scholarly journals Polymerase ζ activity is linked to replication timing in humans: evidence from mutational signatures

2014 ◽  
Author(s):  
Vladimir B Seplyarskiy ◽  
Georgii A. Bazykin ◽  
Ruslan A. Soldatov
Keyword(s):  
Important Determinant ◽  
Experimental Studies ◽  
Point Mutations ◽  
Fold Increase ◽  
Replication Timing ◽  
Costello Syndrome ◽  
Mutational Signatures ◽  
Template Strand ◽  
The Mean ◽  
Hras Gene

Replication timing is an important determinant of germline mutation patterns, with a higher rate of point mutations in late replicating regions. Mechanisms underlying this association remain elusive. One of the suggested explanations is the activity of error-prone DNA polymerases in late-replicating regions. Polymerase ζ (pol ζ), an essential error-prone polymerase biased towards transversions, also has a tendency to produce dinucleotide mutations (DNMs), complex mutational events that simultaneously affect two adjacent nucleotides. Experimental studies have shown that pol ζ is strongly biased towards GC->AA/TT DNMs. Using primate divergence data, we show that the GC->AA/TT pol ζ mutational signature is the most frequent among DNMs, and its rate exceeds the mean rate of other DNM types by a factor of ~10. Unlike the overall rate of DNMs, the pol ζ signature drastically increases with the replication time in the human genome. Finally, the pol ζ signature is enriched in transcribed regions, and there is a strong prevalence of GC->TT over GC->AA DNMs on the non-template strand, indicating association with transcription. A recurrently occurring GC->TT DNM in HRAS gene causes the Costello syndrome; we find a 2-fold increase in the mutation rate, and a 2-fold decrease in the transition/transversion ratio, at distances of up to 1 kb from the DNM, suggesting a link between the Costello syndrome and pol ζ activity. This study uncovers the genomic preferences of pol ζ, shedding light on a novel cause of mutational heterogeneity along the genome.

scholarly journals Generation of Reverse Meniscus Flow by Applying An Electromagnetic Brake

2021 ◽  
Author(s):  
Alexander Vakhrushev ◽  
Abdellah Kharicha ◽  
Ebrahim Karimi-Sibaki ◽  
Menghuai Wu ◽  
Andreas Ludwig ◽  
...  
Keyword(s):  
Magnetic Field ◽  
Lorentz Force ◽  
Applied Magnetic Field ◽  
Numerical Study ◽  
Flow Direction ◽  
Experimental Studies ◽  
Submerged Entry Nozzle ◽  
Mean Flow ◽  
Slab Caster ◽  
The Mean

AbstractA numerical study is presented that deals with the flow in the mold of a continuous slab caster under the influence of a DC magnetic field (electromagnetic brakes (EMBrs)). The arrangement and geometry investigated here is based on a series of previous experimental studies carried out at the mini-LIMMCAST facility at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR). The magnetic field models a ruler-type EMBr and is installed in the region of the ports of the submerged entry nozzle (SEN). The current article considers magnet field strengths up to 441 mT, corresponding to a Hartmann number of about 600, and takes the electrical conductivity of the solidified shell into account. The numerical model of the turbulent flow under the applied magnetic field is implemented using the open-source CFD package OpenFOAM®. Our numerical results reveal that a growing magnitude of the applied magnetic field may cause a reversal of the flow direction at the meniscus surface, which is related the formation of a “multiroll” flow pattern in the mold. This phenomenon can be explained as a classical magnetohydrodynamics (MHD) effect: (1) the closure of the induced electric current results not primarily in a braking Lorentz force inside the jet but in an acceleration in regions of previously weak velocities, which initiates the formation of an opposite vortex (OV) close to the mean jet; (2) this vortex develops in size at the expense of the main vortex until it reaches the meniscus surface, where it becomes clearly visible. We also show that an acceleration of the meniscus flow must be expected when the applied magnetic field is smaller than a critical value. This acceleration is due to the transfer of kinetic energy from smaller turbulent structures into the mean flow. A further increase in the EMBr intensity leads to the expected damping of the mean flow and, consequently, to a reduction in the size of the upper roll. These investigations show that the Lorentz force cannot be reduced to a simple damping effect; depending on the field strength, its action is found to be topologically complex.

Necrotising (malignant) otitis externa in the UK: a growing problem. Review of five cases and analysis of national Hospital Episode Statistics trends

2015 ◽  
Vol 129 (6) ◽  
pp. 600-603 ◽  
Author(s):  
G Chawdhary ◽  
N Liow ◽  
J Democratis ◽  
O Whiteside
Keyword(s):  
Otitis Externa ◽  
Severe Infection ◽  
Fold Increase ◽  
Antibiotic Resistant ◽  
Catchment Population ◽  
Malignant Otitis Externa ◽  
The Mean ◽  
The Uk ◽  
High Index Of Suspicion ◽  
Park Hospital

AbstractBackground:Necrotising (malignant) otitis externa is a severe infection causing temporal bone osteomyelitis. Although rare, our experience (reported herein) shows local doubling of cases in 2013. Hospital Episodes Statistics data for England over 14 years also indicate increased incidence nationally. Specific learning points in management are also discussed.Methods:A retrospective review was conducted of patients admitted in 2013 to Wexham Park Hospital, Slough, UK (catchment population, 450 000). In addition, the UK Government Hospital Episodes Statistics data were interrogated.Results:There were five cases of necrotising (malignant) otitis externa in 2013, representing a local doubling on previous years. The mean age of patients was 82 years. All cultures grew Pseudomonas aeruginosa; no isolates were antibiotic resistant. All patients responded to systemic anti-pseudomonals on clinical, biochemical and radiological parameters. Hospital Episodes Statistics data showed a six-fold increase in the number of cases from 1999 (n = 67) to 2013 (n = 421).Conclusion:Our experience suggests increasing necrotising (malignant) otitis externa incidence, and retrospective analysis of Hospital Episodes Statistics data supports this observation. Necrotising (malignant) otitis externa poses challenges in management, as exemplified in our cases, requiring a high index of suspicion and early aggressive treatment to achieve cure.

Study of a Vibratory Feeder with Repulsive Surface Which Has Directional Characteristic

1980 ◽  
Vol 102 (1) ◽  
pp. 94-101 ◽  
Author(s):  
S. Okabe ◽  
Y. Yokoyama
Keyword(s):  
Experimental Studies ◽  
Directional Characteristic ◽  
Vibratory Feeder ◽  
The Mean ◽  
Theoretical Results

This paper treats the motion of a particle on a vibratory feeder whose track has directional characteristic in repulsive motion, for examples, obliquely bristled track, obliquely sliced track and so on. Under some assumptions, the practical equation for predicting the mean conveying velocity is shown and the relations between conveying condition and the mean conveying velocity are clarified theoretically. These relations are shown in various diagrams. Referring these diagrams, the optimum conveying conditions are discussed also. The theoretical results show that the mean conveying velocity is considerably larger than that of the ordinary feeder. The theoretical results are confirmed by experimental studies.

scholarly journals Iron absorption from a cereal-based meal containing cane sugar fortified with ascorbic acid

1977 ◽  
Vol 38 (2) ◽  
pp. 261-269 ◽  
Author(s):  
D. Derman ◽  
M. Sayers ◽  
S. R. Lynch ◽  
R. W. Charlton ◽  
T. H. Bothwell ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Ferric Hydroxide ◽  
Fold Increase ◽  
Inhibitory Effect ◽  
Cane Sugar ◽  
Iron Nutrition ◽  
Indian Women ◽  
Mean Values ◽  
Maize Meal ◽  
The Mean

1. The feasibility of improving iron nutrition by fortifying cane sugar with ascorbic acid was studied.2. The absorption of Fe added to maize-weal porridge was measured in 116 volunteer multiparous Indian women using the radio-Fe erythrocyte utilization method. The meals were fed with and without tea or coffee and with and without varying amounts of ascorbic acid.3. The mean absorption of Fe from maize-meal porridge was very low (3.8 %), being even further reduced (2.1 %) when tea was drunk with the meal.4. The addition of 50 or 100 mg ascorbic acid to maize-meal porridge caused approximately a 10-fold increase in Fe absorption. The increase was much less when tea was present, being 2-fold and 5-fold with 50 and 100 mg ascorbic acid respectively. The inhibitory effect of tea on Fe absorption could, however, be overcome by giving larger doses of ascorbic acid (250 and 500 mg).5. When contaminating Fe (2.5 mg) in the form of labelled rust (Fe2O3) or ferric hydroxide was added to maize-meal porridge it was poorly absorbed (mean values were 0.01 % and 1.5 % respectively). The addition of 100 mg ascorbic acid increased the mean Fe absorption rates to 0.5 % and 6.7 % with Fe2O3 and Fe(OH)3 respectively. Fe(OH)3 was found to be absorbed about half as well as the intrinsic Fe present in maize-meal porridge.6. It is concluded that ascorbic acid is capable of improving Fe absorption from a cereal source. It can partially overcome the inhibitory effect of tea and might be expected to facilitate the absorption of at least some forms of Fe that may contaminate food.

Retirement intentions of older consultant psychiatrists

2004 ◽  
Vol 28 (4) ◽  
pp. 130-132 ◽  
Author(s):  
Alex Mears ◽  
Tim Kendall ◽  
Cornelius Katona ◽  
Carole Pashley ◽  
Sarah Pajak
Keyword(s):  
Early Retirement ◽  
Response Rate ◽  
Important Determinant ◽  
Clinical Implications ◽  
Consultant Psychiatrist ◽  
Health Officer ◽  
Decisions To Leave ◽  
The Mean ◽  
The Uk ◽  
Retirement Intentions

Aims and MethodThis survey gathered data on the retirement intentions of consultant psychiatrists over the age of 50 years, in order to address retention issues. A questionnaire was sent to all 1438 consultants over this age in the UK.ResultsA total of 848 questionnaires were returned, an adjusted response rate of 59%. The mean age at which consultants intended to retire in this sample was 60 years (s.d. 4.16), suggesting a potential loss of 5725 consultant years. Reasons for early retirement are complex: factors encouraging retirement include too much bureaucracy, lack of free time and heavy case-loads; those discouraging retirement include enjoyment of work, having a good team and money. Mental Health Officer status is an important determinant in the decision to retire early.Clinical ImplicationsWith numerous vacancies in consultant psychiatrist posts throughout the UK, premature retirement is a cause for concern, possibly contributing to an overall reduction in consultant numbers of 5%. Addressing factors that influence consultants' decisions to leave the health service early should form an important part of an overall strategy to increase consultant numbers.

scholarly journals Effects of medetomidine and atipamezole on serum glucose and cortisol levels in captive reindeer (Rangifer tarandus tarandus)

Rangifer ◽  
1999 ◽  
Vol 19 (2) ◽  
pp. 85 ◽  
Author(s):  
Jon M. Arnemo ◽  
Birgit Ranheim
Keyword(s):  
Rangifer Tarandus ◽  
Fold Increase ◽  
Serum Glucose ◽  
Serum Concentrations ◽  
Seasonal Differences ◽  
Blood Concentrations ◽  
Rangifer Tarandus Tarandus ◽  
Adrenoceptor Agonists ◽  
The Mean ◽  
Baseline Levels

<p>Serum concentrations of glucose and Cortisol were measured in five adult captive reindeer (Rangifer tarandus tarandus) at 24 h and 10 min before, and at 0.5, 1,2,4, 8, 12 and 24 h after, treatment with 60 p.g/kg of medetomidine i.v. followed by 300 jig/kg of atipamezole i.v. 60 min later. The experiments were performed in January and repeated in July-August. The animals were used as their own controls and treated with saline in July-August. The wash-out period between experiments in summer was 2 weeks or more. No obvious seasonal differences were observed. Mederomidine induced a 2.5-fold increase in glucose (mean &plusmn; standard error of the mean being 15.4 &plusmn; 0.6 mmol/1 at 1 h) and a 3.5-fold increase Cortisol (349 &plusmn; 28 nmol/1 at 0.5 h). Serum glucose reached control levels within 12 h, and Cortisol declined to baseline levels within 4 h after injection og medetomidine. The use of blood concentrations of glucose and Cortisol to assess nutritonal status, body condition and stress may be significantly biased in animals chemically immobilized with medetomidine or other alpha-2 adrenoceptor agonists.</p>

scholarly journals De Novo Mutational Signature Discovery in Tumor Genomes using SparseSignatures

2018 ◽  
Author(s):  
Avantika Lal ◽  
Keli Liu ◽  
Robert Tibshirani ◽  
Arend Sidow ◽  
Daniele Ramazzotti
Keyword(s):  
Cross Validation ◽  
De Novo ◽  
State Of The Art ◽  
Point Mutations ◽  
Simulated Data ◽  
Large Datasets ◽  
Genome Sequences ◽  
Mutational Signatures ◽  
Mutational Signature ◽  
Current State

AbstractCancer is the result of mutagenic processes that can be inferred from tumor genomes by analyzing rate spectra of point mutations, or “mutational signatures”. Here we present SparseSignatures, a novel framework to extract signatures from somatic point mutation data. Our approach incorporates DNA replication error as a background, employs regularization to reduce noise in non-background signatures, uses cross-validation to identify the number of signatures, and is scalable to large datasets. We show that SparseSignatures outperforms current state-of-the-art methods on simulated data using standard metrics. We then apply SparseSignatures to whole genome sequences of 147 tumors from pancreatic cancer, discovering 8 signatures in addition to the background.

scholarly journals Steroids for delayed cerebral edema after traumatic brain injury

2021 ◽  
Vol 12 ◽  
pp. 46
Author(s):  
G. Lakshmi Prasad
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Brain Edema ◽  
Cerebral Edema ◽  
Head Injuries ◽  
Experimental Studies ◽  
Symptomatic Improvement ◽  
High Dose ◽  
The Mean ◽  
Key Aspects

Background: Brain edema is a common phenomenon after traumatic brain injury (TBI) resulting in increased intracranial pressure and subsequent neurological deterioration. Experimental studies have proven that brain edema is biphasic (cytotoxic followed by vasogenic). Till date, all studies, including the corticosteroid randomization after significant head injury (HI) trial, have used high-dose steroids in the acute period during which the edema is essentially cytotoxic in nature. No clinical data exist pertaining to delayed cerebral edema (vasogenic) and steroids. Methods: Patients who had received steroids for delayed cerebral edema after TBI were retrospectively analyzed over a 2-year period. Steroid dose, timing of steroid prescription, time to improvement of symptoms, and complications were noted. Results: There were six males and three females. Mean age was 41.1 years. There were no severe HI cases. All subjects had cerebral contusions on imaging. Dexamethasone was the preferred steroid starting with 12 mg/day and tapered in 5–7 days. The mean interval to steroid administration after trauma was 7 days. The mean duration of steroid prescription was 6.3 days. All patients had complete symptomatic improvement. The mean time to symptom resolution was 3.8 days. No patients experienced any complications pertinent to steroid usage. Conclusion: This is the first study to document efficacy of steroids for delayed cerebral edema after TBI, at least in mild/moderate head injuries. The timing of steroid usage and dose of steroids is key aspects that might determine its efficacy in TBI which was the drawbacks of the previous studies. Future prospective trials with the above factors in consideration may confirm/refute above findings.

The influence of water temperature and pH on the survival of Fasciola hepatica miracidia

Parasitology ◽  
1984 ◽  
Vol 88 (1) ◽  
pp. 97-104 ◽  
Author(s):  
G. Smith ◽  
B. T. Grenfell
Keyword(s):  
Maximum Likelihood Method ◽  
Fasciola Hepatica ◽  
Good Description ◽  
Survival Function ◽  
Experimental Studies ◽  
Likelihood Method ◽  
Confidence Limits ◽  
Mean Values ◽  
Influence Of Water ◽  
The Mean

SUMMARYExperimental studies on the survival of Fasciola hepatica miracidia show no evidence that miracidial mortality varies with the pH of the medium, at least in the range 6·0–8·0. On the other hand, miracidial mortality is shown to vary with both the temperature of the medium and the age of the larvae. The mean expected life-span of the miracidium decreases from about 35 h at 6°C to about 6° h at 25° C. The Gompertz survival function provides a good description of the miracidial survivorship curves over the range of temperatures used, and we describe, a maximum likelihood method of estimating the mean values of the parameters of this function, together with their approximate 95% confidence limits.

scholarly journals Complex Patterns of Protease Inhibitor Resistance among Antiretroviral Treatment-Experienced HIV-2 Patients from Senegal: Implications for Second-Line Therapy

2013 ◽  
Vol 57 (6) ◽  
pp. 2751-2760 ◽  
Author(s):  
Dana N. Raugi ◽  
Robert A. Smith ◽  
Selly Ba ◽  
Macoumba Toure ◽  
Fatou Traore ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protease Inhibitor ◽  
Fold Increase ◽  
Cross Resistance ◽  
Second Line ◽  
Triple Mutant ◽  
Second Line Therapy ◽  
Line Therapy ◽  
The Mean ◽  
Complex Patterns

ABSTRACTProtease inhibitor (PI)-based antiretroviral therapy (ART) can effectively suppress HIV-2 plasma load and increase CD4 counts; however, not all PIs are equally active against HIV-2, and few data exist to support second-line therapy decisions. To identify therapeutic options for HIV-2 patients failing ART, we evaluated the frequency of PI resistance-associated amino acid changes in HIV-2 sequences from a cohort of 43 Senegalese individuals receiving unboosted indinavir (n= 18 subjects)-, lopinavir/ritonavir (n= 4)-, or indinavir and then lopinavir/ritonavir (n= 21)-containing ART. Common protease substitutions included V10I, V47A, I54M, V71I, I82F, I84V, L90M, and L99F, and most patients harbored viruses containing multiple changes. Based on genotypic data, we constructed a panel of 15 site-directed mutants of HIV-2ROD9containing single- or multiple-treatment-associated amino acid changes in the protease-encoding region ofpol. We then quantified the susceptibilities of the mutants to the HIV-2 “active” PIs saquinavir, lopinavir, and darunavir using a single-cycle assay. Relative to wild-type HIV-2, the V47A mutant was resistant to lopinavir (6.3-fold increase in the mean 50% effective concentration [EC50]), the I54M variant was resistant to darunavir and lopinavir (6.2- and 2.7-fold increases, respectively), and the L90M mutant was resistant to saquinavir (3.6-fold increase). In addition, the triple mutant that included I54M plus I84V plus L90M was resistant to all three PIs (31-, 10-, and 3.8-fold increases in the mean EC50for darunavir, saquinavir, and lopinavir, respectively). Taken together, our data demonstrate that PI-treated HIV-2 patients frequently harbor viruses that exhibit complex patterns of PI cross-resistance. These findings suggest that sequential PI-based regimens for HIV-2 treatment may be ineffective.

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