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  1. Book ; Online: Advancing Drug Resistance Research Through Quantitative Modeling and Synthetic Biology

    Farquhar, K. / Flohr, H. / Charlebois, D. A.

    2020  

    Abstract: Antimicrobial resistance is an emerging global health crisis that is undermining advances in modern medicine and, if unmitigated, threatens to kill 10 million people per year worldwide by 2050. Research over the last decade has demonstrated that the ... ...

    Abstract Antimicrobial resistance is an emerging global health crisis that is undermining advances in modern medicine and, if unmitigated, threatens to kill 10 million people per year worldwide by 2050. Research over the last decade has demonstrated that the differences between genetically identical cells in the same environment can lead to drug resistance. Fluctuations in gene expression, modulated by gene regulatory networks, can lead to non-genetic heterogeneity that results in the fractional killing of microbial populations causing drug therapies to fail; this non-genetic drug resistance can enhance the probability of acquiring genetic drug resistance mutations. Mathematical models of gene networks can elucidate general principles underlying drug resistance, predict the evolution of resistance, and guide drug resistance experiments in the laboratory. Cells genetically engineered to carry synthetic gene networks regulating drug resistance genes allow for controlled, quantitative experiments on the role of non-genetic heterogeneity in the development of drug resistance. In this perspective article, we emphasize the contributions that mathematical, computational, and synthetic gene network models play in advancing our understanding of antimicrobial resistance to discover effective therapies against drug-resistant infections.

    Comment: 16 pages, 2 figures
    Keywords Quantitative Biology - Quantitative Methods ; Physics - Biological Physics ; Quantitative Biology - Molecular Networks
    Publishing date 2020-07-06
    Publishing country us
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Classifying atopic dermatitis: a systematic review of phenotypes and associated characteristics.

    Bosma, A L / Ascott, A / Iskandar, R / Farquhar, K / Matthewman, J / Langendam, M W / Mulick, A / Abuabara, K / Williams, H C / Spuls, P I / Langan, S M / Middelkamp-Hup, M A

    Journal of the European Academy of Dermatology and Venereology : JEADV

    2022  Volume 36, Issue 6, Page(s) 807–819

    Abstract: Atopic dermatitis is a heterogeneous disease, accompanied by a wide variation in disease presentation and the potential to identify many phenotypes that may be relevant for prognosis and treatment. We aimed to systematically review previously reported ... ...

    Abstract Atopic dermatitis is a heterogeneous disease, accompanied by a wide variation in disease presentation and the potential to identify many phenotypes that may be relevant for prognosis and treatment. We aimed to systematically review previously reported phenotypes of atopic dermatitis and any characteristics associated with them. Ovid EMBASE, Ovid MEDLINE and Web of Science were searched from inception till 12 February 2021 for studies attempting to classify atopic dermatitis. Primary outcomes are atopic dermatitis phenotypes and characteristics associated with them in subsequent analyses. A secondary outcome is the methodological approach used to derive them. In total, 8511 records were found. By focussing only on certain clinical phenotypes, 186 studies were eligible for inclusion. The majority of studies were hospital-based (59%, 109/186) and cross-sectional (76%, 141/186). The number of included patients ranged from seven to 526 808. Data-driven approaches to identify phenotypes were only used in a minority of studies (7%, 13/186). Ninety-one studies (49%) investigated a phenotype based on disease severity. A phenotype based on disease trajectory, morphology and eczema herpeticum was investigated in 56 (30%), 22 (12%) and 11 (6%) studies respectively. Thirty-six studies (19%) investigated morphological characteristics in other phenotypes. Investigated associated characteristics differed between studies. In conclusion, we present an overview of phenotype definitions used in literature for severity, trajectory, morphology and eczema herpeticum, including associated characteristics. There is a lack of uniform and consistent use of atopic dermatitis phenotypes across studies.
    MeSH term(s) Cross-Sectional Studies ; Dermatitis, Atopic/therapy ; Eczema ; Humans ; Kaposi Varicelliform Eruption ; Phenotype ; Severity of Illness Index
    Language English
    Publishing date 2022-02-25
    Publishing country England
    Document type Journal Article ; Review ; Systematic Review
    ZDB-ID 1128828-0
    ISSN 1468-3083 ; 0926-9959
    ISSN (online) 1468-3083
    ISSN 0926-9959
    DOI 10.1111/jdv.18008
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    Zs.A 3492: Show issues Location:
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  3. Article ; Online: Adaptive DNA amplification of synthetic gene circuit opens a way to overcome cancer chemoresistance.

    Wan, Yiming / Mu, Quanhua / Krzysztoń, Rafał / Cohen, Joseph / Coraci, Damiano / Helenek, Christopher / Tompkins, Christopher / Lin, Annie / Farquhar, Kevin / Cross, Erin / Wang, Jiguang / Balázsi, Gábor

    Proceedings of the National Academy of Sciences of the United States of America

    2023  Volume 120, Issue 49, Page(s) e2303114120

    Abstract: Drug resistance continues to impede the success of cancer treatments, creating a need for experimental model systems that are broad, yet simple, to allow the identification of mechanisms and novel countermeasures applicable to many cancer types. To ... ...

    Abstract Drug resistance continues to impede the success of cancer treatments, creating a need for experimental model systems that are broad, yet simple, to allow the identification of mechanisms and novel countermeasures applicable to many cancer types. To address these needs, we investigated a set of engineered mammalian cell lines with synthetic gene circuits integrated into their genome that evolved resistance to Puromycin. We identified DNA amplification as the mechanism underlying drug resistance in 4 out of 6 replicate populations. Triplex-forming oligonucleotide (TFO) treatment combined with Puromycin could efficiently suppress the growth of cell populations with DNA amplification. Similar observations in human cancer cell lines suggest that TFOs could be broadly applicable to mitigate drug resistance, one of the major difficulties in treating cancer.
    MeSH term(s) Animals ; Humans ; DNA/metabolism ; Drug Resistance, Neoplasm/genetics ; Genes, Synthetic ; Oligonucleotides ; Puromycin ; Mammals/metabolism ; Neoplasms/drug therapy ; Neoplasms/genetics
    Chemical Substances DNA (9007-49-2) ; Oligonucleotides ; Puromycin (4A6ZS6Q2CL)
    Language English
    Publishing date 2023-11-29
    Publishing country United States
    Document type Journal Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2303114120
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  4. Article: Employment Outcomes among Registered Dietitians following Graduation in Manitoba.

    Mudryj, Adriana / Farquhar, Kayla / Spence, Kerry / Vagianos, Kathy / Suh, Miyoung / Riediger, Natalie

    Canadian journal of dietetic practice and research : a publication of Dietitians of Canada = Revue canadienne de la pratique et de la recherche en dietetique : une publication des Dietetistes du Canada

    2018  Volume 80, Issue 2, Page(s) 87–90

    Abstract: Purpose: ...

    Abstract Purpose:
    MeSH term(s) Attitude of Health Personnel ; Dietetics/education ; Employment/statistics & numerical data ; Humans ; Manitoba ; Medically Underserved Area ; Nutritionists/statistics & numerical data ; Rural Population ; Surveys and Questionnaires
    Language English
    Publishing date 2018-11-15
    Publishing country Canada
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1472222-7
    ISSN 1486-3847
    ISSN 1486-3847
    DOI 10.3148/cjdpr-2018-035
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  5. Article ; Online: Towards control of cellular decision-making networks in the epithelial-to-mesenchymal transition.

    Gómez Tejeda Zañudo, Jorge / Guinn, M Tyler / Farquhar, Kevin / Szenk, Mariola / Steinway, Steven N / Balázsi, Gábor / Albert, Réka

    Physical biology

    2019  Volume 16, Issue 3, Page(s) 31002

    Abstract: We present the epithelial-to-mesenchymal transition (EMT) from two perspectives: experimental/technological and theoretical. We review the state of the current understanding of the regulatory networks that underlie EMT in three physiological contexts: ... ...

    Abstract We present the epithelial-to-mesenchymal transition (EMT) from two perspectives: experimental/technological and theoretical. We review the state of the current understanding of the regulatory networks that underlie EMT in three physiological contexts: embryonic development, wound healing, and metastasis. We describe the existing experimental systems and manipulations used to better understand the molecular participants and factors that influence EMT and metastasis. We review the mathematical models of the regulatory networks involved in EMT, with a particular emphasis on the network motifs (such as coupled feedback loops) that can generate intermediate hybrid states between the epithelial and mesenchymal states. Ultimately, the understanding gained about these networks should be translated into methods to control phenotypic outcomes, especially in the context of cancer therapeutic strategies. We present emerging theories of how to drive the dynamics of a network toward a desired dynamical attractor (e.g. an epithelial cell state) and emerging synthetic biology technologies to monitor and control the state of cells.
    MeSH term(s) Embryonic Development/genetics ; Embryonic Development/physiology ; Epithelial-Mesenchymal Transition ; Gene Regulatory Networks ; Models, Theoretical ; Neoplasm Metastasis/genetics ; Neoplasm Metastasis/physiopathology ; Wound Healing/genetics ; Wound Healing/physiology
    Language English
    Publishing date 2019-03-07
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2133216-2
    ISSN 1478-3975 ; 1478-3967
    ISSN (online) 1478-3975
    ISSN 1478-3967
    DOI 10.1088/1478-3975/aaffa1
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  6. Article ; Online: Surface Modification of Gd Nanoparticles with pH-Responsive Block Copolymers for Use As Smart MRI Contrast Agents.

    Zhu, Liping / Yang, Yuan / Farquhar, Kirsten / Wang, Jingjing / Tian, Chixia / Ranville, James / Boyes, Stephen G

    ACS applied materials & interfaces

    2016  Volume 8, Issue 7, Page(s) 5040–5050

    Abstract: Despite recent advances in the understanding of fundamental cancer biology, cancer remains the second most common cause of death in the United States. One of the primary factors indicative of high cancer morbidity and mortality and aggressive cancer ... ...

    Abstract Despite recent advances in the understanding of fundamental cancer biology, cancer remains the second most common cause of death in the United States. One of the primary factors indicative of high cancer morbidity and mortality and aggressive cancer phenotypes is tumors with a low extracellular pH (pHe). Thus, the ability to measure tumor pHe in vivo using noninvasive and accurate techniques that also provide high spatiotemporal resolution has become increasingly important and is of great interest to researchers and clinicians. In an effort to develop a pH-responsive magnetic resonance imaging (MRI) contrast agent (CA) that has the potential to be used to measure tumor pHe, well-defined pH-responsive polymers, synthesized via reversible addition-fragmentation chain transfer polymerization, were attached to the surface of gadolinium-based nanoparticles (GdNPs) via a "grafting to" method after reduction of the thiocarbonylthio end groups. The successful modification of the GdNPs was verified by transmission electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis and dynamic light scattering. The performance of the pH-responsive polymer modified GdNPs was then evaluated for potential use as smart MRI CAs via monitoring the relaxivity changes with changing environmental pH. The results suggested that the pH-responsive polymers can be used to effectively modify the GdNPs surface to prepare a smart contrast agent for MRI.
    MeSH term(s) Contrast Media/chemical synthesis ; Contrast Media/chemistry ; Gadolinium/chemistry ; Gadolinium/therapeutic use ; Humans ; Magnetic Resonance Imaging ; Microscopy, Electron, Transmission ; Nanoparticles/chemistry ; Polymers/chemistry
    Chemical Substances Contrast Media ; Polymers ; Gadolinium (AU0V1LM3JT)
    Language English
    Publishing date 2016-02
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1944-8252
    ISSN (online) 1944-8252
    DOI 10.1021/acsami.5b12463
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  7. Article: Effect of ethanol on psychomotor performance and on risk taking behaviour.

    Farquhar, K / Lambert, K / Drummond, G B / Tiplady, B / Wright, P

    Journal of psychopharmacology (Oxford, England)

    2002  Volume 16, Issue 4, Page(s) 379–384

    Abstract: Ethanol may increase the willingness to take risks, but this issue remains controversial. We used a risk-taking paradigm in which volunteers answered a series of general knowledge questions with numerical answers and were asked to judge the length of a ... ...

    Abstract Ethanol may increase the willingness to take risks, but this issue remains controversial. We used a risk-taking paradigm in which volunteers answered a series of general knowledge questions with numerical answers and were asked to judge the length of a line that would just fit into a given gap. A maximum score was given for an exactly correct answer. For answers that were less than the correct value, the score was reduced gradually to zero, while answers even slightly over the correct value were penalized considerably. Total points were rewarded by cash payments, so volunteers were taking real risks when making their responses. Performance was assessed in a two-period, double-blind crossover study, comparing ethanol (0.7 g/kg) with placebo in 20 female volunteers aged 19-20 years. Tests were carried out before and at 45 min after dosing. Mean (SD) ethanol blood alcohol concentrations were 65 (10.5) mg/100 ml. Ethanol impaired the skill/ability measure of the length estimation test (SD of difference between length of line and gap), which increased from 5.9 to 6.6 (p < 0.05), indicating a reduced accuracy of estimation. The risk measures in both tasks were not significantly affected. The skill/ability measure in the general knowledge task was not significantly affected. Other performance tests showed that ethanol produced the expected impairment of both speed and accuracy. These results suggest that risk-taking is not increased by ethanol at doses approaching the UK legal limit for driving.
    MeSH term(s) Adult ; Affect/drug effects ; Attention/drug effects ; Breath Tests ; Central Nervous System Depressants/pharmacology ; Double-Blind Method ; Ethanol/pharmacology ; Female ; Handwriting ; Humans ; Knowledge ; Maze Learning/drug effects ; Memory/drug effects ; Motivation ; Psychomotor Performance/drug effects ; Risk-Taking ; Size Perception/drug effects ; Visual Perception/drug effects
    Chemical Substances Central Nervous System Depressants ; Ethanol (3K9958V90M)
    Language English
    Publishing date 2002-12
    Publishing country United States
    Document type Clinical Trial ; Journal Article ; Randomized Controlled Trial
    ZDB-ID 639313-5
    ISSN 0269-8811
    ISSN 0269-8811
    DOI 10.1177/026988110201600415
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