination-dolutegravir-abacavir-and-lamivudine-versus-ritonavir-boosted-atazanavir-plus-tenofovir-disoproxil-fumarate-and-emtricitabine-in-previously-untreated-women-with-hiv-1-infection-aria-week-48-results-from-a-randomised-open-label-non-inferiority
#4
Catherine Orrell, Debbie P Hagins, Elena Belonosova, Norma Porteiro, Sharon Walmsley, Vicenç Falcó, Choy Y Man, Alicia Aylott, Ann M Buchanan, Brian Wynne, Cindy Vavro, Michael Aboud, Kimberly Y Smith
BACKGROUND: Dolutegravir is a once-daily integrase strand transfer inhibitor with no need for pharmacokinetic boosting that is approved for the treatment of HIV-1 infection. Because women are often under-represented in HIV clinical trials, we addressed the safety and efficacy of dolutegravir in women with HIV-1. METHODS: The ARIA study is a randomised, open-label, multicentre, active-controlled, parallel-group, non-inferiority phase 3b study done in 86 hospital and university infectious disease clinics, local health clinics, and private infectious disease clinics in 12 countries and one US territory, in North America, South America, Europe, Africa, and Asia...
July 17, 2017: Lancet HIV
https://www.readbyqxmd.com/read/28727426/fully-atomistic-a%C3%AE-40-and-a%C3%AE-42-oligomers-in-water-observation-of-pore-like-conformations
#5
Matthew John Voelker, Bogdan Barz, Brigita Urbanc
Oligomers formed by amyloid β-protein (Aβ) are central to Alzheimer's disease (AD) pathology, yet their structure remains elusive. Of the two predominant Aβ alloforms, Aβ40 and Aβ42, the latter is more strongly associated with AD. Here, we structurally characterized Aβ40 and Aβ42 monomers through pentamers which were converted from previously derived coarse-grained (DMD4B-HYDRA) simulations into all-atom conformations and subjected to explicit-solvent MD. Free energy landscapes revealed that structural differences between Aβ40 and Aβ42 conformations increase with oligomer order up to trimers...
July 20, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28722656/corrupting-the-dna-damage-response-a-critical-role-for-rad52-in-tumor-cell-survival
#6
Rachel Lieberman, Ming You
The DNA damage response enables cells to survive, maintain genome integrity, and to safeguard the transmission of high-fidelity genetic information. Upon sensing DNA damage, cells respond by activating this multi-faceted DNA damage response leading to restoration of the cell, senescence, programmed cell death, or genomic instability if the cell survives without proper repair. However, unlike normal cells, cancer cells maintain a marked level of genomic instability. Because of this enhanced propensity to accumulate DNA damage, tumor cells rely on homologous recombination repair as a means of protection from the lethal effect of both spontaneous and therapy-induced double-strand breaks (DSBs) in DNA...
July 15, 2017: Aging
https://www.readbyqxmd.com/read/28718373/screening-of-specific-nucleic-acid-aptamers-binding-tumor-markers-in-the-serum-of-the-lung-cancer-patients-and-identification-of-their-activities
#7
Kun Li, Chen-Lin Xiu, Li-Ming Gao, Hua-Gang Liang, Shu-Feng Xu, Ming Shi, Jian Li, Zhi-Wei Liu
Lung cancer is by far the leading cause of cancer death in the world. Despite the improvements in diagnostic methods, the status of early detection was not achieved. So, a new diagnostic method is needed. The aim of this study is to obtain the highly specific nucleic acid aptamers with strong affinity to tumor markers in the serum of the lung cancer patients for targeting the serum. Aptamers specifically binding to tumor markers in the serum of the lung cancer patients were screened from the random single-stranded DNA library with agarose beads as supports and the serum as a target by target-substituting subtractive SELEX technique and real-time quantitative polymerase chain reaction technique...
July 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28717061/apobec-mediated-genomic-alterations-link-immunity-and-viral-infection-during-human-papillomavirus-driven-cervical-carcinogenesis
#8
Lanting Chen, Xuemin Qiu, Na Zhang, Yan Wang, Mingyan Wang, Dajin Li, Ling Wang, Yan Du
Cervical cancer is one of the most frequently diagnosed cancers and is a major cause of death from gynecologic cancers worldwide; the cancer burden from cervical cancer is especially heavy in less developed countries. Most cases of cervical cancer are caused by persistent infection with carcinogenic human papillomavirus (HPV) genotypes 16 and 18. Non-resolving inflammation caused by HPV infection provides a microenvironment that facilitates cancer development. Molecular alterations during the process of HPV-induced carcinogenesis are characterized by DNA methylation within the HPV genome, promoter hypermethylation of tumor suppressor genes in the host genome, as well as genomic instability caused by viral DNA integrating into the host genome...
July 17, 2017: Bioscience Trends
https://www.readbyqxmd.com/read/28716805/sensing-of-viral-and-endogenous-rna-by-zbp1-dai-induces-necroptosis
#9
Jonathan Maelfait, Layal Liverpool, Anne Bridgeman, Katherine B Ragan, Jason W Upton, Jan Rehwinkel
Nucleic acids are potent triggers for innate immunity. Double-stranded DNA and RNA adopt different helical conformations, including the unusual Z-conformation. Z-DNA/RNA is recognised by Z-binding domains (ZBDs), which are present in proteins implicated in antiviral immunity. These include ZBP1 (also known as DAI or DLM-1), which induces necroptosis, an inflammatory form of cell death. Using reconstitution and knock-in models, we report that mutation of key amino acids involved in Z-DNA/RNA binding in ZBP1's ZBDs prevented necroptosis upon infection with mouse cytomegalovirus...
July 17, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28715428/cip29-is-phosphorylated-following-activation-of-the-dna-damage-response-in-xenopus-egg-extracts
#10
Janet Holden, Elaine M Taylor, Howard D Lindsay
Acting through a complex signalling network, DNA lesions trigger a range of cellular responses including DNA repair, cell cycle arrest, altered gene expression and cell death, which help to limit the mutagenic effects of such DNA damage. RNA processing factors are increasingly being recognised as important targets of DNA damage signalling, with roles in the regulation of gene expression and also more directly in the promotion of DNA repair. In this study, we have used a Xenopus laevis egg extract system to analyse the DNA damage-dependent phosphorylation of a putative RNA export factor, Cip29...
2017: PloS One
https://www.readbyqxmd.com/read/28710759/rapid-detection-of-%C3%AE-h2ax-by-flow-cytometry-in-cultured-mammalian-cells
#11
Denis Firsanov, Liudmila Solovjeva, Olga Lublinskaya, Valeriy Zenin, Igor Kudryavtsev, Maria Serebryakova, Maria Svetlova
Methods commonly used for detection of DNA double-strand breaks (DSBs) and analysis of cell death are generally time-consuming, and, therefore, any improvements in these techniques are important for researchers and clinicians. At present, flow cytometry is the most rapid method for detection of DSBs and cell viability. In this chapter, we provide our experience and methodological modification of flow cytometry protocol for the detection of γ-H2AX, a well-known marker of DSBs, in fixed mammalian fibroblasts...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28710417/talen-based-hpv-e7-editing-triggers-necrotic-cell-death-in-cervical-cancer-cells
#12
Sumitra Shankar, Deepti Prasad, Rahul Sanawar, Ani V Das, M Radhakrishna Pillai
Human Papillomavirus E7 and E6 oncoproteins have been considered as suitable candidate anti-viral targets since they cause malignant conversion in cervical cancers. Transcription Activator-Like Effector Nucleases (TALENs) are recent editing tools to knockout genes by inducing double stranded breaks at specific sites in the genome. In here, we have designed specific TALENs to target E7 and analyzed their efficiency in inducing cell death in cervical cancer cells. We found that designed TALENs could yield about 10-12% editing activity as observed from T7E1 and nuclease resistance assays...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28706768/dna-pk-and-p38-mapk-a-kinase-collusion-in-alzheimer-s-disease
#13
Jyotshna Kanungo
The pathogenesis of Alzheimer's disease (AD), characterized by prevalent neuronal death and extracellular deposit of amyloid plaques, is poorly understood. DNA lesions downstream of reduced DNA repair ability have been reported in AD brains. Neurons predominantly use a mechanism to repair double-strand DNA breaks (DSB), which is non-homologous end joining (NHEJ). NHEJ requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK is a holoenzyme comprising the p460 kD catalytic subunit (DNA-PKcs) and its activator Ku, a heterodimer of p86 and p70 subunits...
2017: Brain Disorders & Therapy
https://www.readbyqxmd.com/read/28704486/a-common-bottlenose-dolphin-tursiops-truncatus-prey-handling-technique-for-marine-catfish-ariidae-in-the-northern-gulf-of-mexico
#14
Errol I Ronje, Kevin P Barry, Carrie Sinclair, Mark A Grace, Nélio Barros, Jason Allen, Brian Balmer, Anna Panike, Christina Toms, Keith D Mullin, Randall S Wells
Few accounts describe predator-prey interactions between common bottlenose dolphins (Tursiops truncatus Montagu 1821) and marine catfish (Ariopsis felis Linnaeus 1766, Bagre marinus Mitchill 1815). Over the course of 50,167 sightings of bottlenose dolphin groups in Mississippi Sound and along the Florida coast of the Gulf of Mexico, severed catfish heads were found floating and exhibiting movements at the surface in close proximity to 13 dolphin groups that demonstrated feeding behavior. These observations prompted a multi-disciplinary approach to study the predator-prey relationship between bottlenose dolphins and marine catfish...
2017: PloS One
https://www.readbyqxmd.com/read/28703119/dna-double-strand-break-dsb-induction-and-cell-survival-in-iodine-enhanced-computed-tomography-ct
#15
Seth W Streitmatter, Robert D Stewart, Peter A Jenkins, Tatjana Jevremovic
A multi-scale Monte Carlo model is proposed to assess the dosimetric and biological impact of iodine-based contrast agents commonly used in computed tomography. As presented, the model integrates the general purpose MCNP6 code system for larger-scale radiation transport and dose assessment with the Monte Carlo damage simulation to determine the sub-cellular characteristics and spatial distribution of initial DNA damage. The repair-misrepair-fixation model is then used to relate DNA double strand break (DSB) induction to reproductive cell death...
July 13, 2017: Physics in Medicine and Biology
https://www.readbyqxmd.com/read/28702377/dsrna-binding-domain-of-pkr-is-proteolytically-released-by-enterovirus-a71-to-facilitate-viral-replication
#16
Yu-Hsiu Chang, Kean Seng Lau, Rei-Lin Kuo, Jim-Tong Horng
Enterovirus 71 (EV-A71) causes hand, foot and mouth disease in young children and infants, but can also cause severe neurological complications or even death. The double-stranded RNA (dsRNA)-dependent protein kinase R (PKR), an interferon-induced antiviral protein, phosphorylates the regulatory α-subunit of the eukaryotic translation initiation factor 2 in response to viral infection, thereby blocking the translation of cellular and viral mRNA and promoting apoptosis. The cleavage of PKR after infection with poliovirus, a prototype enterovirus, has been reported by others, but the underlying mechanism of this cleavage and its role in viral replication remain unclear...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28701259/markers-of-protein-synthesis-are-increased-in-fetal-membranes-and-myometrium-after-human-labour-and-delivery
#17
Stella Liong, Martha Lappas
Preterm birth remains one of the leading causes of neonatal death. Inflammation and maternal infection are two of the leading aetiological factors for preterm birth. Labour is associated with increased production of proinflammatory cytokines, chemokines and prolabour mediators in human gestational tissues. In non-gestational tissues, synthesis of proinflammatory and prolabour mediators is regulated by components of the protein synthesis machinery. Therefore, in the present study we investigated the effect of human labour on the expression of three protein synthesis markers, namely eukaryotic elongation factor 2 kinase (EEF2K), mitogen-activated protein kinase interacting protein kinase 1 (MKNK1) and eukaryotic translation initiation factor 4E (EIF4E), and their role in regulating inflammation in human gestational tissues...
July 13, 2017: Reproduction, Fertility, and Development
https://www.readbyqxmd.com/read/28693558/zinc-as-an-adjunct-treatment-for-reducing-case-fatality-due-to-clinical-severe-infection-in-young-infants-study-protocol-for-a-randomized-controlled-trial
#18
Nitya Wadhwa, Sudha Basnet, Uma Chandra Mouli Natchu, Laxman P Shrestha, Shinjini Bhatnagar, Halvor Sommerfelt, Tor A Strand, Siddarth Ramji, K C Aggarwal, Harish Chellani, Anuradha Govil, Mamta Jajoo, N B Mathur, Meenakshi Bhatt, Anup Mohta, Imran Ansari, Srijana Basnet, Ram H Chapagain, Ganesh P Shah, Binod M Shrestha
BACKGROUND: An estimated 2.7 of the 5.9 million deaths in children under 5 years of age occur in the neonatal period. Severe infections contribute to almost a quarter of these deaths. Mortality due to severe infections in developing country settings is substantial despite antibiotic therapy. Effective interventions that can be added to standard therapy for severe infections are required to reduce case fatality. METHODS/DESIGN: This is a double-blind randomized placebo-controlled parallel group superiority trial to investigate the effect of zinc administered orally as an adjunct to standard therapy to infants aged 3 days up to 2 months (59 days) hospitalized with clinical severe infection, that will be undertaken in seven hospitals in Delhi, India and Kathmandu, Nepal...
July 10, 2017: BMC Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28690049/initial-validation-of-blubber-cortisol-and-progesterone-as-indicators-of-stress-response-and-maturity-in-an-otariid-the-california-sea-lion-zalophus-californianus
#19
Nicole E Beaulieu-McCoy, Kathryn K Sherman, Marisa L Trego, Daniel E Crocker, Nicholas M Kellar
Chronic stress can have detrimental effects on an individual's health and reproductive success. The use of cortisol quantification as an indicator of stress in free-ranging cetaceans and phocids is increasing but no studies have applied this technique on blubber in otariids. We measured cortisol concentrations in blubber samples obtained from California sea lions, Zalophus californianus, stranded in San Diego County and those incidentally killed in the California drift gillnet fishery. We also measured progesterone concentrations to assess female reproductive status and, in males, as a potential secondary measure of adrenal steroid production...
July 6, 2017: General and Comparative Endocrinology
https://www.readbyqxmd.com/read/28689664/global-regional-and-national-disease-burden-estimates-of-acute-lower-respiratory-infections-due-to-respiratory-syncytial-virus-in-young-children-in-2015-a-systematic-review-and-modelling-study
#20
Ting Shi, David A McAllister, Katherine L O'Brien, Eric A F Simoes, Shabir A Madhi, Bradford D Gessner, Fernando P Polack, Evelyn Balsells, Sozinho Acacio, Claudia Aguayo, Issifou Alassani, Asad Ali, Martin Antonio, Shally Awasthi, Juliet O Awori, Eduardo Azziz-Baumgartner, Henry C Baggett, Vicky L Baillie, Angel Balmaseda, Alfredo Barahona, Sudha Basnet, Quique Bassat, Wilma Basualdo, Godfrey Bigogo, Louis Bont, Robert F Breiman, W Abdullah Brooks, Shobha Broor, Nigel Bruce, Dana Bruden, Philippe Buchy, Stuart Campbell, Phyllis Carosone-Link, Mandeep Chadha, James Chipeta, Monidarin Chou, Wilfrido Clara, Cheryl Cohen, Elizabeth de Cuellar, Duc-Anh Dang, Budragchaagiin Dash-Yandag, Maria Deloria-Knoll, Mukesh Dherani, Tekchheng Eap, Bernard E Ebruke, Marcela Echavarria, Carla Cecília de Freitas Lázaro Emediato, Rodrigo A Fasce, Daniel R Feikin, Luzhao Feng, Angela Gentile, Aubree Gordon, Doli Goswami, Sophie Goyet, Michelle Groome, Natasha Halasa, Siddhivinayak Hirve, Nusrat Homaira, Stephen R C Howie, Jorge Jara, Imane Jroundi, Cissy B Kartasasmita, Najwa Khuri-Bulos, Karen L Kotloff, Anand Krishnan, Romina Libster, Olga Lopez, Marilla G Lucero, Florencia Lucion, Socorro P Lupisan, Debora N Marcone, John P McCracken, Mario Mejia, Jennifer C Moisi, Joel M Montgomery, David P Moore, Cinta Moraleda, Jocelyn Moyes, Patrick Munywoki, Kuswandewi Mutyara, Mark P Nicol, D James Nokes, Pagbajabyn Nymadawa, Maria Tereza da Costa Oliveira, Histoshi Oshitani, Nitin Pandey, Gláucia Paranhos-Baccalà, Lia N Phillips, Valentina Sanchez Picot, Mustafizur Rahman, Mala Rakoto-Andrianarivelo, Zeba A Rasmussen, Barbara A Rath, Annick Robinson, Candice Romero, Graciela Russomando, Vahid Salimi, Pongpun Sawatwong, Nienke Scheltema, Brunhilde Schweiger, J Anthony G Scott, Phil Seidenberg, Kunling Shen, Rosalyn Singleton, Viviana Sotomayor, Tor A Strand, Agustinus Sutanto, Mariam Sylla, Milagritos D Tapia, Somsak Thamthitiwat, Elizabeth D Thomas, Rafal Tokarz, Claudia Turner, Marietjie Venter, Sunthareeya Waicharoen, Jianwei Wang, Wanitda Watthanaworawit, Lay-Myint Yoshida, Hongjie Yu, Heather J Zar, Harry Campbell, Harish Nair
BACKGROUND: We have previously estimated that respiratory syncytial virus (RSV) was associated with 22% of all episodes of (severe) acute lower respiratory infection (ALRI) resulting in 55 000 to 199 000 deaths in children younger than 5 years in 2005. In the past 5 years, major research activity on RSV has yielded substantial new data from developing countries. With a considerably expanded dataset from a large international collaboration, we aimed to estimate the global incidence, hospital admission rate, and mortality from RSV-ALRI episodes in young children in 2015...
July 6, 2017: Lancet
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