Structural and Functional Relationships of FAN1

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Hyeonseok Jin, Yunje Cho
FANCD2/FANCI-associated nuclease (FAN1) is a 5′ flap structure-specific endonuclease and 5′ to 3′ exonuclease. This nuclease can resolve interstrand cross-links (ICLs) independently of the Fanconi anemia (FA) pathway and controls the progression of stalled replication forks in an FA-dependent manner, thereby maintaining chromosomal stability. Several FAN1 mutations are observed in various cancers and degenerative diseases. Recently, several crystal structures of the FAN1-DNA complexes have been reported, and to date, these represent the only structures for a DNA bound ICL-repair nuclease. Puzzlingly, human FAN1 forms two different quaternary structures with different DNA binding modes, and based on these structures, two ICL-repair mechanisms have been proposed. In one mechanism, monomeric FAN1 recognizes the 5′ flap terminal phosphate via a basic pocket and successively cleaves at every third nucleotide of the DNA substrates. In the other mechanism, dimeric FAN1 scans, latches, and unwinds the postnick duplex of the substrate DNA to direct the scissile phosphodiester group to the active site. In this review, we discuss the structures, function, and proposed mechanisms of FAN1 nuclease, and provide the insights into its role in ICL repair and in processing of stalled replication forks.



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Histone ubiquitination in the DNA damage response

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Michael Uckelmann, Titia K. Sixma
DNA double strand breaks need to be repaired in an organized fashion to preserve genomic integrity. In the organization of faithful repair, histone ubiquitination plays a crucial role. Recent findings suggest an integrated model for DNA repair regulation through site-specific histone ubiquitination and crosstalk to other posttranslational modifications. Here we discuss how site-specific histone ubiquitination is achieved on a molecular level and how different multi-protein complexes work together to integrate different histone ubiquitination states. We propose a model where site-specific H2A ubiquitination organizes the spatio-temporal recruitment of DNA repair factors which will ultimately contribute to DNA repair pathway choice between homologous recombination and non-homologous end joining.



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Unveiling the non-repair face of the base excision repair pathway in RNA processing: A missing link between DNA repair and gene expression?

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Giulia Antoniali, Matilde Clarissa Malfatti, Gianluca Tell
The Base Excision Repair (BER) pathway, initially studied as a mere DNA repair pathway, has been later found to be implicated in the expression of cancer related genes in human. For several years, this intricate involvement in apparently different processes represented a mystery, which we now are starting to unveil.The BER handles simple alkylation and oxidative lesions arising from both endogenous and exogenous sources, including cancer therapy agents. Surprisingly, BER pathway involvement in transcriptional regulation, immunoglobulin variability and switch recombination, RNA metabolism and nucleolar function is astonishingly consolidating. An emerging evidence in tumor biology is that RNA processing pathways participate in DNA Damage Response (DDR) and that defects in these regulatory connections are associated with genomic instability of cancers. In fact, many BER proteins are associated with those involved in RNA metabolism, ncRNA processing and transcriptional regulation, including within the nucleolus, proving a substantial role of the interactome network in determining their non-canonical functions in tumor cells. Maybe these new insights of BER enzymes, along with their emerging function in RNA-decay, may explain BER essential role in tumor development and chemoresistance and may explain the long-time mystery. Here, we would like to summarize different roles of BER pathway in human cells. First, we will give a short description of the classical BER pathway, which has been covered in detail in recent reviews. We will then outline potential new roles of BER in gene expression and RNA metabolism. Although recent works have provided tremendous amount of data in this field, there are still lot of open questions.



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DNA Repair and Systemic Lupus Erythematosus

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Rithy Meas, Matthew J. Burak, Joann B. Sweasy
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with no known cure that affects at least five million people worldwide. Monozygotic twin concordance and familial aggregation studies strongly suggest that lupus results from genetic predisposition along with environmental exposures including UV light. The majority of the common risk alleles associated with genetic predisposition to SLE map to genes associated with the immune system. However, evidence is emerging that implicates a role for aberrant DNA repair in the development of lupus. Here we summarize our current knowledge of the potential association of lupus with mutations in DNA repair genes. We also discuss how defective or aberrant DNA repair could lead to the development of lupus.



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8-Oxo-7,8-dihydroguanine, friend and foe: Epigenetic-like regulator versus initiator of mutagenesis

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Aaron M. Fleming, Cynthia J. Burrows
A high flux of reactive oxygen species during oxidative stress results in oxidative modification of cellular components including DNA. Oxidative DNA "damage" to the heterocyclic bases is considered deleterious because polymerases may incorrectly read the modifications causing mutations. A prominent member in this class is the oxidized guanine base 8-oxo-7,8-dihydroguanine (OG) that is moderately mutagenic effecting G→T transversion mutations. Recent reports have identified that formation of OG in G-rich regulatory elements in the promoters of the VEGF, TNFα, and SIRT1 genes can increase transcription via activation of the base excision repair (BER) pathway. Work in our laboratory with the G-rich sequence in the promoter of VEGF concluded that BER drives a shift in structure to a G-quadruplex conformation leading to gene activation in mammalian cells. More specifically, removal of OG from the duplex context by 8-oxoguanine glycosylase 1 (OGG1) produces an abasic site (AP) that destabilizes the duplex, shifting the equilibrium toward the G-quadruplex fold because of preferential extrusion of the AP into a loop. The AP is bound but inefficiently cleaved by apurinic/apyrimidinic endoDNase I (APE1) that likely allows recruitment of activating transcription factors for gene induction. The ability of OG to induce transcription ascribes a regulatory or epigenetic-like role for this oxidatively modified base. We compare OG to the 5-methylcytosine (5mC) epigenetic pathway including its oxidized derivatives, some of which poise genes for transcription while also being substrates for BER. The mutagenic potential of OG to induce only ∼one-third the number of mutations (G→T) compared to deamination of 5mC producing C→T mutations is described. These comparisons blur the line between friendly epigenetic base modifications and those that are foes, i.e. DNA "damage," causing genetic mutations.



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BERing the burden of damage: Pathway crosstalk and posttranslational modification of base excision repair proteins regulate DNA damage management

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Kristin Limpose, Anita H. Corbett, Paul W. Doetsch
DNA base damage and non-coding apurinic/apyrimidinic (AP) sites are ubiquitous types of damage that must be efficiently repaired to prevent mutations. These damages can occur in both the nuclear and mitochondrial genomes. Base excision repair (BER) is the frontline pathway for identifying and excising damaged DNA bases in both of these cellular compartments. Recent advances demonstrate that BER does not operate as an isolated pathway but rather dynamically interacts with components of other DNA repair pathways to modulate and coordinate BER functions. We define the coordination and interaction between DNA repair pathways as pathway crosstalk. Numerous BER proteins are modified and regulated by post-translational modifications (PTMs), and PTMs could influence pathway crosstalk. Here, we present recent advances on BER/DNA repair pathway crosstalk describing specific examples and also highlight regulation of BER components through PTMs. We have organized and reported functional interactions and documented PTMs for BER proteins into a consolidated summary table. We further propose the concept of DNA repair hubs that coordinate DNA repair pathway crosstalk to identify central protein targets that could play a role in designing future drug targets.



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Evaluation of two novel techniques for increasing radial artery size: a pilot study utilizing volunteers

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Electronic medical record interventions and recurrent perioperative antibiotic administration: a before-and-after study

Abstract

Purpose

Perioperative antibiotics decrease rates of surgical-site infections. Numerous interventions have improved administration of the first antibiotic dose; however, failures in the administration of subsequent doses frequently occur. We hypothesized that modifications to the electronic medical record (EMR) would improve the administration of the second antibiotic dose and that such improvements would be sustained over time.

Methods

This historical cohort before-and-after study of multipronged alerts in the EMR analyzed 1,348 operations on adult patients. The operations lasted ≥ 240 min, utilized cefazolin as the perioperative antibiotic—constituting 1,348 second and 182 third intraoperative antibiotic doses—and did not involve cardiopulmonary bypass. A decision support intervention provided dosing recommendations when clinicians documented antibiotics. The reminder intervention displayed a continuous bar in the EMR, starting at the time the antibiotics were dosed and ending 15 min before subsequent doses were indicated. The primary endpoints of the study were the change in the proportion of correctly administered second dose of cefazolin, given in accordance with hospital guidelines in the month after implementing the intervention, and whether any improvements declined by three to seven months after implementation.

Results

Pre-intervention, 51.4% of second doses of cefazolin were correctly administered. In the immediate post-intervention period, 68.5% were correctly administered, representing a significant absolute improvement of 17.1% (95% confidence interval, 8.1 to 26.1; P < 0.001). Rates did not decline over time; clinicians correctly administered 73.3% of doses in the delayed post-intervention period (P < 0.001 vs pre-intervention).

Conclusions

These inexpensive nonintrusive interventions to the EMR provided modest lasting improvements in proper administration of repeated doses of cefazolin. The fact that only approximately 70% compliance was reached highlights the difficulty in addressing this deficiency.

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In reply: Anesthesia bronchoscopes and CSA Standard Z314.8-14

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Poetry in motion: Increased chromosomal mobility after DNA damage

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Michael J. Smith, Rodney Rothstein
Double-strand breaks (DSBs) are among the most lethal DNA lesions, and a variety of pathways have evolved to manage their repair in a timely fashion. One such pathway is homologous recombination (HR), in which information from an undamaged donor site is used as a template for repair. Although many of the biochemical steps of HR are known, the physical movements of chromosomes that must underlie the pairing of homologous sequence during mitotic DSB repair have remained mysterious. Recently, several groups have begun to use a variety of genetic and cell biological tools to study this important question. These studies reveal that both damaged and undamaged loci increase the volume of the nuclear space that they explore after the formation of DSBs. This DSB-induced increase in chromosomal mobility is regulated by many of the same factors that are important during HR, such as ATR-dependent checkpoint activation and the recombinase Rad51, suggesting that this phenomenon may facilitate the search for homology. In this perspective, we review current research into the mobility of chromosomal loci during HR, as well as possible underlying mechanisms, and discuss the critical questions that remain to be answered. Although we focus primarily on recent studies in the budding yeast, Saccharomyces cerevisiae, examples of experiments performed in higher eukaryotes are also included, which reveal that increased mobility of damaged loci is a process conserved throughout evolution.



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Dormant origins as a built-in safeguard in eukaryotic DNA replication against genome instability and disease development

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Naoko Shima, Kayla D. Pederson
DNA replication is a prerequisite for cell proliferation, yet it can be increasingly challenging for a eukaryotic cell to faithfully duplicate its genome as its size and complexity expands. Dormant origins now emerge as a key component for cells to successfully accomplish such a demanding but essential task. In this perspective, we will first provide an overview the fundamental processes eukaryotic cells have developed to regulate origin licensing and firing. With a special focus on mammalian systems, we will then highlight the role of dormant origins in preventing replication-associated genome instability and their functional interplay with proteins involved in the DNA damage repair response for tumor suppression. Lastly, deficiencies in the origin licensing machinery will be discussed in relation to its influence on stem cell maintenance and human diseases.



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DNA requirements for interaction of the C-terminal region of Ku80 with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs)

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Sarvan Kumar Radhakrishnan, Susan P. Lees-Miller
Non-homologous end joining (NHEJ) is the major pathway for the repair of ionizing radiation induced DNA double strand breaks (DSBs) in human cells. Critical to NHEJ is the DNA-dependent interaction of the Ku70/80 heterodimer with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form the DNA-PK holoenzyme. However, precisely how Ku recruits DNA-PKcs to DSBs ends to enhance its kinase activity has remained enigmatic, with contradictory findings reported in the literature. Here we address the role of the Ku80 C-terminal region (CTR) in the DNA-dependent interaction of Ku70/80 with DNA-PKcs using purified components and defined DNA structures. Our results show that the Ku80 CTR is required for interaction with DNA-PKcs on short segments of blunt ended 25bp dsDNA or 25bp dsDNA with a 15-base poly dA single stranded (ss) DNA extension, but this requirement is less stringent on longer dsDNA molecules (35bp blunt ended dsDNA) or 25bp duplex DNA with either a 15-base poly dT or poly dC ssDNA extension. Our work clarifies the role of the Ku80 CTR and dsDNA ends on the interaction of DNA-PKcs with Ku and provides key information to guide assembly and biology of NHEJ complexes.



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Ultrasonography-guided modified thoracolumbar interfascial plane block: a new approach

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Role of recombination and replication fork restart in repeat instability

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Erica J. Polleys, Nealia C.M. House, Catherine H. Freudenreich
Eukaryotic genomes contain many repetitive DNA sequences that exhibit size instability. Some repeat elements have the added complication of being able to form secondary structures, such as hairpin loops, slipped DNA, triplex DNA or G-quadruplexes. Especially when repeat sequences are long, these DNA structures can form a significant impediment to DNA replication and repair, leading to DNA nicks, gaps, and breaks. In turn, repair or replication fork restart attempts within the repeat DNA can lead to addition or removal of repeat elements, which can sometimes lead to disease. One important DNA repair mechanism to maintain genomic integrity is recombination. Though early studies dismissed recombination as a mechanism driving repeat expansion and instability, recent results indicate that mitotic recombination is a key pathway operating within repetitive DNA. The action is two-fold: first, it is an important mechanism to repair nicks, gaps, breaks, or stalled forks to prevent chromosome fragility and protect cell health; second, recombination can cause repeat expansions or contractions, which can be deleterious. In this review, we summarize recent developments that illuminate the role of recombination in maintaining genome stability at DNA repeats.



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A systematic review of vasopressor blood pressure targets in critically ill adults with hypotension

Abstract

Purpose

Clinicians must balance the risks from hypotension with the potential adverse effects of vasopressors. Experts have recommended a mean arterial pressure (MAP) target of at least 65 mmHg, and higher in older patients and in patients with chronic hypertension or atherosclerosis. We conducted a systematic review of randomized-controlled trials comparing higher vs lower blood pressure targets for vasopressor therapy administered to hypotensive critically ill patients.

Methods

We searched MEDLINE®, EMBASE™, and the Cochrane Central Register of Controlled Trials for studies of higher vs lower blood pressure targets for vasopressor therapy in critically ill hypotensive adult patients. Two reviewers independently assessed trial eligibility based on titles and abstracts, and they then selected full-text reports. Outcomes, subgroups, and analyses were prespecified. We used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to rate the overall confidence in the estimates of intervention effects.

Results

Of 8001 citations, we retrieved 57 full-text articles and ultimately included two randomized-controlled trials (894 patients). Higher blood pressure targets were not associated with lower mortality (relative risk [RR], 1.05; 95% confidence interval [CI], 0.90 to 1.23; P = 0.54), and neither age (P = 0.17) nor chronic hypertension (P = 0.32) modified the overall effect. Nevertheless, higher blood pressure targets were associated with a greater risk of new-onset supraventricular cardiac arrhythmia (RR, 2.08; 95% CI, 1.28 to 3.38; P < 0.01).

Conclusion

Current evidence does not support a MAP target > 70 mmHg in hypotensive critically ill adult patients requiring vasopressor therapy.

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CtIP/Ctp1/Sae2, Molecular Form Fit For Function

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Sara N. Andres, R. Scott Williams
Vertebrate CtIP, and its fission yeast (Ctp1), budding yeast (Sae2) and plant (Com1) orthologs have emerged as key regulatory molecules in cellular responses to DNA double strand breaks (DSBs). By modulating the nucleolytic 5′-3′ resection activity of the Mre11/Rad50/Nbs1 (MRN) DSB repair processing and signaling complex, CtIP/Ctp1/Sae2/Com1 is integral to the channeling of DNA double strand breaks through DSB repair by homologous recombination (HR). Nearly two decades since its discovery, emerging new data are defining the molecular underpinnings for CtIP DSB repair regulatory activities. CtIP homologs are largely intrinsically unstructured proteins comprised of expanded regions of low complexity sequence, rather than defined folded domains typical of DNA damage metabolizing enzymes and nucleases. A compact structurally conserved N-terminus forms a functionally critical tetrameric helical dimer of dimers (THDD) region that bridges CtIP oligomers, and is flexibly appended to a conserved C-terminal Sae2-homology DNA binding and DSB repair pathway choice regulatory hub which influences nucleolytic activities of the MRN core nuclease complex. The emerging evidence from structural, biophysical, and biological studies converges on CtIP having functional roles in DSB repair that include: 1) dynamic DNA strand coordination through direct DNA binding and DNA bridging activities, 2) MRN nuclease complex cofactor functions that direct MRN endonucleolytic cleavage of protein-blocked DSB ends and 3) acting as a protein binding hub targeted by the cell cycle regulatory apparatus, which influences CtIP expression and activity via layers of post-translational modifications, protein-protein interactions and DNA binding.



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Bed Partner Often Fuels Loved One's Insomnia

FRIDAY, June 9, 2017 -- If your bed partner routinely struggles to fall asleep, you probably have some well-meaning advice. But it may be best to keep it to yourself. Australian sleep specialists found that when a loved one had insomnia, the...

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New Drugs Show Promise as First to Prevent Migraine

FRIDAY, June 9, 2017 -- A host of new drugs that appear to prevent migraine headaches are in the final stages of testing and approval in the United States. "What's really exciting about this is that until this development, we have not had a...

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In Vitro Evaluation of 188Re-HEDP: A Mechanistic View of Bone Pain Palliations

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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WATCH: 7-year-old who survived cancer poses with 1st day of school photo

Sophi Eber's teacher took a picture of her on the last day of first grade at Renner Elementary School in Kansas City, Missouri, on May 25. (Source: ABC News: Health)

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Genetic diversity of human papillomavirus types 35, 45 and 58 in cervical cancer in Brazil

AbstractIn Brazil, most studies of intra-type variants of human papillomavirus (HPV) have focused on HPV16 and HPV18, but other high-risk HPV types have not been studied. Here, we report the prevalence of lineages and variants of HPV35, HPV45 and HPV58 in cervical cancers from the Amazonian and Southeast Brazilian regions. The most frequent sublineages were A1 for HPV35, B2 for HPV45, and A2 for HPV58. The Southeast region had a higher frequency of the B2 sublineage of HPV45, and for HPV35, the genetic and nucleotide sequence diversity were higher in the Southeast region, suggesting that regional factors are influencing the diversity and lineage prevalence. (Source: Archives of Virology)

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RIG-I: a multifunctional protein beyond a pattern recognition receptor.

Authors: Xu XX, Wan H, Nie L, Shao T, Xiang LX, Shao JZ Abstract It was widely known that retinoic acid inducible gene I (RIG-I) functions as a cytosolic pattern recognition receptor that initiates innate antiviral immunity by detecting exogenous viral RNAs. However, recent studies showed that RIG-I participates in other various cellular activities by sensing endogenous RNAs under different circumstances. For example, RIG-I facilitates the therapy resistance and expansion of breast cancer cells and promotes T cell-independent B cell activation through interferon signaling activation by recognizing non-coding RNAs and endogenous retroviruses in certain situations. While in hepatocellular carcinoma and acute myeloid leukemia, RIG-I acts as a tumor suppressor through either augmenting...

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Attitudes and Perceptions of Cancer Patients Toward Biospecimen Donation for Cancer Research: A Cross-Sectional Survey Among Chinese Cancer Patients.

CONCLUSIONS: Most Chinese cancer patients were willing to consider donating blood and tissue samples for cancer research. Several factors, including age, gender, first hospitalization, and education level, can influence their willingness to donate biospecimens. We need to provide proper education to increase understanding of patients in biobanking activities. IMPACT: This study provides novel empirical data on the likelihood of donating surplus and additional biospecimens and clinical health information among Chinese cancer patients. PMID: 28594242 [PubMed - as supplied by publisher] (Source: Biopreservation and Biobanking)

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Hospital cancer screenings - Hood River News

Hospital cancer screenings Hood River News #Receive a free screening for cancers that arise in the head or neck region, including the nasal cavity, sinuses, lips, mouth, thyroid glands, salivary glands, throat, or larynx (voice box). #Registration is strongly recommended. To register, or for ...

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Evolutionary Dynamics and Significance of Multiple Subclonal Mutations in Cancer

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Robert A. Beckman, Lawrence A. Loeb
For the last 40 years the authors have collaborated on trying to understand the complexities of human cancer by formulating testable mathematical models that are based on mutation accumulation in human malignancies. We summarize the concepts encompassed by multiple mutations in human cancers in the context of source, accumulation during carcinogenesis and tumor progression, and therapeutic consequences. We conclude that the efficacious treatment of human cancer by targeted therapy will involve individualized, uniquely directed specific agents singly and in simultaneous combinations, and take into account the importance of targeting resistant subclonal mutations, particularly those subclones with alterations in DNA repair genes, DNA polymerase, and other genes required to maintain genetic stability.



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The Top1 paradox: friend and foe of the eukaryotic genome

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Nayun Kim, Sue Jinks-Robertson
Topoisomerases manage the torsional stress associated with the separation of DNA strands during transcription and DNA replication. Eukaryotic Topoisomerase I (Top1) is a Type IB enzyme that nicks and rejoins only one strand of duplex DNA, and it is especially important during transcription. By resolving transcription-associated torsional stress, Top1 reduces the accumulation of genome-destabilizing R-loops and non-B DNA structures. The DNA nicking activity of Top1, however, can also initiate genome instability in the form of illegitimate recombination, homologous recombination and mutagenesis. In this review, we focus on the diverse, and often opposing, roles of Top1 in regulating eukaryotic genome stability.



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Close encounters: moving along bumps, breaks, and bubbles on expanded trinucleotide tracts

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Aris Polyzos, Cynthia McMurray
Expansion of simple triplet repeats (TNR) underlies more than 30 severe degenerative diseases. There is a good understanding of the major pathways generating an expansion, and the associated polymerases that operate during gap filling synthesis at these "difficult to copy" sequences. However, the mechanism by which a TNR is repaired depends on the type of lesion, the structural features imposed by the lesion, the assembled replication/repair complex, and the polymerase that encounters it. The relationships among these parameters are exceptionally complex and how they direct pathway choice is poorly understood. In this review, we consider the properties of polymerases, and how encounters with GC-rich or abnormal structures might influence polymerase choice and the success of replication and repair. Insights over the last three years have highlighted new mechanisms that provide interesting choices to consider in protecting genome stability.



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Taming Tricky DSBs: ATM on duty

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Thomas Clouaire, Aline Marnef, Gaëlle Legube
Ataxia Telangiectasia Mutated (ATM) has been known for decades as the main kinase mediating the DNA Double-Strand Break Response (DDR). Extensive studies have revealed its dual role in locally promoting detection and repair of DSBs as well as in activating global DNA damage checkpoints. However, recent studies pinpoint additional unanticipated functions for ATM in modifying both the local chromatin landscape and the global chromosome organization, more particularly at persistent breaks. Given the emergence of a novel and unexpected class of DSBs prevalently arising in transcriptionally active genes and intrinsically difficult to repair, a specific role of ATM at refractory DSBs could be an important and so far overlooked feature of Ataxia Telangiectasia (A-T) a severe disorder associated with ATM mutations.



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Value of diagnostic imaging for the symptomatic male breast: Can we avoid unnecessary biopsies?

Publication date: Available online 9 June 2017
Source:Clinical Imaging
Author(s): Eric T. Foo, Amie Y. Lee, Kimberly M. Ray, Genevieve A. Woodard, Rita I. Freimanis, Bonnie N. Joe
PurposeTo review the use of diagnostic breast imaging and outcomes for symptomatic male patients.MethodsWe retrospectively evaluated 122 males who underwent diagnostic imaging for breast symptoms at our academic center.ResultsThe majority (94%) of cases had negative or benign imaging, with gynecomastia being the most common diagnosis (78%). There were two malignancies, both of which had positive imaging. Fifteen patients underwent percutaneous biopsy, and over half (53%) were palpation-guided biopsies initiated by the referring clinician despite negative imaging. Diagnostic imaging demonstrated 100% sensitivity and 96% specificity for identifying cancer.ConclusionsMalignancy is rarely a cause of male breast symptoms. Diagnostic breast imaging is useful to establish benignity and avert unnecessary biopsies.



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Genome Instabilities Arising from Ribonucleotides in DNA

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Hannah L. Klein
Genomic DNA is transiently contaminated with ribonucleotide residues during the process of DNA replication through misincorporation by the replicative DNA polymerases α, δ and ε, and by the normal replication process on the lagging strand, which uses RNA primers. These ribonucleotides are efficiently removed during replication by RNase H enzymes and the lagging strand synthesis machinery. However, when ribonucleotides remain in DNA they can distort the DNA helix, affect machineries for DNA replication, transcription and repair, and can stimulate genomic instabilities which are manifest as increased mutation, recombination and chromosome alterations. The genomic instabilities associated with embedded ribonucleotides are considered here, along with a discussion of the origin of the lesions that stimulate particular classes of instabilities.



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Mechanistic Insights into Transcription Coupled DNA Repair

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Bibhusita Pani, Evgeny Nudler
Transcription-coupled DNA repair (TCR) acts on lesions in the transcribed strand of active genes. Helix distorting adducts and other forms of DNA damage often interfere with the progression of the transcription apparatus. Prolonged stalling of RNA polymerase can promote genome instability and also induce cell cycle arrest and apoptosis. These generally unfavorable events are counteracted by RNA polymerase-mediated recruitment of specific proteins to the sites of DNA damage to perform TCR and eventually restore transcription. In this perspective we discuss the decision-making process to employ TCR and we elucidate the intricate biochemical pathways leading to TCR in E. coli and human cells.



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8-Oxo-7,8-dihydroguanine, friend and foe: Epigenetic-like regulator versus initiator of mutagenesis

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Aaron M. Fleming, Cynthia J. Burrows
A high flux of reactive oxygen species during oxidative stress results in oxidative modification of cellular components including DNA. Oxidative DNA "damage" to the heterocyclic bases is considered deleterious because polymerases may incorrectly read the modifications causing mutations. A prominent member in this class is the oxidized guanine base 8-oxo-7,8-dihydroguanine (OG) that is moderately mutagenic effecting G→T transversion mutations. Recent reports have identified that formation of OG in G-rich regulatory elements in the promoters of the VEGF, TNFα, and SIRT1 genes can increase transcription via activation of the base excision repair (BER) pathway. Work in our laboratory with the G-rich sequence in the promoter of VEGF concluded that BER drives a shift in structure to a G-quadruplex conformation leading to gene activation in mammalian cells. More specifically, removal of OG from the duplex context by 8-oxoguanine glycosylase 1 (OGG1) produces an abasic site (AP) that destabilizes the duplex, shifting the equilibrium toward the G-quadruplex fold because of preferential extrusion of the AP into a loop. The AP is bound but inefficiently cleaved by apurinic/apyrimidinic endoDNase I (APE1) that likely allows recruitment of activating transcription factors for gene induction. The ability of OG to induce transcription ascribes a regulatory or epigenetic-like role for this oxidatively modified base. We compare OG to the 5-methylcytosine (5mC) epigenetic pathway including its oxidized derivatives, some of which poise genes for transcription while also being substrates for BER. The mutagenic potential of OG to induce only ∼one-third the number of mutations (G→T) compared to deamination of 5mC producing C→T mutations is described. These comparisons blur the line between friendly epigenetic base modifications and those that are foes, i.e. DNA "damage," causing genetic mutations.



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Poetry in motion: Increased chromosomal mobility after DNA damage

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Michael J. Smith, Rodney Rothstein
Double-strand breaks (DSBs) are among the most lethal DNA lesions, and a variety of pathways have evolved to manage their repair in a timely fashion. One such pathway is homologous recombination (HR), in which information from an undamaged donor site is used as a template for repair. Although many of the biochemical steps of HR are known, the physical movements of chromosomes that must underlie the pairing of homologous sequence during mitotic DSB repair have remained mysterious. Recently, several groups have begun to use a variety of genetic and cell biological tools to study this important question. These studies reveal that both damaged and undamaged loci increase the volume of the nuclear space that they explore after the formation of DSBs. This DSB-induced increase in chromosomal mobility is regulated by many of the same factors that are important during HR, such as ATR-dependent checkpoint activation and the recombinase Rad51, suggesting that this phenomenon may facilitate the search for homology. In this perspective, we review current research into the mobility of chromosomal loci during HR, as well as possible underlying mechanisms, and discuss the critical questions that remain to be answered. Although we focus primarily on recent studies in the budding yeast, Saccharomyces cerevisiae, examples of experiments performed in higher eukaryotes are also included, which reveal that increased mobility of damaged loci is a process conserved throughout evolution.



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Histone ubiquitination in the DNA damage response

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Michael Uckelmann, Titia K. Sixma
DNA double strand breaks need to be repaired in an organized fashion to preserve genomic integrity. In the organization of faithful repair, histone ubiquitination plays a crucial role. Recent findings suggest an integrated model for DNA repair regulation through site-specific histone ubiquitination and crosstalk to other posttranslational modifications. Here we discuss how site-specific histone ubiquitination is achieved on a molecular level and how different multi-protein complexes work together to integrate different histone ubiquitination states. We propose a model where site-specific H2A ubiquitination organizes the spatio-temporal recruitment of DNA repair factors which will ultimately contribute to DNA repair pathway choice between homologous recombination and non-homologous end joining.



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CtIP/Ctp1/Sae2, Molecular Form Fit For Function

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Sara N. Andres, R. Scott Williams
Vertebrate CtIP, and its fission yeast (Ctp1), budding yeast (Sae2) and plant (Com1) orthologs have emerged as key regulatory molecules in cellular responses to DNA double strand breaks (DSBs). By modulating the nucleolytic 5′-3′ resection activity of the Mre11/Rad50/Nbs1 (MRN) DSB repair processing and signaling complex, CtIP/Ctp1/Sae2/Com1 is integral to the channeling of DNA double strand breaks through DSB repair by homologous recombination (HR). Nearly two decades since its discovery, emerging new data are defining the molecular underpinnings for CtIP DSB repair regulatory activities. CtIP homologs are largely intrinsically unstructured proteins comprised of expanded regions of low complexity sequence, rather than defined folded domains typical of DNA damage metabolizing enzymes and nucleases. A compact structurally conserved N-terminus forms a functionally critical tetrameric helical dimer of dimers (THDD) region that bridges CtIP oligomers, and is flexibly appended to a conserved C-terminal Sae2-homology DNA binding and DSB repair pathway choice regulatory hub which influences nucleolytic activities of the MRN core nuclease complex. The emerging evidence from structural, biophysical, and biological studies converges on CtIP having functional roles in DSB repair that include: 1) dynamic DNA strand coordination through direct DNA binding and DNA bridging activities, 2) MRN nuclease complex cofactor functions that direct MRN endonucleolytic cleavage of protein-blocked DSB ends and 3) acting as a protein binding hub targeted by the cell cycle regulatory apparatus, which influences CtIP expression and activity via layers of post-translational modifications, protein-protein interactions and DNA binding.



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DNA Repair and Systemic Lupus Erythematosus

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Rithy Meas, Matthew J. Burak, Joann B. Sweasy
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with no known cure that affects at least five million people worldwide. Monozygotic twin concordance and familial aggregation studies strongly suggest that lupus results from genetic predisposition along with environmental exposures including UV light. The majority of the common risk alleles associated with genetic predisposition to SLE map to genes associated with the immune system. However, evidence is emerging that implicates a role for aberrant DNA repair in the development of lupus. Here we summarize our current knowledge of the potential association of lupus with mutations in DNA repair genes. We also discuss how defective or aberrant DNA repair could lead to the development of lupus.



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Replicative DNA polymerase defects in human cancers: consequences, mechanisms, and implications for therapy

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Stephanie R. Barbari, Polina V. Shcherbakova
The fidelity of DNA replication relies on three error avoidance mechanisms acting in series: nucleotide selectivity of replicative DNA polymerases, exonucleolytic proofreading, and post-replicative DNA mismatch repair (MMR). MMR defects are well known to be associated with increased cancer incidence. Due to advances in DNA sequencing technologies, the past several years have witnessed a long-predicted discovery of replicative DNA polymerase defects in sporadic and hereditary human cancers. The polymerase mutations preferentially affect conserved amino acid residues in the exonuclease domain and occur in tumors with an extremely high mutation load. Thus, a concept has formed that defective proofreading of replication errors triggers the development of these tumors. Recent studies of the most common DNA polymerase variants, however, suggested that their pathogenicity may be determined by functional alterations other than loss of proofreading. In this review, we summarize our current understanding of the consequences of DNA polymerase mutations in cancers and the mechanisms of their mutator effects. We also discuss likely explanations for a high recurrence of some but not other polymerase variants and new ideas for therapeutic interventions emerging from the mechanistic studies.



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Unveiling the non-repair face of the base excision repair pathway in RNA processing: A missing link between DNA repair and gene expression?

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Giulia Antoniali, Matilde Clarissa Malfatti, Gianluca Tell
The Base Excision Repair (BER) pathway, initially studied as a mere DNA repair pathway, has been later found to be implicated in the expression of cancer related genes in human. For several years, this intricate involvement in apparently different processes represented a mystery, which we now are starting to unveil.The BER handles simple alkylation and oxidative lesions arising from both endogenous and exogenous sources, including cancer therapy agents. Surprisingly, BER pathway involvement in transcriptional regulation, immunoglobulin variability and switch recombination, RNA metabolism and nucleolar function is astonishingly consolidating. An emerging evidence in tumor biology is that RNA processing pathways participate in DNA Damage Response (DDR) and that defects in these regulatory connections are associated with genomic instability of cancers. In fact, many BER proteins are associated with those involved in RNA metabolism, ncRNA processing and transcriptional regulation, including within the nucleolus, proving a substantial role of the interactome network in determining their non-canonical functions in tumor cells. Maybe these new insights of BER enzymes, along with their emerging function in RNA-decay, may explain BER essential role in tumor development and chemoresistance and may explain the long-time mystery. Here, we would like to summarize different roles of BER pathway in human cells. First, we will give a short description of the classical BER pathway, which has been covered in detail in recent reviews. We will then outline potential new roles of BER in gene expression and RNA metabolism. Although recent works have provided tremendous amount of data in this field, there are still lot of open questions.



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Role of recombination and replication fork restart in repeat instability

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Erica J. Polleys, Nealia C.M. House, Catherine H. Freudenreich
Eukaryotic genomes contain many repetitive DNA sequences that exhibit size instability. Some repeat elements have the added complication of being able to form secondary structures, such as hairpin loops, slipped DNA, triplex DNA or G-quadruplexes. Especially when repeat sequences are long, these DNA structures can form a significant impediment to DNA replication and repair, leading to DNA nicks, gaps, and breaks. In turn, repair or replication fork restart attempts within the repeat DNA can lead to addition or removal of repeat elements, which can sometimes lead to disease. One important DNA repair mechanism to maintain genomic integrity is recombination. Though early studies dismissed recombination as a mechanism driving repeat expansion and instability, recent results indicate that mitotic recombination is a key pathway operating within repetitive DNA. The action is two-fold: first, it is an important mechanism to repair nicks, gaps, breaks, or stalled forks to prevent chromosome fragility and protect cell health; second, recombination can cause repeat expansions or contractions, which can be deleterious. In this review, we summarize recent developments that illuminate the role of recombination in maintaining genome stability at DNA repeats.



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Structural and Functional Relationships of FAN1

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Hyeonseok Jin, Yunje Cho
FANCD2/FANCI-associated nuclease (FAN1) is a 5′ flap structure-specific endonuclease and 5′ to 3′ exonuclease. This nuclease can resolve interstrand cross-links (ICLs) independently of the Fanconi anemia (FA) pathway and controls the progression of stalled replication forks in an FA-dependent manner, thereby maintaining chromosomal stability. Several FAN1 mutations are observed in various cancers and degenerative diseases. Recently, several crystal structures of the FAN1-DNA complexes have been reported, and to date, these represent the only structures for a DNA bound ICL-repair nuclease. Puzzlingly, human FAN1 forms two different quaternary structures with different DNA binding modes, and based on these structures, two ICL-repair mechanisms have been proposed. In one mechanism, monomeric FAN1 recognizes the 5′ flap terminal phosphate via a basic pocket and successively cleaves at every third nucleotide of the DNA substrates. In the other mechanism, dimeric FAN1 scans, latches, and unwinds the postnick duplex of the substrate DNA to direct the scissile phosphodiester group to the active site. In this review, we discuss the structures, function, and proposed mechanisms of FAN1 nuclease, and provide the insights into its role in ICL repair and in processing of stalled replication forks.



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DNA requirements for interaction of the C-terminal region of Ku80 with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs)

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Sarvan Kumar Radhakrishnan, Susan P. Lees-Miller
Non-homologous end joining (NHEJ) is the major pathway for the repair of ionizing radiation induced DNA double strand breaks (DSBs) in human cells. Critical to NHEJ is the DNA-dependent interaction of the Ku70/80 heterodimer with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form the DNA-PK holoenzyme. However, precisely how Ku recruits DNA-PKcs to DSBs ends to enhance its kinase activity has remained enigmatic, with contradictory findings reported in the literature. Here we address the role of the Ku80 C-terminal region (CTR) in the DNA-dependent interaction of Ku70/80 with DNA-PKcs using purified components and defined DNA structures. Our results show that the Ku80 CTR is required for interaction with DNA-PKcs on short segments of blunt ended 25bp dsDNA or 25bp dsDNA with a 15-base poly dA single stranded (ss) DNA extension, but this requirement is less stringent on longer dsDNA molecules (35bp blunt ended dsDNA) or 25bp duplex DNA with either a 15-base poly dT or poly dC ssDNA extension. Our work clarifies the role of the Ku80 CTR and dsDNA ends on the interaction of DNA-PKcs with Ku and provides key information to guide assembly and biology of NHEJ complexes.



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BERing the burden of damage: Pathway crosstalk and posttranslational modification of base excision repair proteins regulate DNA damage management

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Kristin Limpose, Anita H. Corbett, Paul W. Doetsch
DNA base damage and non-coding apurinic/apyrimidinic (AP) sites are ubiquitous types of damage that must be efficiently repaired to prevent mutations. These damages can occur in both the nuclear and mitochondrial genomes. Base excision repair (BER) is the frontline pathway for identifying and excising damaged DNA bases in both of these cellular compartments. Recent advances demonstrate that BER does not operate as an isolated pathway but rather dynamically interacts with components of other DNA repair pathways to modulate and coordinate BER functions. We define the coordination and interaction between DNA repair pathways as pathway crosstalk. Numerous BER proteins are modified and regulated by post-translational modifications (PTMs), and PTMs could influence pathway crosstalk. Here, we present recent advances on BER/DNA repair pathway crosstalk describing specific examples and also highlight regulation of BER components through PTMs. We have organized and reported functional interactions and documented PTMs for BER proteins into a consolidated summary table. We further propose the concept of DNA repair hubs that coordinate DNA repair pathway crosstalk to identify central protein targets that could play a role in designing future drug targets.



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Dormant origins as a built-in safeguard in eukaryotic DNA replication against genome instability and disease development

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Naoko Shima, Kayla D. Pederson
DNA replication is a prerequisite for cell proliferation, yet it can be increasingly challenging for a eukaryotic cell to faithfully duplicate its genome as its size and complexity expands. Dormant origins now emerge as a key component for cells to successfully accomplish such a demanding but essential task. In this perspective, we will first provide an overview the fundamental processes eukaryotic cells have developed to regulate origin licensing and firing. With a special focus on mammalian systems, we will then highlight the role of dormant origins in preventing replication-associated genome instability and their functional interplay with proteins involved in the DNA damage repair response for tumor suppression. Lastly, deficiencies in the origin licensing machinery will be discussed in relation to its influence on stem cell maintenance and human diseases.



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The Top1 paradox: friend and foe of the eukaryotic genome

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Nayun Kim, Sue Jinks-Robertson
Topoisomerases manage the torsional stress associated with the separation of DNA strands during transcription and DNA replication. Eukaryotic Topoisomerase I (Top1) is a Type IB enzyme that nicks and rejoins only one strand of duplex DNA, and it is especially important during transcription. By resolving transcription-associated torsional stress, Top1 reduces the accumulation of genome-destabilizing R-loops and non-B DNA structures. The DNA nicking activity of Top1, however, can also initiate genome instability in the form of illegitimate recombination, homologous recombination and mutagenesis. In this review, we focus on the diverse, and often opposing, roles of Top1 in regulating eukaryotic genome stability.



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Genome Instabilities Arising from Ribonucleotides in DNA

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Hannah L. Klein
Genomic DNA is transiently contaminated with ribonucleotide residues during the process of DNA replication through misincorporation by the replicative DNA polymerases α, δ and ε, and by the normal replication process on the lagging strand, which uses RNA primers. These ribonucleotides are efficiently removed during replication by RNase H enzymes and the lagging strand synthesis machinery. However, when ribonucleotides remain in DNA they can distort the DNA helix, affect machineries for DNA replication, transcription and repair, and can stimulate genomic instabilities which are manifest as increased mutation, recombination and chromosome alterations. The genomic instabilities associated with embedded ribonucleotides are considered here, along with a discussion of the origin of the lesions that stimulate particular classes of instabilities.



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Ultralow thermal conductivity of cerium-doped Nd 2 Zr 2 O 7 over a wide doping range

Abstract

In this paper, we report an ultralow thermal conductivity and a high-temperature phase stability of the (Nd_1−x Ce_x )₂Zr₂O_7+x system over the temperature range from room temperature to 1600 °C and over a wide composition range (0.2 ≤ x ≤ 0.8), and the (Nd_1−x Ce_x )₂Zr₂O_7+x system is therefore considered a strong candidate material for the fabrication of next-generation high-temperature thermal barrier coatings. The observed thermal conductivities (0.65–1.0 W/mK) are about 60–40% lower than those of undoped Nd₂Zr₂O₇ over the same temperature range (100–700 °C) and indicate a glass-like behavior. For comparison, the variation in the thermal conductivity with the temperature of the (Gd_1−x Ce_x )₂Zr₂O_7+x system with similar point defects was also measured, and the observed behavior was almost the same as that of undoped Gd₂Zr₂O₇ and was mostly determined by phonon–phonon scattering (λ ∝ 1/T). The effect of point defect scattering and strong phonon scattering sources (rattlers) on the thermal conductivity is also discussed in this paper. The results of this study suggest that the ultralow thermal conductivity of (Nd_1−x Ce_x )₂Zr₂O_7+x can be attributed to the presence of rattlers because of the large difference between the ionic radii of the Nd³⁺ and Ce⁴⁺ ions.

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Close encounters: moving along bumps, breaks, and bubbles on expanded trinucleotide tracts

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Aris Polyzos, Cynthia McMurray
Expansion of simple triplet repeats (TNR) underlies more than 30 severe degenerative diseases. There is a good understanding of the major pathways generating an expansion, and the associated polymerases that operate during gap filling synthesis at these "difficult to copy" sequences. However, the mechanism by which a TNR is repaired depends on the type of lesion, the structural features imposed by the lesion, the assembled replication/repair complex, and the polymerase that encounters it. The relationships among these parameters are exceptionally complex and how they direct pathway choice is poorly understood. In this review, we consider the properties of polymerases, and how encounters with GC-rich or abnormal structures might influence polymerase choice and the success of replication and repair. Insights over the last three years have highlighted new mechanisms that provide interesting choices to consider in protecting genome stability.



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Evolutionary Dynamics and Significance of Multiple Subclonal Mutations in Cancer

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Robert A. Beckman, Lawrence A. Loeb
For the last 40 years the authors have collaborated on trying to understand the complexities of human cancer by formulating testable mathematical models that are based on mutation accumulation in human malignancies. We summarize the concepts encompassed by multiple mutations in human cancers in the context of source, accumulation during carcinogenesis and tumor progression, and therapeutic consequences. We conclude that the efficacious treatment of human cancer by targeted therapy will involve individualized, uniquely directed specific agents singly and in simultaneous combinations, and take into account the importance of targeting resistant subclonal mutations, particularly those subclones with alterations in DNA repair genes, DNA polymerase, and other genes required to maintain genetic stability.



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Taming Tricky DSBs: ATM on duty

Publication date: Available online 9 June 2017
Source:DNA Repair
Author(s): Thomas Clouaire, Aline Marnef, Gaëlle Legube
Ataxia Telangiectasia Mutated (ATM) has been known for decades as the main kinase mediating the DNA Double-Strand Break Response (DDR). Extensive studies have revealed its dual role in locally promoting detection and repair of DSBs as well as in activating global DNA damage checkpoints. However, recent studies pinpoint additional unanticipated functions for ATM in modifying both the local chromatin landscape and the global chromosome organization, more particularly at persistent breaks. Given the emergence of a novel and unexpected class of DSBs prevalently arising in transcriptionally active genes and intrinsically difficult to repair, a specific role of ATM at refractory DSBs could be an important and so far overlooked feature of Ataxia Telangiectasia (A-T) a severe disorder associated with ATM mutations.



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Rational synthesis and tailored optical and magnetic characteristics of Fe 3 O 4 –Au composite nanoparticles

Abstract

To minimize saturation magnetization (Ms) degradation and simultaneously maintain the optical and magnetic responsiveness characteristics of Fe₃O₄/Au nanocomposites, we successfully prepared Fe₃O₄–Au seeds composite nanoparticles (NPs) by a novel seed deposition process. The effects of gold seeds coating amounts and the concentration of Fe₃O₄ NPs on the morphologies of final products are extensively characterized. The results of energy-dispersive spectrometry mapping show that the gold seeds are uniformly adhered onto the Fe₃O₄ NPs surfaces in precisely controlled amount. Importantly, with the electronic redistribution between Fe₃O₄ and Au NPs interfaces, the obvious position shifting of Fe 2p and Au 4f electronic binding energy peaks is observed. Upon increasing surface coatings of gold seeds, the electron deficiency on the gold NPs leads to the redshift of the absorption peak. Though Ms declines slightly due to the diamagnetic contribution from decorated gold seeds, the developed Fe₃O₄–Au seeds composite NPs possess the robust magnetic responsiveness and they are amenable to be separated and recycled by the external magnet, which facilitates great potential applications in biological, medical and photocatalytic fields.

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Well-oriented bioarchitecture for immobilization of chloroperoxidase on graphene oxide nanosheets by site-specific interactions and its catalytic performance

Abstract

Chloroperoxidase (CPO) was immobilized on graphene oxide (GO) nanosheets via site-specific interactions of concanavalin (ConA) with saccharide groups on the CPO surface to make GO-ConA-CPO nano-architectonics. Enzymatic oxidative decolorization of malachite green was used to investigate the catalytic performance of GO-ConA-CPO. The GO-ConA-CPO showed high activity (based on the decolorization efficiency), i.e., 93.68% in 15 min. Moreover, GO-ConA-CPO showed better thermostability and remained higher activity against pH change and high concentrations of oxidant H₂O₂ compared with GO-CPO and the free enzyme. When incubated at 60 °C for 1.5 h, 63.02% of the activity of GO-ConA-CPO and 35.75% of GO-CPO remained compared with that at 25 °C, while free CPO remained only 8.46% in the same condition. The tolerance of GO-ConA-CPO to H₂O₂ improved from 2.5 to 6 mmol L⁻¹, and the suitable pH range enlarged from 2.5–3.0 to 2.0–4.5. After 8 cycles, the GO-ConA-CPO can keep 52% activity of that in the first run. The enzymatic kinetic constants indicated that introducing CPO into GO-ConA-CPO bioarchitecture improved the diffusion of reactants and products.

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Enhanced photoelectrochemical performance of n-Si/n-ZnO nanowire arrays using graphene interlayers

Abstract

We report a powerful approach to improve the photoelectrochemical (PEC) performance of the Si/ZnO nanowire array (NWA) photoanodes via incorporating a graphene layer. The Si/Graphene/ZnO NWAs shows the highest photocurrent, which is, respectively, 1.6 times of that for the Si/ZnO NWAs, and 6.2 times of that for the Si wafers. The introducing of ZnO NWAs and graphene greatly reduces the light reflectance, especially in the UV light region. Carrier recombination at the effective n-Si/n-ZnO junction can compensate the high valence band level of Si and thus enhances the contribution of Si to the photocurrent. The graphene interlayers offer a fast passway for the photogenerated electrons in ZnO to recombine with the photogenerated holes in Si, resulting in enhanced PEC performance of the Si/graphene/ZnO NWAs. This study demonstrates the n/graphene/n heterojunction is a promising configuration for efficient solar water splitting.

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Facile synthesis and characterization of pH-dependent pristine MgO nanostructures for visible light emission

Abstract

Herein, we demonstrate a strategy for facile synthesis of pristine MgO nanostructures at different pH values ranging from 7.9, 8.3 and 12.5 to explore their photoluminescence studies. These pH-dependent MgO nanostructures were characterized by various standard techniques such as XRD, SEM, EDS, TEM and photoluminescence (PL) spectroscopy. The obtained PL results clearly demonstrate that the PL emission spectra strongly depend upon growth environment. These nanostructures show a broad PL emission in visible region ranging from 400 to 680 nm at excitation wavelength of 330 nm. Hence, this study provides a unique feature to tailor the PL property of pristine MgO nanostructures which could be potentially used in luminescence harvesting for various optical display devices and sensing applications.

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Rational synthesis and tailored optical and magnetic characteristics of Fe 3 O 4 –Au composite nanoparticles

Abstract

To minimize saturation magnetization (Ms) degradation and simultaneously maintain the optical and magnetic responsiveness characteristics of Fe₃O₄/Au nanocomposites, we successfully prepared Fe₃O₄–Au seeds composite nanoparticles (NPs) by a novel seed deposition process. The effects of gold seeds coating amounts and the concentration of Fe₃O₄ NPs on the morphologies of final products are extensively characterized. The results of energy-dispersive spectrometry mapping show that the gold seeds are uniformly adhered onto the Fe₃O₄ NPs surfaces in precisely controlled amount. Importantly, with the electronic redistribution between Fe₃O₄ and Au NPs interfaces, the obvious position shifting of Fe 2p and Au 4f electronic binding energy peaks is observed. Upon increasing surface coatings of gold seeds, the electron deficiency on the gold NPs leads to the redshift of the absorption peak. Though Ms declines slightly due to the diamagnetic contribution from decorated gold seeds, the developed Fe₃O₄–Au seeds composite NPs possess the robust magnetic responsiveness and they are amenable to be separated and recycled by the external magnet, which facilitates great potential applications in biological, medical and photocatalytic fields.

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Antibacterial polyacrylonitrile nanofibers produced by alkaline hydrolysis and chlorination

Abstract

Antibacterial polyacrylonitrile (PAN) nanofibers were developed by alkaline hydrolysis and subsequent chlorination. It was shown that the hydrolyzed nanofibers could serve as an N-halamine precursor through chlorination of the amide groups obtained by partial hydrolysis of the nitrile groups. The hydrolysis conditions were optimized, so that sufficient chlorine for effective antibacterial activities could be obtained on the surfaces. The chemical and physical structural changes were well characterized with FTIR, TGA, DSC and SEM. It was found that even though the hydrolyzed nanofibers cyclized with ionic and free radical mechanisms, the chlorinated nanofibers cyclized with only free radical mechanism as evidenced by its higher onset of cyclization temperature. On the other hand, the hydrolysis and chlorination process significantly improved the mechanical properties of the nanofibers. Moreover, the chlorinated nanofibers showed potent antibacterial activities against S. aureus and E. coli with about 6 logs inactivation. The developed antibacterial PAN nanofibers possess great potential for use in various fields, medical industry in particular.

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Thermal expansion coefficients in Invar processed by selective laser melting

Abstract

This work investigates whether the unique low thermal expansion property of Invar (64Fe–36Ni) is retained after processing using the additive manufacturing process selective laser melting (SLM). Using this process, near-full-density components (99.96%) were formed by melting thin (20 μm) layers of powdered Invar (15–45 μm particle size). The mechanical properties of SLM Invar were comparable to that of cold-drawn Invar36^®; however, the thermal coefficient of expansion was observed to be a lower value and negative up until 100 °C. This negative value was attributed to residual stress in the as-deposited parts. The low thermal expansion property of Invar was still maintained when processed using a non-conventional layer-based additive manufacturing technique.

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Relationship between microstructure and dielectric property of hydroxyl-terminated butadiene–acrylonitrile copolymer-based polyurethanes

Abstract

Exploring novel dielectric polymer materials with high dielectric performance would play a crucial role in the high energy density capacitor applications. In this work, novel polyurethanes (PUs) for high dielectric performance were fabricated using containing polar nitrile group (–C ≡ N) of hydroxyl-terminated polybutadiene–acrylonitrile copolymer (HTBN) as soft segment and the hexamethylene diisocyanate (HDI), toluene diisocyanate (TDI) and methylene diphenyl diisocyanate (MDI) as hard segment component. Effect of diisocyanate chemical structure on microphase separation, crystallization, dielectric property and mechanical properties of HTBN-based PUs, and the relationship between structure and dielectric property of HTBN-based PUs were investigated. The HTBN-based PUs showed high dielectric constant (>6.4) and low dissipation factor (<0.077) at the frequency range from 1 to 10⁶ Hz. The crystallinity, degree of microphase separation and dielectric constant of HDI-/HTBN-based PU showed higher than that of MDI/HTBN and TDI-/HTBN-based PUs. Our results indicated that the dielectric constant and dissipation factor of PUs are not only dependent on the dipole orientation of hard and soft segments, but also strongly dependent on their microstructure including degree of microphase separation and crystallinity.

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Inorganic graphenylene as a promising novel boron nitrogen membrane for hydrogen purification: a computational study

Abstract

A novel boron nitrogen monolayer named as inorganic graphenylene (IGP) was proposed for H₂ purification, and its stability was confirmed by the calculated cohesive energy and phonon dispersion spectrum. Using the density function theory (DFT) calculations and molecular dynamic (MD) simulations, we found that the IGP membrane can fulfill the requirements of both the high H₂ permeance (~10⁻³ mol/m² s Pa) and high H₂ selectivities (>10⁷) over H₂O, CO₂, N₂, CO, and CH₄ at 300 K. Excitingly, the MD results matched well with the DFT calculations including the selectivity, permeance as well as the adsorption properties of different gases.

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Charge-based deep level transient spectroscopy of B-doped and undoped polycrystalline diamond films

Abstract

The undoped and B-doped polycrystalline diamond thin film was synthesized by hot filament chemical vapor deposition and microwave plasma, respectively. The structural characterization was performed by scanning electron microscopy, X-ray diffraction and Raman spectroscopy. The electrical properties of synthesized diamond layer were characterized by dc-conductivity method and charge deep level transient spectroscopy. The B-doped diamond layers show higher sp²/sp³ ratios in comparison with that of undoped layers what can have an essential influence on the localized density of states associated with shallow hydrogen acceptor states what is reflected in the values of activation energies which reached the values of 38 meV for B-doped and 55 meV for undoped diamond layers, respectively. The existence of deep level traps, as, for example, associated with B-related acceptors, was not observed.

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High-pressure synthesis and thermoelectric performance of tellurium doped with bismuth

Abstract

Recently, it was found that element semiconductor tellurium (Te) has a high thermoelectric performance. However, it needs to be doped with high-toxic arsenic (As) to tune the carrier concentration of Te. In this paper, low-toxic bismuth (Bi) was employed as dopant to optimize the thermoelectric performance of Te combining with a high-pressure synthesis method. The effect of substituting Bi on the electrical transport and thermal transport properties of Te has been investigated. The results show that the solubility limit of Bi in Te is about 0.1 mol%. However, the trace amounts of Bi doping can tune the carrier concentration of Te effectively and thereby optimize its power factor. The thermal conductivity of non-doped Te prepared by high pressure is much lower than that of the sample prepared at ambient pressure. And Bi doping can further decrease the value due to the phonons scattered by the heavy impurity atom. An enhanced figure of merit ZT ~ 0.72 was obtained at 517 K, which is about four times that of non-doped Te and is comparable to the state-of-the-art thermoelectric alloys with more complex composition such as Bi₂Te₃ and PbTe.

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Ultralow thermal conductivity of cerium-doped Nd 2 Zr 2 O 7 over a wide doping range

Abstract

In this paper, we report an ultralow thermal conductivity and a high-temperature phase stability of the (Nd_1−x Ce_x )₂Zr₂O_7+x system over the temperature range from room temperature to 1600 °C and over a wide composition range (0.2 ≤ x ≤ 0.8), and the (Nd_1−x Ce_x )₂Zr₂O_7+x system is therefore considered a strong candidate material for the fabrication of next-generation high-temperature thermal barrier coatings. The observed thermal conductivities (0.65–1.0 W/mK) are about 60–40% lower than those of undoped Nd₂Zr₂O₇ over the same temperature range (100–700 °C) and indicate a glass-like behavior. For comparison, the variation in the thermal conductivity with the temperature of the (Gd_1−x Ce_x )₂Zr₂O_7+x system with similar point defects was also measured, and the observed behavior was almost the same as that of undoped Gd₂Zr₂O₇ and was mostly determined by phonon–phonon scattering (λ ∝ 1/T). The effect of point defect scattering and strong phonon scattering sources (rattlers) on the thermal conductivity is also discussed in this paper. The results of this study suggest that the ultralow thermal conductivity of (Nd_1−x Ce_x )₂Zr₂O_7+x can be attributed to the presence of rattlers because of the large difference between the ionic radii of the Nd³⁺ and Ce⁴⁺ ions.

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Photoluminescence of carbon dots and their applications in Hela cell imaging and Fe 3+ ion detection

Abstract

Carbon dots are a new and important form of zero-dimensional carbonaceous nanomaterials. In our present work, disperse water-soluble fluorescent carbon dots were prepared using coffee grounds as raw material by hydrothermal treatment. The as-prepared carbon dots exhibit an excitation-dependent and high photostable photoluminescence behavior which can be applied to Hela cell imaging. Notably, the fluorescence of the carbon dots can be quenched by Fe³⁺ ions, which can serve as a useful fluorescent probe for detecting Fe³⁺ ions.

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High-temperature thermal conductivity of biomorphic SiC/Si ceramics

Abstract

Thermal conductivity of biomorphic SiC/Si, a silicon carbide + silicon containing two phase material, was evaluated using the laser steady-state heat flux method. These materials were processed via silicon melt infiltration of wood-derived carbon scaffolds. In this approach, heat flux was measured through the thickness when one side of the specimen was heated with a 10.6-µm CO₂ laser. A thin mullite layer was applied to the heated surface to ensure absorption and minimize reflection losses, as well as to ensure a consistent emissivity to facilitate radiative loss corrections. The influence of the mullite layer was accounted for in the thermal conductivity calculations. The effect of microstructure and composition (inherited from the wood carbonaceous performs) on measured conductivity was evaluated. To establish a baseline for comparison, a dense, commercially available sintered SiC ceramic was also evaluated. It was observed that at a given temperature, thermal conductivity falls between that of single-crystal silicon and fine-grained polycrystalline SiC and can be rationalized in terms of the SiC volume fraction in biomorphic SiC/Si material.

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I. David Brown: The chemical bond in inorganic chemistry: the bond valence model, 2nd ed

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Enhancing the mechanical properties of high strain rate rolled Mg–6Zn–1Mn alloy by pre-rolling

Abstract

The effect of pre-rolling prior to the high strain rate rolling (HSRR) on the dynamic recrystallization (DRX), dynamic precipitation and mechanical properties of Mg–6Zn–1Mn (ZM61) was investigated. Aiming this, a set of pre-rolling tests were carried out at the temperature of 300 °C with pre-rolling strain of 20 and 40%. The results show that pre-rolling treatment greatly homogenize the microstructure and refine DRX grains. The original twins induced by pre-rolling accelerate the DRX process and provide more nucleation sites for DRX grains. The precipitates induced by pre-rolling increase the precipitation density and lead to a strong interaction between DRX grains and precipitates. The ZM61 alloy sheet prepared with 20% pre-rolling strain at 300 °C followed by HSRR at 300 °C exhibits the UTS of 392 MPa and elongation of 16.8%. The advanced mechanical properties can be ascribed to the combined effect of grain refinement hardening and nano-precipitation strengthening.

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Self-healing supramolecular hydrogel of poly(vinyl alcohol)/chitosan carbon dots

Abstract

Supramolecular hydrogels are non-covalent three-dimensional networked materials with many advantages compared to covalently cross-linked ones. In this present work, a supramolecular polymer hydrogel composed of poly(vinyl alcohol) (PVA) and chitosan carbon dots (CDs) was prepared by using the freezing/thawing method. To demonstrate the performance characteristics of such a polymer hydrogel, infrared spectrum, SEM, thermal analysis, swelling ratio, rheological study, self-healing test, etc., were adopted. The result showed that PVA/CDs supramolecular hydrogel not only has excellent self-healing property, but also has good thermal stability. This study work shows the great potential of the PVA/CDs hydrogel as an exciting polymer hydrogel material in the field of environmental management and biological medicine to design multifunctional materials. The simple nontoxic ingredients may also make the hydrogels suitable substitutes for biomedical applications pending further research.

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Ionic liquid-based polymeric microreactors and their applicability

Abstract

This work examines the applicability of encapsulated 1-methyl-3-butylimidazolium hexafluorophosphate within a polyurea shell (BMIm[PF₆]@polyurea) to act as microreactors by dissolving platinum acetylacetonate or cinchonine in the ionic liquid phase pre-emulsification. Their applicability was tested in hydrosilylation and Michael addition reactions, respectively. The capsules crack within the first catalytic cycle indicating a fragile shell is formed. In addition, the development of particulated BMIm[PF₆] within polyurethane is described. These BMIm[PF₆]@polyurethane capsules were characterized and analyzed using scanning electron microscopy, X-ray diffraction, solid-state NMR, infrared and thermal gravimetric analysis. Finally, their ability to act as microreactors in the Michael addition reaction was tested. The capsules morphology does not undergo any changes after the reaction.

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Comparison of the quantum efficiency and the responsivity of the single-walled carbon nanotube photodetector with different electrode metals

Abstract

In this paper, experimental measurements of the photoconductivity in single-walled carbon nanotube (SWCNT) thin films were taken using four different electrodes (Pt, Pd, Au and Ti). Our work shows the impact of the light power intensities and wavelengths on the photoresponse signal. In this context, we have performed the electrical transport characteristics of the device at room temperature under visible continuous wavelength illumination. The photoconductivity measurements, achieved without gating, have shown a strong photoresponse enhancement at the nanotubes/electrode junctions. The obtained response has been generally attributed to the dissociation and subsequent diffusion of photoexcited carriers. We have also proven that a good choice of the metal electrode evidently enhances the photoconductivity of SWCNT-thin film. Due to its high work function and its excellent adhesivity on the thin film of SWCNTs, Au electrodes have shown the most important results than the others metals. The highest quantum efficiency ( \( \eta \) ) calculated in our case is about 12%, and the responsivity reaches 121.48 mA/W for Au–SWCNT contact.

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Surface treatments of solvated mesophase pitch-based carbon fibers

Abstract

The effects of oxidation treatments and surface coating on the surface properties of the solvated mesophase pitch-based carbon fiber (CF) are investigated to improve the mechanical properties of the potentially low-cost CF composites. The CFs were treated with air, O₃, CO₂/H₂O, or HNO₃ solution or modified with an epoxy coating. The surface of the treated fibers was characterized by adsorption of methylene blue, NaOH uptake, fragmentation test, composite flexural test, and optical microscopy and SEM examination. Gaseous oxidization is considered a suitable and economical process for this potentially low-cost and low packing density CFs. O₃ oxidation is more effective than other oxidation treatments and introduces more acidic functional groups and a suitable surface area on the surface of the treated CFs, leading to a shorter fiber critical length and higher interfacial shear strength between the CF and the epoxy resin. Surface coating in 5 wt% of epoxy/acetone solution also effectively reduces fiber critical length due to improved fiber surface wettability. After surface treatment, the CFs can be directly fabricated into composite materials without weaving and knitting. Increased flexural strength and modulus of the composites are achieved by the use of O₃-oxidized fibers and fiber surface coatings. Optical microscopy and SEM confirm that the composites fabricated with the surface-treated fibers have less debonded area or voids than the untreated ones.

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Friction and wear on hard alloy coatings of the Cr 3 C 2 –Ti system over silicified graphite in water

Abstract

Establishing basic friction parameters of new hard alloys to be used for the fabrication of sliding weight-bearing components that work in conjunction with silicified graphite in water lubrication is an important task. Completing this task will help determine principles for selecting a tailored arrangement of components to comply with the operational conditions of the friction pair. The antifriction properties and durability of chromium carbide hard alloys during sliding friction over silicified graphite in water are conditions generated by alloy hardness and chromium carbide volume fraction in the material structure. The wear of a friction pair may be reduced by one order of magnitude if explosively pressed chromium carbide and titanium-based alloys replace such traditional materials as silicified graphite or hard alloys of chromium carbide with nickel.

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Regulatory effects of Interleukin (IL)-15 on allergen-induced airway obstruction

Publication date: Available online 9 June 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Sathisha Upparahalli Venkateshaiah, Xiang Zhu, Priya Rajavelu, Rituraj Niranjan, Murli Manohar, Alok K. Verma, Joseph A. Lasky, Anil Mishra
BackgroundAirway obstruction is a physiologic feature of asthma and IL-15 may have an important role in the pathogenesis of asthma.ObjectiveWe tested the hypothesis that regulation of IL-15 is critical for the preservation of allergen-induced airway hyperresponsiveness (AHR), airway resistance and compliance in response to methacholine.MethodsAirway inflammation, AHR, resistance and compliance were assessed in IL-15- gene deficient mice and IL-15 overexpressing mice in an allergen-induced murine model of asthma. We assessed eosinophils by anti-MBP immunostaining, goblet cells hyperplasia by PAS staining, and cytokines and chemokine levels by performing qPCR and ELISA analyses.ResultsHerein, we made a novel observation that IL-15 deficiency promotes baseline airway resistance in naïve mice. Moreover, rIL-15 delivery to the lung downregulates expression of proinflammatory cytokines, and improves allergen-induced AHR, resistance and compliance. These observations were further validated in DOX-inducible CC-10-IL-15 transgenic mice. DOX exposed Aspergillus extract challenged CC-10-IL-15 bitransgenic mice exhibited significantly reduced levels of proinflammatory cytokines (IL-4, IL-5, IL-13) and decreased goblet cell hyperplasia. Airway obstruction including AHR and resistance was diminished in allergen challenged DOX exposed mice compared to non-DOX exposed CC-10-IL-15 bitransgenic mice. Mechanistically, we observed that IL-15-mediated protection of airway obstruction is associated with induced IFN-γ and IL-10-producing regulatory CD4⁺CD25⁺Foxp3⁺ T cells. Additionally, we found that a human IL-15 agonist (ALT-803) improved airway resistance and compliance in an experimental asthma model.ConclusionWe report our novel finding that IL-15 has a potent inhibitory effect on the airway obstruction that occurs in response to environmental allergens.

Teaser

IL-15 deficiency promotes airway obstruction and IL-15 overexpression protects mice from allergen-Induced airway obstruction including AHR , resistance and compliance in an experimental asthma model.


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Cancer in primary immunodeficiency diseases: Cancer incidence in the United States Immune Deficiency Network Registry

Publication date: Available online 9 June 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Paul C. Mayor, Kevin H. Eng, Kelly L. Singel, Scott I. Abrams, Kunle Odunsi, Kirsten B. Moysich, Ramsay Fuleihan, Elizabeth Garabedian, Patricia Lugar, Hans D. Ochs, Francisco A. Bonilla, Rebecca H. Buckley, Kathleen E. Sullivan, Zuhair K. Ballas, Charlotte Cunningham-Rundles, Brahm H. Segal
BackgroundWe evaluated the overall and site-specific incidence of cancer in subjects with primary immunodeficiency diseases (PIDD) enrolled in the United States Immune Deficiency Network (USIDNET) registry compared with age-adjusted cancer incidence in the Surveillance, Epidemiology and End Results Program (SEER) database. We hypothesized that subjects with PIDD would have an increased incidence of cancer due to impaired immune function.MethodsOverall and site-specific cancer incidence rates were evaluated in subjects with PIDD (n = 3,658) enrolled in the USIDNET registry from 2003-2015, and compared with age-adjusted incidence rates in the SEER database.ResultsWe observed a 1.42-fold excess relative risk of cancer in subjects with PIDD compared to the age-adjusted SEER population (p<0.001). Men with PIDD had a 1.91-fold excess relative risk of cancer compared to the age-adjusted male population (p<0.001), while women with PIDD had similar overall cancer rates compared to the age-adjusted female population. Of the four most common malignancies in men and women in SEER (lung, colon, breast, and prostate cancers), we found no significant increase in these diagnoses in subjects with PIDD. Significant increases in lymphoma in both men (10-fold increase, p<0.001) and women (8.34-fold increase, p<0.001) with PIDD were observed.ConclusionsExcess incidence of cancer occurred in subjects with PIDD. An excess of lymphoma in specific PIDD populations principally drove this increased incidence, while no increased risk of the most common solid tumor malignancies was observed. These data point to a restricted role of the immune system in protecting from specific cancers.

Teaser

This study demonstrates that patients with primary immunodeficiency diseases have an increased risk of certain cancers, but have similar risks as the age-matched general population of developing the most common solid tumor malignancies.


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Age-specific profiling of cutaneous allergy at high temporal resolution suggests age-related alterations in regulatory immune function

Publication date: Available online 9 June 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Magnus David Lynch, John Paul McFadden, Jonathan Michael White, Piu Banerjee, Ian Richard White
We report the age-specific prevalence of cutaneous allergy in 45110 patients over a 30 year period. Our analysis reveals complex allergen-specific sensitization profiles which may reflect alterations in T-cell mediated immunity and regulatory immune function.



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A new fluorescent-avidin-based method for quantifying basophil activation in whole blood

Publication date: Available online 9 June 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Kaori Mukai, R. Sharon Chinthrajah, Kari C. Nadeau, Mindy Tsai, Nicolas Gaudenzio, Stephen J. Galli

Teaser

We report herein a simple new fluorescent-avidin-based method to detect activated basophils in the whole blood of normal or allergic subjects, and compare this method to a basophil activation test based on detection of CD63.


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Asthma Control Status in Pregnancy, BMI, and Maternal Vitamin D Levels

Publication date: Available online 9 June 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Hooman Mirzakhani, George O'Connor, Leonard B. Bacharier, Robert S. Zeiger, Michael X. Schatz, Scott T. Weiss, Augusto A. Litonjua

Teaser

Higher maternal 25OHD levels at early pregnancy could reduce the associated risk of uncontrolled asthma status during pregnancy. Obesity might attenuate this effect and is a predictor of uncontrolled status during pregnancy.


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Identification of CD146 as a novel molecular actor involved in systemic sclerosis

Publication date: Available online 9 June 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Elise Kaspi, Xavier Heim, Brigitte Granel, Benjamin Guillet, Jimmy Stalin, Marie Nollet, Alexandrine Bertaud-Foucault, Andrée Robaglia-Schlupp, Patrice Roll, Pierre Cau, Aurélie Leroyer, Richard Bachelier, Audrey Benyamine, Françoise Dignat-George, Marcel Blot-Chabaud, Nathalie Bardin




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Hemophilia A Inhibitor Treatment: The Promise of Engineered T Cell Therapy

Publication date: Available online 9 June 2017
Source:Translational Research
Author(s): Kalpana Parvathaneni, Maha Abdeladhim, Kathleen P. Pratt, David W. Scott
Hemophilia A is a bleeding disorder caused by mutations in the gene encoding factor VIII (FVIII), a cofactor protein that is essential for normal blood clotting. Approximately one in three patients with severe hemophilia A produce neutralizing antibodies (inhibitors) that block its biologic function in the clotting cascade. Current efforts to eliminate inhibitors consist of repeated FVIII injections under what is termed an "ITI" protocol (Immune Tolerance Induction). However, this method is extremely costly and approximately 30% of patients undergoing ITI do not achieve peripheral tolerance. Human T regulatory cells (Tregs) have been proposed as a new strategy to treat this anti-drug antibody response, as well as other diseases. Polyclonal Tregs are nonspecific and could potentially cause general immunosuppression. Novel approaches to induce tolerance to FVIII include the use of engineered human and mouse antigen-specific Tregs, or alternatively antigen-specific cytotoxic cells, to delete, anergize or kill FVIII-specific lymphocytes. In this review, we discuss the current state of engineered T-cell therapies, and we describe recent progress in applying these therapies to induce FVIII-specific tolerance.



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