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Articles 1 - 25 of 25
Full-Text Articles in Pharmacology, Toxicology and Environmental Health
Kinome Profiling Identifies Mark3 And Stk10 As Potential Therapeutic Targets In Uveal Melanoma, Usman Baqai, Alison M. Kurimchak, Isabella Trachtenberg, Timothy J. Purwin, Jelan I. Haj, Anna Han, Kristine Luo, Nikole Fandino Pachon, Angela Jeon, Vivian Chua, Michael A. Davies, J Silvio Gutkind, Jeffrey L. Benovic, James S. Duncan, Andrew E. Aplin
Kinome Profiling Identifies Mark3 And Stk10 As Potential Therapeutic Targets In Uveal Melanoma, Usman Baqai, Alison M. Kurimchak, Isabella Trachtenberg, Timothy J. Purwin, Jelan I. Haj, Anna Han, Kristine Luo, Nikole Fandino Pachon, Angela Jeon, Vivian Chua, Michael A. Davies, J Silvio Gutkind, Jeffrey L. Benovic, James S. Duncan, Andrew E. Aplin
Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers
Most uveal melanoma cases harbor activating mutations in either GNAQ or GNA11. Despite activation of the mitogen-activated protein kinase (MAPK) signaling pathway downstream of Gαq/11, there are no effective targeted kinase therapies for metastatic uveal melanoma. The human genome encodes numerous understudied kinases, also called the "dark kinome". Identifying additional kinases regulated by Gαq/11 may uncover novel therapeutic targets for uveal melanoma. In this study, we treated GNAQ-mutant uveal melanoma cell lines with a Gαq/11 inhibitor, YM-254890, and conducted a kinase signaling proteomic screen using multiplexed-kinase inhibitors followed by mass spectrometry. We observed downregulated expression and/or activity of 22 kinases. …
Which Hypothesis Best Explains The Development Of Cancer?, Ariel M. Mayer
Which Hypothesis Best Explains The Development Of Cancer?, Ariel M. Mayer
The Science Journal of the Lander College of Arts and Sciences
There are three theories of cancer development analyzed in this review. The first theory is the immunological theory, which states that cancer is a result of the immune system failing to detect a cancerous cell in which results in uncontrolled cell growth. The second theory is the somatic mutation theory, which states that genetic mutations are a direct cause cancer. The third theory is the stem cell theory which states that cancer results from an uncontrolled stem cell. The difference in each theory helps guide a clinician’s judgment in how to treat cancer. If a clinician believes in the immunological …
What Are The Most Appropriate Treatments, Preventions And Family Planning Options For Patients With Factor V Leiden?, Simha Wolf
The Science Journal of the Lander College of Arts and Sciences
The management of Venous Thromboembolism in terms of treatments and prevention has been well researched for patients who have been discovered as positive for Factor V Leiden genetic clotting disorder, in either the homozygous or the heterozygous genotype. In fact, the research and development of new agents called Direct oral anticoagulants aim to treat and prevent clotting events while minimizing the risks of bleeding. Although several risk factors have been identified in relation to VTE, Factor V Leiden mutation presents a seemingly higher risk due to its unpredictable incidences of clotting events, even in patients with optimal health characteristics. Yet, …
Multigenerational Genomic And Epigenetic Effects Of Manufactured Silver Nanomaterials In Caenorhabditis Elegans, Anye Wamucho
Multigenerational Genomic And Epigenetic Effects Of Manufactured Silver Nanomaterials In Caenorhabditis Elegans, Anye Wamucho
Theses and Dissertations--Toxicology and Cancer Biology
There has been an increase in the incorporation of silver nanomaterials into consumer products due to their antimicrobial properties. Therefore there is potential for silver nanoparticles (Ag-NPs) to leach out into the environment during different life-cycle stages of these nanomaterial-containing products. Concern about the toxicity of Ag-NPs has led to investigations into their toxic effects on a variety of organisms mainly using acute and sub-chronic, single-generation exposures. The focus of this project was to understand the effects of long-term continuous multigenerational exposure to AgNO3 and Ag-NPs in both pristine and environmentally transformed forms, on the model organism, Caenorhabditis elegans …
Uvb Induced Mutation Of P53 In Non Melanoma Skin Cancer, Raizy Berger
Uvb Induced Mutation Of P53 In Non Melanoma Skin Cancer, Raizy Berger
The Science Journal of the Lander College of Arts and Sciences
There is a clear correlation between excessive sun exposure and the development of skin cancer. UVB radiation from the sun is potent, and as the ozone layer gets depleted, more UVB can reach Earth and cause cell damage. UV radiation causes DNA lesions, such as 6-4 photoproducts and cyclobutane pyrimidine dimers. Cyclobutane pyrimidine dimers are more abundant and take longer to be repaired and therefore are responsible for most of the mutation and DNA damage. These DNA lesions lead to mutation of the p53 gene. The signature mutation on p53 from UV radiation is a CC to TT mutation, which …
Tgf-Β Signaling: New Insights Into Aortic Aneurysms, Sean E. Thatcher
Tgf-Β Signaling: New Insights Into Aortic Aneurysms, Sean E. Thatcher
Pharmacology and Nutritional Sciences Faculty Publications
No abstract provided.
Chemical Activation Of A Food Deprivation Signal Extends Lifespan., Mark Lucanic, Theo Garrett, Ivan Yu, Fernando Calahorro, Azar Asadi Shahmirzadi, Aaron Miller, Matthew S Gill, Robert E. Hughes, Lindy Holden-Dye, Gordon J. Lithgow
Chemical Activation Of A Food Deprivation Signal Extends Lifespan., Mark Lucanic, Theo Garrett, Ivan Yu, Fernando Calahorro, Azar Asadi Shahmirzadi, Aaron Miller, Matthew S Gill, Robert E. Hughes, Lindy Holden-Dye, Gordon J. Lithgow
Natural Sciences and Mathematics | Student Professional Publications
Model organisms subject to dietary restriction (DR) generally live longer. Accompanying this lifespan extension are improvements in overall health, based on multiple metrics. This indicates that pharmacological treatments that mimic the effects of DR could improve health in humans. To find new chemical structures that extend lifespan, we screened 30 000 synthetic, diverse drug-like chemicals in Caenorhabditis elegans and identified several structurally related compounds that acted through DR mechanisms. The most potent of these NP1 impinges upon a food perception pathway by promoting glutamate signaling in the pharynx. This results in the overriding of a GPCR pathway involved in the …
Characterization Of The Catalytic Ck2 Subunits With Substitutions At Residues Involved In Inhibitor Binding, Paul Desormeaux
Characterization Of The Catalytic Ck2 Subunits With Substitutions At Residues Involved In Inhibitor Binding, Paul Desormeaux
Electronic Thesis and Dissertation Repository
CK2 is a constitutively active, ubiquitously expressed and pleiotropic serine/threonine protein kinase that is implicated in many cellular functions including tumorigenesis. CK2 has two catalytic subunits, CK2a and CK2a’, that carry out its function in the cell. Previous studies have indicated that inhibitor-refractory mutants have been effective in recovering residual CK2 activity, in the presence of inhibitors, when compared to wild type CK2. Based on these observations, inhibitor-refractory mutants were created for both CK2a and CK2a’ and tested with various concentrations with two CK2-specific inhibitors, CX-4945 and inhibitor VIII. The CK2a triple mutant (V66A/I174A/H160D) was tested in inducible U2OS Flp-In …
Cd151-Α3Β1 Integrin Complexes Are Prognostic Markers Of Glioblastoma And Cooperate With Egfr To Drive Tumor Cell Motility And Invasion, Pengcheng Zhou, Sonia Erfani, Zeyi Liu, Changhe Jia, Yecang Chen, Bingwei Xu, Xinyu Deng, Jose E. Alfáro, Li Chen, Dana L. Napier, Michael Lu, Jian-An Huang, Chunming Liu, Olivier Thibault, Rosalind Segal, Binhua P. Zhou, Natasha Kyprianou, Craig Horbinski, Xiuwei H. Yang
Cd151-Α3Β1 Integrin Complexes Are Prognostic Markers Of Glioblastoma And Cooperate With Egfr To Drive Tumor Cell Motility And Invasion, Pengcheng Zhou, Sonia Erfani, Zeyi Liu, Changhe Jia, Yecang Chen, Bingwei Xu, Xinyu Deng, Jose E. Alfáro, Li Chen, Dana L. Napier, Michael Lu, Jian-An Huang, Chunming Liu, Olivier Thibault, Rosalind Segal, Binhua P. Zhou, Natasha Kyprianou, Craig Horbinski, Xiuwei H. Yang
Pharmacology and Nutritional Sciences Faculty Publications
Glioblastoma, one of the most aggressive forms of brain cancer, is featured by high tumor cell motility and invasiveness, which not only fuel tumor infiltration, but also enable escape from surgical or other clinical interventions. Thus, better understanding of how these malignant traits are controlled will be key to the discovery of novel biomarkers and therapies against this deadly disease. Tetraspanin CD151 and its associated α3β1 integrin have been implicated in facilitating tumor progression across multiple cancer types. How these adhesion molecules are involved in the progression of glioblastoma, however, remains largely unclear. Here, we examined an in-house tissue microarray-based …
Cc2d1a Regulates Human Intellectual And Social Function As Well As Nf-Κb Signaling Homeostasis., M. Chiara Manzini, Lan Xiong, Ranad Shaheen, Dimira E Tambunan, Stefania Di Costanzo, Vanessa Mitisalis, +15 Additional Authors
Cc2d1a Regulates Human Intellectual And Social Function As Well As Nf-Κb Signaling Homeostasis., M. Chiara Manzini, Lan Xiong, Ranad Shaheen, Dimira E Tambunan, Stefania Di Costanzo, Vanessa Mitisalis, +15 Additional Authors
Pharmacology and Physiology Faculty Publications
Autism spectrum disorder (ASD) and intellectual disability (ID) are often comorbid, but the extent to which they share common genetic causes remains controversial. Here, we present two autosomal-recessive "founder" mutations in the CC2D1A gene causing fully penetrant cognitive phenotypes, including mild-to-severe ID, ASD, as well as seizures, suggesting shared developmental mechanisms. CC2D1A regulates multiple intracellular signaling pathways, and we found its strongest effect to be on the transcription factor nuclear factor κB (NF-κB). Cc2d1a gain and loss of function both increase activation of NF-κB, revealing a critical role of Cc2d1a in homeostatic control of intracellular signaling. Cc2d1a knockdown in neurons …
The Rak/Frk Tyrosine Kinase Associates With And Internalizes The Epidermal Growth Factor Receptor, Ling Jin, Rolf J. Craven
The Rak/Frk Tyrosine Kinase Associates With And Internalizes The Epidermal Growth Factor Receptor, Ling Jin, Rolf J. Craven
Pharmacology and Nutritional Sciences Faculty Publications
Src is the founding member of a diverse family of intracellular tyrosine kinases, and Src has a key role in promoting cancer growth, in part, through its association with receptor tyrosine kinases. However, some Src-related proteins have widely divergent physiological roles, and these proteins include the Rak/Frk tyrosine kinase (Frk stands for Fyn-related kinase), which inhibits cancer cell growth and suppresses tumorigenesis. Rak/Frk phosphorylates and stabilizes the Pten tumor suppressor, protecting it from degradation, and Rak/Frk associates with the retinoblastoma (Rb) tumor suppressor. However, the role of Rak/Frk in receptor-mediated signaling is largely unknown. Here, we demonstrate that Rak/Frk associates …
Decomposing The Energetic Impact Of Drug-Resistant Mutations: The Example Of Hiv-1 Protease-Drv Binding, Yufeng Cai, Celia Schiffer
Decomposing The Energetic Impact Of Drug-Resistant Mutations: The Example Of Hiv-1 Protease-Drv Binding, Yufeng Cai, Celia Schiffer
Celia A. Schiffer
HIV-1 protease is a major drug target for AIDS therapy. With the appearance of drug-resistant HIV-1 protease variants, understanding the mechanism of drug resistance becomes critical for rational drug design. Computational methods can provide more details about inhibitor-protease binding than crystallography and isothermal titration calorimetry. The latest FDA-approved HIV-1 protease inhibitor is Darunavir (DRV). Herein, each DRV atom is evaluated by free energy component analysis for its contribution to the binding affinity with wild-type protease and ACT, a drug-resistant variant. This information can contribute to the rational design of new HIV-1 protease inhibitors.
Hydrophobic Core Flexibility Modulates Enzyme Activity In Hiv-1 Protease, Seema Mittal, Yufeng Cai, Madhavi Nalam, Daniel Bolon, Celia Schiffer
Hydrophobic Core Flexibility Modulates Enzyme Activity In Hiv-1 Protease, Seema Mittal, Yufeng Cai, Madhavi Nalam, Daniel Bolon, Celia Schiffer
Celia A. Schiffer
Human immunodeficiency virus Type-1 (HIV-1) protease is crucial for viral maturation and infectivity. Studies of protease dynamics suggest that the rearrangement of the hydrophobic core is essential for enzyme activity. Many mutations in the hydrophobic core are also associated with drug resistance and may modulate the core flexibility. To test the role of flexibility in protease activity, pairs of cysteines were introduced at the interfaces of flexible regions remote from the active site. Disulfide bond formation was confirmed by crystal structures and by alkylation of free cysteines and mass spectrometry. Oxidized and reduced crystal structures of these variants show the …
Evaluation Of The Substrate Envelope Hypothesis For Inhibitors Of Hiv-1 Protease, Sripriya Chellappan, Visvaldas Kairys, Miguel Fernandes, Celia Schiffer, Michael Gilson
Evaluation Of The Substrate Envelope Hypothesis For Inhibitors Of Hiv-1 Protease, Sripriya Chellappan, Visvaldas Kairys, Miguel Fernandes, Celia Schiffer, Michael Gilson
Celia A. Schiffer
Crystallographic data show that various substrates of HIV protease occupy a remarkably uniform region within the binding site; this region has been termed the substrate envelope. It has been suggested that an inhibitor that fits within the substrate envelope should tend to evade viral resistance because a protease mutation that reduces the affinity of the inhibitor will also tend to reduce the affinity of substrate, and will hence decrease the activity of the enzyme. Accordingly, inhibitors that fit the substrate envelope better should be less susceptible to clinically observed resistant mutations, since these must also allow substrates to bind. The …
Discovery Of Hiv-1 Protease Inhibitors With Picomolar Affinities Incorporating N-Aryl-Oxazolidinone-5-Carboxamides As Novel P2 Ligands, Akbar Ali, G. S. Kiran Kumar Reddy, Hong Cao, Saima Anjum, Madhavi Nalam, Celia Schiffer, Tariq Rana
Discovery Of Hiv-1 Protease Inhibitors With Picomolar Affinities Incorporating N-Aryl-Oxazolidinone-5-Carboxamides As Novel P2 Ligands, Akbar Ali, G. S. Kiran Kumar Reddy, Hong Cao, Saima Anjum, Madhavi Nalam, Celia Schiffer, Tariq Rana
Celia A. Schiffer
Here, we describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors incorporating N-phenyloxazolidinone-5-carboxamides into the (hydroxyethylamino)sulfonamide scaffold as P2 ligands. Series of inhibitors with variations at the P2 phenyloxazolidinone and the P2' phenylsulfonamide moieties were synthesized. Compounds with the (S)-enantiomer of substituted phenyloxazolidinones at P2 show highly potent inhibitory activities against HIV-1 protease. The inhibitors possessing 3-acetyl, 4-acetyl, and 3-trifluoromethyl groups at the phenyl ring of the oxazolidinone fragment are the most potent in each series, with K(i) values in the low picomolar (pM) range. The electron-donating groups 4-methoxy and 1,3-dioxolane are preferred at P2' phenyl ring, …
Association Of A Novel Human Immunodeficiency Virus Type 1 Protease Substrate Cleft Mutation, L23i, With Protease Inhibitor Therapy And In Vitro Drug Resistance, Elizabeth Johnston, Mark Winters, Soo-Yon Rhee, Thomas Merigan, Celia Schiffer, Robert Shafer
Association Of A Novel Human Immunodeficiency Virus Type 1 Protease Substrate Cleft Mutation, L23i, With Protease Inhibitor Therapy And In Vitro Drug Resistance, Elizabeth Johnston, Mark Winters, Soo-Yon Rhee, Thomas Merigan, Celia Schiffer, Robert Shafer
Celia A. Schiffer
We observed a previously uncharacterized mutation in the protease substrate cleft, L23I, in 31 of 4,303 persons undergoing human immunodeficiency virus type 1 genotypic resistance testing. In combination with V82I, L23I was associated with a sevenfold reduction in nelfinavir susceptibility and a decrease in replication capacity. In combination with other drug resistance mutations, L23I was associated with multidrug resistance and a compensatory increase in replication capacity.
Toward The Design Of Mutation-Resistant Enzyme Inhibitors: Further Evaluation Of The Substrate Envelope Hypothesis, Visvaldas Kairys, Michael Gilson, Viney Lather, Celia Schiffer, Miguel Fernandes
Toward The Design Of Mutation-Resistant Enzyme Inhibitors: Further Evaluation Of The Substrate Envelope Hypothesis, Visvaldas Kairys, Michael Gilson, Viney Lather, Celia Schiffer, Miguel Fernandes
Celia A. Schiffer
Previous studies have shown the usefulness of the substrate envelope concept in the analysis and prediction of drug resistance profiles for human immunodeficiency virus protease mutants. This study tests its applicability to several other therapeutic targets: Abl kinase, chitinase, thymidylate synthase, dihydrofolate reductase, and neuraminidase. For the targets where many (> or =6) mutation data are available to compute the average mutation sensitivity of inhibitors, the total volume of an inhibitor molecule that projects outside the substrate envelope V(out), is found to correlate with average mutation sensitivity. Analysis of a locally computed volume suggests that the same correlation would hold …
Pten Enters The Nucleus By Diffusion, Fenghua Liu, Stefan Wagner, Robert Campbell, Jeffrey Nickerson, Celia Schiffer, Alonzo Ross
Pten Enters The Nucleus By Diffusion, Fenghua Liu, Stefan Wagner, Robert Campbell, Jeffrey Nickerson, Celia Schiffer, Alonzo Ross
Celia A. Schiffer
Despite much evidence for phosphatidylinositol phosphate (PIP)-triggered signaling pathways in the nucleus, there is little understanding of how the levels and activities of these proteins are regulated. As a first step to elucidating this problem, we determined whether phosphatase and tensin homolog deleted on chromosome 10 (PTEN) enters the nucleus by passive diffusion or active transport. We expressed various PTEN fusion proteins in tsBN2, HeLa, LNCaP, and U87MG cells and determined that the largest PTEN fusion proteins showed little or no nuclear localization. Because diffusion through nuclear pores is limited to proteins of 60,000 Da or less, this suggests that …
Structural Stability Of Disulfide Mutants Of Basic Pancreatic Trypsin Inhibitor: A Molecular Dynamics Study, Celia Schiffer, Wilfred Van Gunsteren
Structural Stability Of Disulfide Mutants Of Basic Pancreatic Trypsin Inhibitor: A Molecular Dynamics Study, Celia Schiffer, Wilfred Van Gunsteren
Celia A. Schiffer
The structure and folding of basic pancreatic trypsin inhibitor (BPTI) has been studied extensively by experimental means. We report a computer simulation study of the structural stability of various disulfide mutants of BPTI, involving eight 250-psec molecular dynamics simulations of the proteins in water, with and without a phosphate counterion. The presence of the latter alters the relative stability of the single disulfide species [5-55] and [30-51]. This conclusion can explain results of mutational studies and the conservation of residues in homologues of BPTI, and suggests a possible role of ions in stabilizing one intermediate over another in unfolding or …
Structure Of A Phage Display-Derived Variant Of Human Growth Hormone Complexed To Two Copies Of The Extracellular Domain Of Its Receptor: Evidence For Strong Structural Coupling Between Receptor Binding Sites, Celia Schiffer, Mark Ultsch, Scott Walsh, William Somers, Abraham De Vos, Anthony Kossiakoff
Structure Of A Phage Display-Derived Variant Of Human Growth Hormone Complexed To Two Copies Of The Extracellular Domain Of Its Receptor: Evidence For Strong Structural Coupling Between Receptor Binding Sites, Celia Schiffer, Mark Ultsch, Scott Walsh, William Somers, Abraham De Vos, Anthony Kossiakoff
Celia A. Schiffer
The structure of the ternary complex between the phage display- optimized, high-affinity Site 1 variant of human growth hormone (hGH) and two copies of the extracellular domain (ECD) of the hGH receptor (hGHR) has been determined at 2.6 A resolution. There are widespread and significant structural differences compared to the wild-type ternary hGH hGHR complex. The hGH variant (hGH(v)) contains 15 Site 1 mutations and binds>10(2) tighter to the hGHR ECD (hGH(R1)) at Site 1. It is biologically active and specific to hGHR. The hGH(v) Site 1 interface is somewhat smaller and 20% more hydrophobic compared to the wild-type …
Prediction Of Homologous Protein Structures Based On Conformational Searches And Energetics, Celia Schiffer, James Caldwell, Peter Kollman, Robert Stroud
Prediction Of Homologous Protein Structures Based On Conformational Searches And Energetics, Celia Schiffer, James Caldwell, Peter Kollman, Robert Stroud
Celia A. Schiffer
A "knowledge-based" method of predicting the unknown structure of a protein from a homologous known structure using energetics to determine a sidechain conformation is proposed. The method consists of exchanging the residues in the known structure for the sequence of the unknown protein. Then a conformational search with molecular mechanics energy minimization is done on the exchanged residues. The lowest energy conformer is the one picked to be the predicted structure. In the structure of bovine trypsin, the importance of including a solvation energy term in the search is demonstrated for solvent accessible residues, while molecular mechanics alone is enough …
Discovery And Selection Of Tmc114, A Next Generation Hiv-1 Protease Inhibitor, Dominique Surleraux, Abdellah Tahri, Wim Verschueren, Geert Pille, Herman De Kock, Tim Jonckers, Anik Peeters, Sandra De Meyer, Hilde Azijn, Rudi Pauwels, Marie-Pierre De Bethune, Nancy King, Moses Prabu-Jeyabalan, Celia Schiffer, Piet Wigerinck
Discovery And Selection Of Tmc114, A Next Generation Hiv-1 Protease Inhibitor, Dominique Surleraux, Abdellah Tahri, Wim Verschueren, Geert Pille, Herman De Kock, Tim Jonckers, Anik Peeters, Sandra De Meyer, Hilde Azijn, Rudi Pauwels, Marie-Pierre De Bethune, Nancy King, Moses Prabu-Jeyabalan, Celia Schiffer, Piet Wigerinck
Celia A. Schiffer
The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high …
Analysis Of Archived Dried Blood Spots By Mass Spectrometry For Vitamin D And Real-Time Pcr For Its Enzymes And Receptor, Amod N. Joshi
Analysis Of Archived Dried Blood Spots By Mass Spectrometry For Vitamin D And Real-Time Pcr For Its Enzymes And Receptor, Amod N. Joshi
Browse all Theses and Dissertations
Vitamin D is an essential micronutrient required for maintenance of the skeletal system and its deficiency leads to diminished availability of calcium for maintaining bone mineralization. Vitamin D deficiency (VDD) during pregnancy and/or in early infancy can lead to rickets and a fragile bone state resulting in fractures with minimal forces. Such multiple unexplained fractures (MUF) present in infants at less than 6 months of age are often misdiagnosed as cases of child abuse. Therefore, it is important to evaluate the status of vitamin D in early infancy. The analysis of dried blood spots (DBS) provides a unique screening method …
Compensatory Evolution Of Gene Regulation In Response To Stress By Escherichia Coli Lacking Rpos, Daniel M. Stoebel, Karsten Hokamp, Michael S. Last, Charles J. Dorman
Compensatory Evolution Of Gene Regulation In Response To Stress By Escherichia Coli Lacking Rpos, Daniel M. Stoebel, Karsten Hokamp, Michael S. Last, Charles J. Dorman
All HMC Faculty Publications and Research
The RpoS sigma factor protein of Escherichia coli RNA polymerase is the master transcriptional regulator of physiological responses to a variety of stresses. This stress response comes at the expense of scavenging for scarce resources, causing a trade-off between stress tolerance and nutrient acquisition. This trade-off favors non-functional rpoS alleles in nutrient-poor environments. We used experimental evolution to explore how natural selection modifies the regulatory network of strains lacking RpoS when they evolve in an osmotically stressful environment. We found that strains lacking RpoS adapt less variably, in terms of both fitness increase and changes in patterns of transcription, than …
Historical Development Of The Linear Nonthreshold Dose-Response Model As Applied To Radiation, Ronald L. Kathren
Historical Development Of The Linear Nonthreshold Dose-Response Model As Applied To Radiation, Ronald L. Kathren
The University of New Hampshire Law Review
[Excerpt] "Despite the nearly universal adoption of the linear nonthreshold dose response model (LNT) as the primary basis for radiation protection standards for the past half century, the LNT remains highly controversial and a contentious topic of discussion among health physicists, radiation biologists, and other radiological scientists. Indeed, it has been pointed out that the LNT has assumed the status of a paradigm, synonymous with an ideal, standard, or paragon or perhaps to some, a sacred cow. Reduced to its very basics, the LNT postulates that every increment of ionizing radiation dose, however small, carries with it a commensurate increase …