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  • 1
    Language: English
    In: Nucleic acids research, 2014-05-01, Vol.42 (9), p.5644-5656
    Description: DNA double-strand breaks (DSBs) can cause chromosomal rearrangements and extensive loss of heterozygosity (LOH), hallmarks of cancer cells. Yet, how such events are normally suppressed is unclear. Here we identify roles for the DNA damage checkpoint pathway in facilitating homologous recombination (HR) repair and suppressing extensive LOH and chromosomal rearrangements in response to a DSB. Accordingly, deletion of Rad3ATR, Rad26ATRIP, Crb253BP1 or Cdc25 overexpression leads to reduced HR and increased break-induced chromosome loss and rearrangements. We find the DNA damage checkpoint pathway facilitates HR, in part, by promoting break-induced Cdt2-dependent nucleotide synthesis. We also identify additional roles for Rad17, the 9-1-1 complex and Chk1 activation in facilitating break-induced extensive resection and chromosome loss, thereby suppressing extensive LOH. Loss of Rad17 or the 9-1-1 complex results in a striking increase in break-induced isochromosome formation and very low levels of chromosome loss, suggesting the 9-1-1 complex acts as a nuclease processivity factor to facilitate extensive resection. Further, our data suggest redundant roles for Rad3ATR and Exo1 in facilitating extensive resection. We propose that the DNA damage checkpoint pathway coordinates resection and nucleotide synthesis, thereby promoting efficient HR repair and genome stability.
    Subject(s): Cell Cycle Checkpoints ; Checkpoint Kinase 2 - metabolism ; Chromosomes, Fungal - genetics ; Comparative Genomic Hybridization ; DNA Breaks, Double-Stranded ; DNA Cleavage ; Exodeoxyribonucleases - metabolism ; Genome Integrity, Repair and ; Genome, Fungal ; Genomic Instability ; Loss of Heterozygosity ; Nucleotides - biosynthesis ; Recombinational DNA Repair ; Schizosaccharomyces - genetics ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe ; Schizosaccharomyces pombe Proteins - metabolism
    ISSN: 0305-1048
    E-ISSN: 1362-4962
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 2
    Language: English
    In: Molecular and Cellular Biology, 2007-11-01, Vol.27 (21), p.7745-7757
    Description: Article Usage Stats Services MCB Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter current issue Spotlights in the Current Issue MCB About MCB Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy MCB RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0270-7306 Online ISSN: 1098-5549 Copyright © 2014 by the American Society for Microbiology.   For an alternate route to MCB .asm.org, visit: MCB       
    Subject(s): Alleles ; Base Sequence ; Chromosomes, Fungal - metabolism ; Crossing Over, Genetic ; DNA Breaks, Double-Stranded ; DNA Repair ; Genetic Markers ; Loss of Heterozygosity - genetics ; Models, Genetic ; Molecular Sequence Data ; Multiprotein Complexes - metabolism ; Mutation - genetics ; Phylogeny ; Rad51 Recombinase - metabolism ; Recombination, Genetic ; Schizosaccharomyces - cytology ; Schizosaccharomyces - genetics ; Schizosaccharomyces pombe ; Schizosaccharomyces pombe Proteins - metabolism ; Telomere - metabolism ; Translocation, Genetic
    ISSN: 0270-7306
    E-ISSN: 1098-5549
    Source: HighWire Press (Free Journals)
    Source: Hellenic Academic Libraries Link
    Source: PubMed Central
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  • 3
    Language: English
    In: The EMBO journal, 2003-03-17, Vol.22 (6), p.1419-1430
    Description: We have examined the genetic requirements for efficient repair of a site‐specific DNA double‐strand break (DSB) in Schizosaccharomyces pombe. Tech nology was developed in which a unique DSB could be generated in a non‐essential minichromosome, Ch16, using the Saccharomyces cerevisiae HO‐endonuclease and its target site, MATa. DSB repair in this context was predominantly through interchromosomal gene conversion. We found that the homologous recombination (HR) genes rhp51+, rad22A+, rad32+ and the nucleotide excision repair gene rad16+ were required for efficient interchromosomal gene conversion. Further, DSB‐induced cell cycle delay and efficient HR required the DNA integrity checkpoint gene rad3+. Rhp55 was required for interchromosomal gene conversion; however, an alternative DSB repair mechanism was used in an rhp55Δ background involving ku70+ and rhp51+. Surprisingly, DSB‐induced minichromosome loss was significantly reduced in ku70Δ and lig4Δ non‐homologous end joining (NHEJ) mutant backgrounds compared with wild type. Furthermore, roles for Ku70 and Lig4 were identified in suppressing DSB‐induced chromosomal rearrangements associated with gene conversion. These findings are consistent with both competitive and cooperative interactions between components of the HR and NHEJ pathways.
    Subject(s): Chromosomes, Fungal ; Deoxyribonucleases, Type II Site-Specific - genetics ; Deoxyribonucleases, Type II Site-Specific - metabolism ; DNA Damage ; DNA integrity checkpoint ; DNA Repair - genetics ; DNA, Fungal - genetics ; DNA, Fungal - metabolism ; Fungal Proteins - genetics ; Fungal Proteins - metabolism ; Gamma Rays ; Gene Conversion ; Genes, Fungal ; HO-endonuclease ; homologous recombination ; Models, Biological ; Mutation ; non-homologous end joining ; Recombination, Genetic ; Saccharomyces cerevisiae - genetics ; Saccharomyces cerevisiae Proteins - genetics ; Saccharomyces cerevisiae Proteins - metabolism ; Schizosaccharomyces - genetics ; Schizosaccharomyces - radiation effects ; site-specific DNA double-strand break
    ISSN: 0261-4189
    ISSN: 1460-2075
    E-ISSN: 1460-2075
    Source: HighWire Press (Free Journals)
    Source: PubMed Central
    Source: Get It Now
    Source: Wiley-Blackwell Full Collection 2014
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  • 4
    Language: English
    In: Frontiers in neurology, 2017, Vol.8, p.267-267
    Description: Phantom limb pain (PLP) is prevalent in patients post-amputation and is difficult to treat. We assessed the efficacy of mirror therapy in relieving PLP in unilateral, upper extremity male amputees. Fifteen participants from Walter Reed and Brooke Army Medical Centers were randomly assigned to one of two groups: mirror therapy (  = 9) or control (  = 6, covered mirror or mental visualization therapy). Participants were asked to perform 15 min of their assigned therapy daily for 5 days/week for 4 weeks. The primary outcome was pain as measured using a 100-mm Visual Analog Scale. Subjects in the mirror therapy group had a significant decrease in pain scores, from a mean of 44.1 (SD = 17.0) to 27.5 (SD = 17.2) mm (  = 0.002). In addition, there was a significant decrease in daily time experiencing pain, from a mean of 1,022 (SD = 673) to 448 (SD = 565) minutes (  = 0.003). By contrast, the control group had neither diminished pain (  = 0.65) nor decreased overall time experiencing pain (  = 0.49). A pain decrement response seen by the 10th treatment session was predictive of final efficacy. These results confirm that mirror therapy is an effective therapy for PLP in unilateral, upper extremity male amputees, reducing both severity and duration of daily episodes. NCT0030144 ClinicalTrials.gov.
    Subject(s): amputee ; mental visualization ; mirror therapy ; Neuroscience ; phantom limb pain ; upper extremity
    ISSN: 1664-2295
    E-ISSN: 1664-2295
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 5
    Language: English
    In: Journal of nursing scholarship, 2021-05, Vol.53 (3), p.323-332
    Description: Purpose To provide a summary of research on ontology development in the Centre of eIntegrated Care at Dublin City University, Ireland. Design Design science methods using Open Innovation 2.0. Methods This was a co‐participatory study focusing on adoption of health informatics standards and translation of nursing knowledge to advance nursing theory through a nursing knowledge graph (NKG). In this article we outline groundwork research conducted through a focused analysis to advance structural interoperability and to inform integrated care in Ireland. We provide illustrated details on a simple example of initial research available through open access. Findings For this phase of development, the initial completed research is presented and discussed. Conclusions We conclude by promoting the use of knowledge graphs for visualization of diverse knowledge translation, which can be used as a primer to gain valuable insights into nursing interventions to inform big data science in the future. Clinical Relevance In line with stated global policy, the uptake and use of health informatics standards in design science within the profession of nursing is a priority. Nursing leaders should initially focus on health informatics standards relating to structural interoperability to inform development of NKGs. This will provide a robust foundation to gain valuable insights into articulating the nursing contribution in relation to the design of digital health and progress the nursing contribution to targeted data sources for the advancement of United Nations Sustainable Development Goal Three.
    Subject(s): Analysis ; Big Data ; Clinical nursing ; Clinical standards ; COVID-19 ; Curie, Marie (1867-1934) ; Graphs ; Health care ; Health informatics ; Health services ; Innovations ; Integrated delivery systems ; Integrated services ; Intellectual disabilities ; Intellectual disability ; Interoperability ; Knowledge ; Knowledge graph ; Medical care ; Medical informatics ; Methods ; Nurses ; Nursing ; Ontology ; Professionals ; Quality management ; R&D ; Research & development ; Science ; Standards ; Sustainable development ; Telemedicine ; Translation ; Uptake ; Visualization ; Visualization (Computers)
    ISSN: 1527-6546
    E-ISSN: 1547-5069
    Source: Hellenic Academic Libraries Link
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  • 6
    Language: English
    In: NeuroImage clinical, 2019-01-01, Vol.23, p.101882-101882
    Description: Phantom limb pain (PLP) following amputation, which is experienced by the vast majority of amputees, has been reported to be relieved with daily sessions of mirror therapy. During each session, a mirror is used to view the reflected image of the intact limb moving, providing visual feedback consistent with the movement of the missing/phantom limb. To investigate potential neural correlates of the treatment effect, we measured brain responses in volunteers with unilateral leg amputation using functional magnetic resonance imaging (fMRI) during a four-week course of mirror therapy. Mirror therapy commenced immediately following baseline scans, which were repeated after approximately two and four week intervals. We focused on responses in the region of sensorimotor cortex corresponding to primary somatosensory and motor representations of the missing leg. At baseline, prior to starting therapy, we found a strong and unexpected response in sensorimotor cortex of amputees to visually presented images of limbs. This response was stronger for images of feet compared to hands and there was no such response in matched controls. Further, this response to visually presented limbs was no longer present at the end of the four week mirror therapy treatment, when perceived phantom limb pain was also reduced. A similar pattern of results was also observed in extrastriate and parietal regions typically responsive to viewing hand actions, but not in regions corresponding to secondary somatosensory cortex. Finally, there was a significant correlation between initial visual responsiveness in sensorimotor cortex and reduction in PLP suggesting a potential marker for predicting efficacy of mirror therapy. Thus, enhanced visual responsiveness in sensorimotor cortex is associated with PLP and modulated over the course of mirror therapy.
    Subject(s): Amputation ; fMRI ; Life Sciences & Biomedicine ; Neuroimaging ; Neurosciences & Neurology ; Phantom limb pain ; Regular ; Science & Technology ; Sensorimotor ; Vision
    ISSN: 2213-1582
    E-ISSN: 2213-1582
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 7
    Language: English
    In: Journal of clinical pharmacology, 2010-06, Vol.50 (6), p.623-635
    Description: Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of sodium‐dependent glucose cotransporter 2 (SGLT2). The pharmacokinetics and pharmacodynamics of sergliflozin were evaluated following single oral dose administration of sergliflozin etabonate (5–500 mg) in healthy volunteers (n = 22) and patients with type 2 diabetes mellitus (n = 8). The prodrug was rapidly and extensively converted to sergliflozin; the latter displayed linear kinetics, reached maximum plasma concentrations at ∼30 to 45 minutes postdose (tmax), and had a plasma elimination half‐life (t1/2) of ∼0.5 to 1 hour. Both prodrug and active entity showed low glomerular filtration and/or extensive renal tubular reabsorption, with 〈0.5% of the administered dose being recovered in the urine. In both populations, sergliflozin etabonate produced a dose‐related glucosuria under fasting conditions and following glucose loading but did not appreciably affect urinary electrolyte excretion or fluid balance. The magnitude and duration of the glucosuric effect closely paralleled plasma sergliflozin concentrations. Sergliflozin did not significantly affect fasting plasma glucose levels but produced transient attenuation of the plasma glucose AUC following glucose challenge. Single doses of sergliflozin etabonate 5 to 500 mg were well tolerated, and there were no clinically significant adverse laboratory findings.
    Subject(s): Administration, Oral ; Adolescent ; Adult ; Analysis ; Area Under Curve ; Benzhydryl Compounds - administration & dosage ; Benzhydryl Compounds - pharmacokinetics ; Benzhydryl Compounds - pharmacology ; Care and treatment ; Diabetes ; Diabetes Mellitus, Type 2 - drug therapy ; Diabetes Mellitus, Type 2 - metabolism ; Diabetes Mellitus, Type 2 - urine ; Diagnosis ; Dose-Response Relationship, Drug ; Drug interactions ; Drug Monitoring - methods ; Female ; Glucose ; Glucose - administration & dosage ; Glucose - metabolism ; Glucosides - administration & dosage ; Glucosides - blood ; Glucosides - pharmacokinetics ; Glucosides - pharmacology ; Glucosides - urine ; Glycosuria - metabolism ; Health aspects ; Humans ; Hypoglycemic Agents - administration & dosage ; Hypoglycemic Agents - pharmacokinetics ; Hypoglycemic Agents - pharmacology ; Male ; Middle Aged ; Patients ; pharmacodynamics ; Pharmacokinetics ; Prodrugs - administration & dosage ; Prodrugs - pharmacokinetics ; Prodrugs - pharmacology ; sergliflozin etabonate ; SGLT2 inhibitor ; single dose ; Type 2 diabetes ; type 2 diabetes mellitus ; Water-Electrolyte Balance - drug effects
    ISSN: 0091-2700
    E-ISSN: 1552-4604
    Source: Wiley Online Library All Backfiles
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  • 8
    Language: English
    In: Ecology and evolution, 2017-10, Vol.7 (19), p.8113-8125
    Description: Herein, we use genetic data from 277 sleeper sharks to perform coalescent‐based modeling to test the hypothesis of early Quaternary emergence of the Greenland shark (Somniosus microcephalus) from ancestral sleeper sharks in the Canadian Arctic‐Subarctic region. Our results show that morphologically cryptic somniosids S. microcephalus and Somniosus pacificus can be genetically distinguished using combined mitochondrial and nuclear DNA markers. Our data confirm the presence of genetically admixed individuals in the Canadian Arctic and sub‐Arctic, and temperate Eastern Atlantic regions, suggesting introgressive hybridization upon secondary contact following the initial species divergence. Conservative substitution rates fitted to an Isolation with Migration (IM) model indicate a likely species divergence time of 2.34 Ma, using the mitochondrial sequence DNA, which in conjunction with the geographic distribution of admixtures and Pacific signatures likely indicates speciation associated with processes other than the closing of the Isthmus of Panama. This time span coincides with further planetary cooling in the early Quaternary period followed by the onset of oscillating glacial‐interglacial cycles. We propose that the initial S. microcephalus–S. pacificus split, and subsequent hybridization events, were likely associated with the onset of Pleistocene glacial oscillations, whereby fluctuating sea levels constrained connectivity among Arctic oceanic basins, Arctic marginal seas, and the North Atlantic Ocean. Our data demonstrates support for the evolutionary consequences of oscillatory vicariance via transient oceanic isolation with subsequent secondary contact associated with fluctuating sea levels throughout the Quaternary period—which may serve as a model for the origins of Arctic marine fauna on a broad taxonomic scale. Using genetic data, we perform coalescent‐based modeling to test the hypothesis of the early Quaternary emergence of the Greenland shark (Somniosus microcephalus) from ancestral sleeper sharks in the Canadian Arctic‐Subarctic region. Our results show that morphologically cryptic somniosids S. microcephalus and Somniosus pacificus can be genetically distinguished using combined mitochondrial and nuclear DNA markers. We demonstrate support for the evolutionary consequences of oscillatory vicariance with secondary contact in via transient oceanic isolation associated with fluctuating sea levels during the late Miocene and Quaternary periods—which may serve as a model for origins of Arctic and Antarctic marine fauna on a broad taxonomic scale.
    Subject(s): Admixtures ; Basins ; Dalatiidae ; Deoxyribonucleic acid ; Divergence ; DNA ; elasmobranch ; Fauna ; Geographical distribution ; Glacial periods ; Greenland shark ; Hybridization ; interspecific gene flow ; introgressive hybridization ; isolation with migration ; Marine fauna ; Migration ; Mitochondrial DNA ; Nucleotide sequence ; Ocean basins ; Original Research ; Origins ; Oscillations ; Pleistocene ; Polar environments ; Quaternary ; Sharks ; Somniosus microcephalus ; Speciation
    ISSN: 2045-7758
    E-ISSN: 2045-7758
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    Source: ProQuest Central
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  • 9
    Language: English
    In: Journal of clinical pharmacology, 2010-06, Vol.50 (6), p.636-646
    Description: Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of the sodium‐dependent glucose cotransporter‐2 in the renal tubule. The pharmacokinetics and pharmacodynamics of sergliflozin were examined during administration of sergliflozin etabonate (500 or 1000 mg) or placebo 3 times daily (tid) for 14 days in healthy overweight or obese human volunteers (n = 18). At the doses tested, sergliflozin showed less than dose‐proportional pharmacokinetic characteristics. Mean half‐life of the active entity was approximately 2 hours; there was no evidence of drug accumulation. Sergliflozin etabonate produced rapid and sustained suppression of renal glucose reabsorption, resulting in a dose‐related glucosuria, and a transient increase in urinary electrolyte and fluid loss; plasma glucose, insulin, and electrolyte levels were unchanged. Sergliflozin etabonate produced a rapid, dose‐related reduction in body weight (mean changes of −0.09, −1.55, and −1.74 kg from baseline to day 15 with placebo, sergliflozin etabonate 500 mg, and sergliflozin etabonate 1000 mg, respectively), apparently through increased urinary calorie loss rather than through osmotic diuresis. Sergliflozin etabonate 500 or 1000 mg tid was generally well tolerated; no clinically significant adverse events were identified. Renal function (creatinine clearance) was not affected by sergliflozin etabonate, although urinary microalbumin, N‐acetyl‐beta‐D‐glucosaminidase, and β2‐microglobulin levels tended to increase.
    Subject(s): Adolescent ; Adult ; Analysis ; Benzhydryl Compounds - administration & dosage ; Benzhydryl Compounds - adverse effects ; Benzhydryl Compounds - pharmacokinetics ; Benzhydryl Compounds - pharmacology ; Blood Glucose - drug effects ; Body Weight - drug effects ; Care and treatment ; Causes of ; Diagnosis ; Dose-Response Relationship, Drug ; Drug interactions ; Drug Monitoring - methods ; Electrolytes ; Female ; Glucose ; Glucosides - administration & dosage ; Glucosides - adverse effects ; Glucosides - pharmacokinetics ; Glucosides - pharmacology ; Glycosuria - chemically induced ; Half-Life ; Humans ; Insulin - blood ; Male ; Middle Aged ; multiple dose ; Obesity ; Obesity - blood ; Obesity - urine ; Overweight - blood ; Overweight - urine ; pharmacodynamics ; Pharmacokinetics ; Prodrugs - administration & dosage ; Prodrugs - adverse effects ; Prodrugs - pharmacokinetics ; Prodrugs - pharmacology ; Sergliflozin etabonate ; SGLT2 inhibitor ; Type 2 diabetes ; type 2 diabetes mellitus ; Water-Electrolyte Balance - drug effects
    ISSN: 0091-2700
    E-ISSN: 1552-4604
    Source: Wiley Online Library All Backfiles
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  • 10
    Language: English
    In: Annals of clinical and translational neurology, 2014-09, Vol.1 (9), p.633-638
    Description: Background Mirror therapy has been demonstrated to reduce phantom limb pain (PLP) experienced by unilateral limb amputees. Research suggests that the visual feedback of observing a limb moving in the mirror is critical for therapeutic efficacy. Objective Since mirror therapy is not an option for bilateral lower limb amputees, the purpose of this study was to determine if direct observation of another person's limbs could be used to relieve PLP. Methods We randomly assigned 20 bilateral lower limb amputees with PLP to visual observation (n = 11) or mental visualization (n = 9) treatment. Treatment consisted of seven discrete movements which were mimicked by the amputee's phantom limbs moving while visually observing the experimenter's limbs moving, or closing the eyes while visualizing and attempting the movements with their phantom limbs, respectively. Participants performed movements for 20 min daily for 1 month. Response to therapy was measured using a 100‐mm visual analog scale (VAS) and the McGill Short‐Form Pain Questionnaire (SF‐MPQ). Results Direct visual observation significantly reduced PLP in both legs (P 〈 0.05). Amputees assigned to the mental visualization condition did not show a significant reduction in PLP. Interpretation Direct visual observation therapy is an inexpensive and effective treatment for PLP that is accessible to bilateral lower limb amputees.
    Subject(s): Amputation ; Data analysis ; Diabetes ; Feedback ; Feet ; Pain ; Patients ; Rehabilitation ; Virtual reality ; Visualization
    ISSN: 2328-9503
    E-ISSN: 2328-9503
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    Source: Wiley-Blackwell Full Collection 2014
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