Artykuły w czasopismach: „G switch”

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Gohil, S. "POS0626 MONEY MATTERS: ASSESSING THE VALUE OF THE ADALIMUMAB BIOSIMILAR SWITCH FOR RHEUMATOLOGY PATIENTS". Annals of the Rheumatic Diseases 80, Suppl 1 (19.05.2021): 551.2–551. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2566.

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Background:The adalimumab biosimilar switch plan, actioned 2018-19 was one of the most complex of all biologic switches across several specialties. Non-medical switches are considered to ensure the best value medicines are prescribed for patients in line with NICE Technology Appraisals.Objectives:This 2 year follow up review explores the value of the switch for Rheumatology (R) patients in comparison to two other major specialisms; Dermatology (R) and Gastroenterology (G).Methods:403 homecare (HC) patients had been identified as eligible for switch to a citrate containing biosimilar (R;189, G;176, D;38) between April-December 2019. 35 hospital FP10 patients receiving the citrate-free originator biologic were also identified for switch to the citrate containing biosimilar and prescription processing via HC (R; 24, G; 9, D;2). Biosimilar switch information was communicated via patient letters/clinic reviews. FP10 patients also received remote pharmacist telephone support, as part of a PDSA (Plan, Do, Study, Act) quality improvement pilot. Data in regard to switch refusal, treatment cessation, withheld treatment and patient satisfaction ratings for pharmacist phonecalls (1 = unsatisfactory, 5=very satisfied) was documented.Results:235/403 HC patients successfully switched (R;99, G;107, D;29). 64/403 HC patients switched back to the originator (R;47, G;12; D;5). Of the 64 switch back HC patients; 52% = reported lack of efficacy; 27% = injection site pain and 21% = various other factors such as blepharitis, insomnia and hair loss. 38/403 HC patients refused the switch and remained on the originator biologic (R;11, G;27, D;0). 31/403 HC patients switched to an alternative biologic (R;19, G;9, D;3). 32/403 HC patients stopped treatment (R;13, G;19, D;0). Treatment was withheld for 3/403 HC patients (R;0, G;2, D;1). 100% of FP10 patients switched to HC. 31/35 FP10 patients switched to the biosimilar (R; 22, G; 7, D; 2). 3/31 patients switched back to the originator due to lack of efficacy or side effects. 4 patients refused the switch to biosimilar (R;3, G;1, D;0). 89% of patients were very satisfied with the pharmacist telephone support.Conclusion:In summary, 58% of all eligible HC patients switched in comparison to 89% of FP10 patients who received pharmacist telephone support; total cost saving following HC and FP10 switch = £270,000. Rheumatology demonstrated the least success in HC switching (52%) and the highest HC switch back figure (25%). Injection site pain and subjective lack of efficacy appear to be the main reasons for ongoing switch backs. The PDSA project demonstrates that a thorough pharmacist assessment of patient concerns in rationalising the use of a biologic agent versus biosimilar can be valuable for patients. Further cost effective adalimumab biosimilars have recently been launched. This seminal review emphasises the ongoing need for robust critical appraisals of biosimilars, with consideration for both clinical and cost effective parameters, before establishing their placement in treatment pathways.Acknowledgements:Mark Easter, UHCW and Interim Integrated Care System Chief Pharmacist, Hardeep Bagga, Deputy Chief Pharmacist, UHCW Pharmacy Homecare Team and UHCW Specialist Rheumatology, Gastroenterology and Dermatology Clinical Teams.Disclosure of Interests:None declared

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Mott, Helen R., i Darerca Owen. "Allostery and dynamics in small G proteins". Biochemical Society Transactions 46, nr 5 (9.10.2018): 1333–43. http://dx.doi.org/10.1042/bst20170569.

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The Ras family of small guanine nucleotide-binding proteins behave as molecular switches: they are switched off and inactive when bound to GDP but can be activated by GTP binding in response to signal transduction pathways. Early structural analysis showed that two regions of the protein, which change conformation depending on the nucleotide present, mediate this switch. A large number of X-ray, NMR and simulation studies have shown that this is an over-simplification. The switch regions themselves are highly dynamic and can exist in distinct sub-states in the GTP-bound form that have different affinities for other proteins. Furthermore, regions outside the switches have been found to be sensitive to the nucleotide state of the protein, indicating that allosteric change is more widespread than previously thought. Taken together, the accrued knowledge about small G protein structures, allostery and dynamics will be essential for the design and testing of the next generation of inhibitors, both orthosteric and allosteric, as well as for understanding their mode of action.

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Gohil, S. "AB1343-HPR A QUALITATIVE REVIEW ASSESSING THEMATIC OUTCOMES FROM THE PHARMACY-LED ADALIMUMAB BIOSIMILAR SWITCH PLAN ACROSS 3 SPECIALITIES; RHEUMATOLOGY, GASTROENTEROLOGY AND DERMATOLOGY AT UNIVERSITY HOSPITALS OF COVENTRY AND WARWICKSHIRE (UHCW)". Annals of the Rheumatic Diseases 79, Suppl 1 (czerwiec 2020): 1959.1–1960. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3880.

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Background:The advent of biosimilars has heralded a new era for cost effective biologic prescribing in the NHS. As patents expire for originator biologics, less expensive versions are now widely available as biosimilars. Non-medical switches (for reasons unrelated to a patient’s health) ensure prescribing of best value medicines, and cost savings can be redirected to patient care.1This practice resonates with recommendations from Lord Carter’s 2016 report regarding reducing unwarranted variation in the NHS and adopting cost saving opportunities.2In 2018/19, following loss of patent exclusivity for the expensive adalimumab originator biologic, UHCW worked in accordance with national directives to drive forward one of the largest non-medical biosimilar switches.Objectives:This qualitative review aims to explore the success of the adalimumab biosimilar switch and key themes associated with switch backs/refusals across the Rheumatology (R), Gastroenterology (G) and Dermatology (D) specialities at UHCW.Methods:The switch plan occurred between April-December 2019. 403 patients (R;189, G;176, D; 38) were eligible for switch. Patients were informed of the plan in advance via a patient information leaflet/hospital clinic visits. Switch refusals, withheld treatments and cancellations were documented and patients were advised to contact the hospital pharmacy/clinical teams if they encountered any concerns, adverse effects or lack of efficacy post switch. The clinician would then advise on subsequent management.Results:During April-December 2019, 264/403 patients had been successfully switched (R;122, G;109, D;33). 33/403 patients switched back to the originator biologic (R;22, G;10; D;1). Of the 22 rheumatology switch back patients; 6 patients reported injection site pain and variably headache, fatigue, disease relapse, gastrointestinal (GI) upset, erythema; 10=reported lack of efficacy and variably influenza-type symptoms, relapse in associated psoriasis, difficulty in walking/sleeping, hair loss, excessive perspiration, facial cellulitis, foot drop and GI upset; 1=blepharitis;1=latex allergy before injection; 3=later declined switch; 1=damaged two devices and did not wish to continue biosimilar. Of the 10 gastroenterology switch back patients; 1=injection site pain; 2=lack of efficacy; 1=developed needle phobia; 1=latex allergy before injection; 1=switch detrimental to health; 2=unstable disease; 1=insomnia; 1=pregnancy. The 1 dermatology switch back patient reported injection site pain and bleeding.38/403 patients refused the switch and remained on the originator biologic (R;11, G;27, D;0). 29/403 patients had treatment cancellations and were switched to an alternative biologic (R;17, G;9, D;3). 32/403 patients stopped treatment (R;13, G;19, D;0). Treatment was withheld for 7/403 patients (R;4, G;2, D;1).Conclusion:The UHCW adalimumab biosimilar switch plan succeeded in switching a total of 66% of patients; thus an annual cost saving of £73,020. Injection site pain, most likely due to the biosimilar citrate content, and lack of efficacy according to patient perception and subsequent clinical review, were the most predominant causative themes for switch backs. Gastroenterology patients accounted for 71% (27/38) of the total switch refusals. Additional data regarding patient refusals, identifies future opportunities to improve patient counselling and drive further cost savings.References:[1]Azevedo V, et al. Biosimilars: considerations for clinical practice. Considerations in Medicine. 2017;1(1):13–8[2]Lord Carter of Coles. (2016) Operational productivity and performance in English NHS Acute Hospitals: Unwarranted variations [Online]Acknowledgments:Mark Easter, Chief Pharmacist, Hardeep Bagga, Deputy Chief Pharmacist, UHCW Pharmacy Homecare Team, UHCW Specialist Clinical Teams.Disclosure of Interests:None declared

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Sarma, Yadavalli V. S. "A G/o/G system with slow switch". Stochastic Analysis and Applications 7, nr 1 (styczeń 1989): 117–24. http://dx.doi.org/10.1080/07362998908809171.

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Chen, Wenguo, Rui Wang, Huiying Wang i Zhen Yang. "Design, Simulation, and Fabrication of a New Three-Axis Inertial Switch with a Triangular Movable Electrode Structure". Micromachines 14, nr 1 (30.12.2022): 94. http://dx.doi.org/10.3390/mi14010094.

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A new three-axis inertial switch is proposed. The triangle-structured movable electrode is designed to improve the inertial switch’s dynamic response performance, especially the movable electrode’s dynamic stability performance. The static mechanical analysis indicated that the displacement of the movable electrode to the fixed electrode in the sensitive direction is the minimum when the acceleration is applied to this designed inertial switch. The dynamic simulation analysis showed that the threshold of the designed inertial is about 235 g. The threshold in the non-sensitive direction is about 240 g, 270 g, 300 g, and 350 g when the directions of applied acceleration deviate 15°, 30°, 45°, and 60° from the sensitive direction, respectively. These results indicated that the designed inertial could resist the impact in non-sensitive directions and improve the stability in sensitive directions. The prototype of the inertial switch was fabricated and tested successfully. The testing results indicate that the threshold of the fabricated inertial switch is about 219 g. The test results verify the dynamic stability performance of the designed inertial switch.

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Ferrarelli, L. K. "A disease-causing G protein switch". Science 352, nr 6283 (14.04.2016): 304–6. http://dx.doi.org/10.1126/science.352.6283.304-r.

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Ghusinga, Khem Raj, Timothy C. Elston i Alan M. Jones. "Towards resolution of a paradox in plant G-protein signaling". Plant Physiology 188, nr 2 (16.11.2021): 807–15. http://dx.doi.org/10.1093/plphys/kiab534.

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Abstract G-proteins are molecular on–off switches that are involved in transmitting a variety of extracellular signals to their intracellular targets. In animal and yeast systems, the switch property is encoded through nucleotides: a GDP-bound state is the “off-state” and the GTP-bound state is the “on-state”. The G-protein cycle consists of the switch turning on through nucleotide exchange facilitated by a G-protein coupled receptor and the switch turning off through hydrolysis of GTP back to GDP, facilitated by a protein designated REGULATOR OF G SIGNALING 1 (RGS). In plants, G-protein signaling dramatically differs from that in animals and yeast. Despite stringent conservation of the nucleotide binding and catalytic structures over the 1.6 billion years that separate the evolution of plants and animals, genetic and biochemical data indicate that nucleotide exchange is less critical for this switch to operate in plants. Also, the loss of the single RGS protein in Arabidopsis (Arabidopsis thaliana) confers unexpectedly weaker phenotypes consistent with a diminished role for the G cycle, at least under static conditions. However, under dynamic conditions, genetic ablation of RGS in Arabidopsis results in a strong phenotype. We explore explanations to this conundrum by formulating a mathematical model that takes into account the accruing evidence for the indispensable role of phosphorylation in G-protein signaling in plants and that the G-protein cycle is needed to process dynamic signal inputs. We speculate that the plant G-protein cycle and its attendant components evolved to process dynamic signals through signaling modulation rather than through on–off, switch-like regulation of signaling. This so-called change detection may impart greater fitness for plants due to their sessility in a dynamic light, temperature, and pest environment.

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Nishimura, Shoichi, i Yong Jiang. "An M/G/l Vacation Model with Two Service Modes". Probability in the Engineering and Informational Sciences 9, nr 3 (lipiec 1995): 355–74. http://dx.doi.org/10.1017/s0269964800003922.

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Consider an M/G/1 type queueing system with two service modes: regular speed and high speed. The service rule is characterized by two switch-over levels nR and nH, where nR and nH are given integers with 0 ≤ nH < nR. The server switches from regular speed mode to high speed mode when the number of customers present at a service completion epoch is equal to or larger than nR and switches from high speed mode to regular speed mode when the number of customers present decreases to nH. A key feature of the model is that the server takes a vacation for setup operations before a new service mode is available. This paper derives for the general model an expression for the generating function of the equilibrium queue-length distribution in terms of the switch-over levels. Two unknown parameters appear in the generating functions. Using a recursive method, we solve these unknown parameters and obtain a computationally tractable algorithm for the steady-state probabilities.

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Wong, Wei. "A regulatory switch in obesity". Science 370, nr 6521 (3.12.2020): 1177.7–1178. http://dx.doi.org/10.1126/science.370.6521.1177-g.

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Deng, Jufeng, Dian Song i Shijie Su. "Highly Sensitive Inertial Micro-Switch for Achieving Adjustable Multi-Threshold Acceleration". Actuators 12, nr 2 (26.01.2023): 53. http://dx.doi.org/10.3390/act12020053.

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An inertial micro-switch with multi-threshold acceleration detection capability has been proposed, taking advantage of electromechanical coupling behavior. A mathematical model of electromechanical coupling behavior was established to display the dependence of highly sensitivity on pull-in characteristic and show the ability to detect threshold acceleration by controlling the voltage applied to the inertial micro-switch. The capability of sensitivity and detection that was described in mathematical model was implemented to occur at the inertial switch and showed agreement with that of a simulation. Inertia switches that were comprised of various microstructures with dimensions ranging 3.5 µm from 180 µm were manufactured by means of the micro-electro-mechanical system (MEMS) manufacturing process, and their functions were evaluated by a dropping system. The control method related to the manufacturing of inertial switches was obtained by analyzing the effect of the structural parameters of the inertial switch on threshold voltage and threshold acceleration, resulting in a relatively small error between simulation and experiment. The inertial micro-switch showed high sensitivity to achieving the pull-in effect at 30 V, sense multi-threshold acceleration ranging from 500 g to 2000 g in 2.46 ms and provided enough time for outputting the acceleration signal. Furthermore, the multi-threshold acceleration can be adjusted by controlling the voltage applied to inertial micro-switches. In addition, other functions of inertial micro-switches, such as lower residual stress, high recoverability, and repeatability, have been displayed.

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Ramini, A., M. I. Younis i Q. T. Su. "A low-g electrostatically actuated resonant switch". Smart Materials and Structures 22, nr 2 (21.12.2012): 025006. http://dx.doi.org/10.1088/0964-1726/22/2/025006.

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Han, Yingzhou, Guozhe Xuan, Jiahao Zhao i Zheng You. "Low-G Triggered Acceleration Switch for Near-Zero Power Wake-Up Application". Micromachines 13, nr 8 (17.08.2022): 1333. http://dx.doi.org/10.3390/mi13081333.

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A low-g triggered micro-electromechanical system (MEMS) resonant acceleration switch is designed, fabricated and tested in this paper for near-zero power wake-up applications. The switch is actuated by ambient low-g vibration, consuming zero power while waiting for vibration at its resonant frequency. A cantilever beam and proof mass structure is adopted in the switch. The patterns of spiral cantilever beams are designed for low resonant frequency and threshold. Once the vibration with resonant frequency exceeds the acceleration threshold of the switch, the movable electrode becomes sufficiently displaced to contact the fixed electrodes and causes them to trigger. The dynamic responses of the switch are tested on a piezoelectric stack. The experimental results show that the switch closes under vibration at a frequency as low as 39.3 Hz and at an acceleration threshold of 0.074 g. A wake-up sensor node connected to the switch can awaken when the switch is under vibration as an intended characteristics.

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Chen, Wenguo, Rui Wang, Huiying Wang, Dejian Kong i Shulei Sun. "The Analysis of the Influence of Threshold on the Dynamic Contact Process of a Fabricated Vertically Driven MEMS Inertial Switch". Micromachines 10, nr 11 (18.11.2019): 791. http://dx.doi.org/10.3390/mi10110791.

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In this work, to evaluate the influence of the threshold on the dynamic contact process, five models (number 1, 2, 3, 4, 5) with different thresholds were proposed and fabricated with surface micromachining technology. The contact time and response time were used to characterize the dynamic contact performance. The dynamic contact processes of the inertial switches with gradually increasing thresholds were researched using analytical, simulation, and experimental methods. The basic working principle analysis of the inertial switch shows that the contact time of the inertial switch with a low-g value can be extended by using a simply supported beam as the fixed electrode, but the high-G inertial needs more elasticity for fixed electrode. The simulation results indicate that the response time and contact time decrease with the increment in the designed threshold. Prototypes were tested using a dropping hammer system, and the test result indicates that the contact time of the inertial switch with a fixed electrode of the simply supported beam is about 15 and 5 μs when the threshold is about 280 and 580 g, respectively. Meanwhile, the contact time can be extended to 100 μs for the inertial switch using a spring as the fixed electrode when the threshold is about 280 and 580 g. These test results not only prove that the spring fixed electrode can effectively extend the contact time, but also prove that the style of the fixed electrode is the deciding factor affecting the contact time of the high-G inertial switch.

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Stajic, J. "Stretching graphene to switch it off". Science 344, nr 6187 (29.05.2014): 985. http://dx.doi.org/10.1126/science.344.6187.985-g.

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Shi, Shuo, Juan Zhao, Xing Gao, Chunyan Lv, Li Yang, Jian Hao, Hailiang Huang i in. "Molecular “light switch” for G-quadruplex DNA: cycling the switch on and off". Dalton Transactions 41, nr 19 (2012): 5789. http://dx.doi.org/10.1039/c2dt30076a.

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Li, Yiping, Qinjian Wang, Shu Liang, Chuanteng Feng, Hong Yang, Hang Yu, Dan Yuan i Shujuan Yang. "Effect of Switching Antiretroviral Treatment Regimen in Patients With Drug-Resistant HIV-1 Infection: Retrospective Observational Cohort Study". JMIR Public Health and Surveillance 8, nr 6 (24.06.2022): e33429. http://dx.doi.org/10.2196/33429.

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Background Evidence on the efficacy of antiretroviral therapy (ART) regimen switches on the mortality of patients with HIV drug resistance (HIVDR) is limited. Objective We aim to provide policy guidance for ART regimen selection and evaluate the effectiveness of ART regime switches for people living with HIV and HIV-1 drug resistance. Methods This retrospective observational cohort study included 179 people living with HIV and HIV-1 drug resistance from 2011 to 2020. The time that participants switched treatment regimens either to protease inhibitor (PI)–based ART regimens (PIs) or nonnucleoside reverse transcriptase inhibitor (NNRTI)–based ART regimens (NNRTIs) was taken as an observation starting point and followed up every 12 months. The parametric g-formula was used to estimate the 5-year risk of mortality under the situations of (1) natural course, (2) immediate switch to NNRTIs, (3) immediate switch to PIs, and (4) if CD4(+) T cells<200 switched to PIs. Results The follow-up time of the 179 patients ranged from 30 to 119 months. The median follow-up time was 90 months. During a follow-up of 15,606 person-months, 27 individuals died in the cohort. The estimated 5-year risk of mortality under natural course, immediate switch to NNRTIs, immediate switch to PIs, and if CD4(+), and switch to PIs if T cells<200 were 11.62% (95% CI 7.82-17.11), 31.88% (95% CI 20.79-44.94), 2.87% (95% CI 0.32-7.07), and 5.30% (95% CI 2.07-10.21), respectively. The risk ratios (RRs) of immediate switch to NNRTIs, immediate switch to PIs, and switch to PIs if CD4(+) T cells<200, compared with natural course mortality rate, were 2.74 (95% CI 2.01-3.47), 0.25 (95% CI: 0.04-0.54), and 0.46 (95% CI 0.22-0.71), respectively. The risk differences were 20.26% (95% CI 10.96-28.61), –8.76% (95% CI –13.34 to –5.09) and –6.32% (95% CI –9.75 to –3.11), respectively. Conclusions Our study found that a PI-based ART regimen was beneficial for reducing mortality in people living with HIV and HIV-1 drug resistance. More effort should be given to find HIV-1 drug resistance earlier to ensure a timely adjustment to PI-based ART, thereby maximizing the benefit of early switch treatment for people living with HIV and HIV-1 drug resistance.

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Hinde, Paul, Padraig Deighan i Charles J. Dorman. "Characterization of the Detachable Rho-Dependent Transcription Terminator of the fimE Gene in Escherichia coli K-12". Journal of Bacteriology 187, nr 24 (15.12.2005): 8256–66. http://dx.doi.org/10.1128/jb.187.24.8256-8266.2005.

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ABSTRACT The fim genetic switch in the chromosome of Escherichia coli K-12 is an invertible DNA element that harbors the promoter for transcription of the downstream fim structural genes and a transcription terminator that acts on the upstream fimE regulatory gene. Switches oriented appropriately for structural gene transcription also allow fimE mRNA to read through, whereas those in the opposite orientation terminate the fimE message. We show here that termination is Rho dependent and is suppressed in a rho mutant or by bicyclomycin treatment when fimE mRNA is expressed by the fimE gene, either from a multicopy recombinant plasmid or in its native chromosomal location. Two cis-acting elements within the central portion of the 314-bp invertible DNA switch were identified as contributors to Rho-dependent termination and dissected. These fim sequence elements show similarities to well-characterized Rho utilization (rut) sites and consist of a boxA motif and a C-rich and G-poor region of approximately 40 bp. Deletion of the boxA motif alone had only a subtle negative effect on Rho function. However, when this element was deleted in combination with the C-rich, G-poor region, Rho function was considerably decreased. Altering the C-to-G ratio in favor of G in this portion of the switch also strongly attenuated transcription termination. The implications of the existence of a fimE-specific Rho-dependent terminator within the invertible switch are discussed in the context of the fim regulatory circuit.

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Gautam, N. "A Conformational Switch Regulates Receptor-G Protein Interaction". Structure 11, nr 4 (kwiecień 2003): 359–60. http://dx.doi.org/10.1016/s0969-2126(03)00054-6.

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Oh, S. A., Y. Suh, M. G. Pang i K. Lee. "Cloning of avian G(0)/G(1) switch gene 2 genes and developmental and nutritional regulation of G(0)/G(1) switch gene 2 in chicken adipose tissue1". Journal of Animal Science 89, nr 2 (1.02.2011): 367–75. http://dx.doi.org/10.2527/jas.2010-3339.

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Gros, B., N. Plevris, N. Constantine-Cooke, M. Lyons, C. O’Hare, C. Noble, I. D. Arnott, G. R. Jones, C. W. Lees i L. A. A. P. Derikx. "P745 Multiple infliximab biosimilar switches appear to be safe and effective in a real-world inflammatory bowel disease cohort". Journal of Crohn's and Colitis 17, Supplement_1 (30.01.2023): i876. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0875.

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Abstract Background Switching from originator to biosimilar infliximab (IFX) is effective and safe. However, data on multiple switching are scarce. The Edinburgh IBD unit has undertaken three switch programmes: (1) Remicade to CT-P13 (2016), (2) CT-P13 to SB2 (2020), and (3) SB2 to CT-P13 (2021). The primary endpoint of this study was to assess CT-P13 persistence following switch from SB2. Secondary endpoints included persistence stratified by the number of biosimilar switches (single, double and triple), effectiveness and safety. Methods We performed a prospective, observational, cohort study. All adult IBD patients on IFX biosimilar SB2 underwent an elective switch to CT-P13. Patients were reviewed in a virtual biologic clinic with protocol driven collection of clinical disease activity, CRP, faecal calprotectin (FC), IFX trough / antibody levels, and drug survival. Results 297 patients (CD n=196 [66%], UC/IBDU n=101, [34%]) were switched. This was the third, second and first IFX switch for 67 /297 (22.5%), 138 /297 (46.5%) and 92 /297 (31%) of the cohort respectively. Patients who underwent multiple IFX biosimilar switches had longer disease duration (p=0.0001) and IFX duration (p=0.0001) and were less often on combination therapy with an immunomodulator (p=0.0001). 90.6% of patients remained on IFX during a median follow-up of 7.5 months [6.8-8.1] (figure 1). The number of switches was not independently associated with IFX persistence after adjusting for confounders (table 1). Clinical (p=0.77), biochemical (CRP ≤5mg/mL; p=0.75) and faecal biomarker (FC<250µg/g; p=0.63) remission were comparable at baseline, week 12 and week 24 (figure 2). Conclusion Multiple successive switches from IFX originator to biosimilars are effective and safe in patients with IBD, irrespective of the number of IFX switches.

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Zhang, Zheng Z., Nicholas R. Pannunzio, Chih-Lin Hsieh, Kefei Yu i Michael R. Lieber. "The role of G-density in switch region repeats for immunoglobulin class switch recombination". Nucleic Acids Research 42, nr 21 (6.11.2014): 13186–93. http://dx.doi.org/10.1093/nar/gku1100.

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Wildish, David J., i Adriana E. Radulovici. "Amphipods in estuaries: the sibling species low salinity switch hypothesis". Zoosystematics and Evolution 96, nr 2 (19.11.2020): 797–805. http://dx.doi.org/10.3897/zse.96.55896.

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A novel low salinity switch hypothesis is proposed to account for the speciation of an obligate estuarine (oligohaline) amphipod, Orchestia aestuarensis, from a closely-related one, Orchestia mediterranea, found in both estuarine and marine conditions (euryhaline). The underlying genetic mechanisms could involve: 1. A dimorphic allele, or linked set of alleles, carried by the euryhaline amphipod which controls the ability to breed in low salinity conditions in estuaries and which is selected for in these conditions, producing the oligohaline amphipod. 2. A genetically-assimilated gene or genes, controlling the ability to breed in low salinity conditions in estuaries, which is/are “switched on” by low salinity conditions. 3. Allopatric speciation from a euryhaline to an oligohaline amphipod species where low salinity conditions is the selective switch. It is possible that other estuarine, sibling, amphipod pairs have evolved by salinity switching. In the North Atlantic coastal region, this could include: Gammarus tigrinus/G. daiberi and G. salinus/G. zaddachi (Amphipoda, Gammaridae).

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Xi, Zhanwen, Nan Kong, Weirong Nie, Yun Cao i Can Zheng. "High g MEMS inertial switch capable of direction detection". Sensors and Actuators A: Physical 296 (wrzesień 2019): 7–16. http://dx.doi.org/10.1016/j.sna.2019.06.052.

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Gao, Heng, Xiong Zheng, Tong Yang, Qingqing Zhang, Chenxiao Yan, Xiaoshun Zhou i Yong Shao. "A pH-triggered G-triplex switch with K+ tolerance". Chemical Communications 56, nr 53 (2020): 7349–52. http://dx.doi.org/10.1039/d0cc02757j.

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Shafiq, Arooj, Louise J. Campbell, Darerca Owen i Helen R. Mott. "NMR resonance assignments for the active and inactive conformations of the small G protein RalA". Biomolecular NMR Assignments 14, nr 1 (8.01.2020): 87–91. http://dx.doi.org/10.1007/s12104-019-09925-7.

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AbstractThe Ral proteins (RalA and RalB) are small G proteins of the Ras family that have been implicated in exocytosis, endocytosis, transcriptional regulation and mitochondrial fission, as well as having a role in tumourigenesis. RalA and RalB are activated downstream of the master regulator, Ras, which causes the nucleotide exchange of GDP for GTP. Here we report the 1H, 15 N and 13C resonance assignments of RalA in its active form bound to the GTP analogue GMPPNP. We also report the backbone assignments of RalA in its inactive, GDP-bound form. The assignments give insight into the switch regions, which change conformation upon nucleotide exchange. These switch regions are invisible in the spectra of the active, GMPPNP bound form but the residues proximal to the switches can be monitored. RalA is also an important drug target due to its over activation in some cancers and these assignments will be extremely useful for NMR-based screening approaches.

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Roy, Deepankar, Kefei Yu i Michael R. Lieber. "Mechanism of R-Loop Formation at Immunoglobulin Class Switch Sequences". Molecular and Cellular Biology 28, nr 1 (22.10.2007): 50–60. http://dx.doi.org/10.1128/mcb.01251-07.

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ABSTRACT R-loops have been described in vivo at the immunoglobulin class switch sequences and at prokaryotic and mitochondrial origins of replication. However, the biochemical mechanism and determinants of R-loop formation are unclear. We find that R-loop formation is nearly eliminated when RNase T1 is added during transcription but not when it is added afterward. Hence, rather than forming simply as an extension of the RNA-DNA hybrid of normal transcription, the RNA must exit the RNA polymerase and compete with the nontemplate DNA strand for an R-loop to form. R-loops persist even when transcription is done in Li+ or Cs+, which do not support G-quartet formation. Hence, R-loop formation does not rely on G-quartet formation. R-loop formation efficiency decreases as the number of switch repeats is decreased, although a very low level of R-loop formation occurs at even one 49-bp switch repeat. R-loop formation decreases sharply as G clustering is reduced, even when G density is kept constant. The critical level for R-loop formation is approximately the same point to which evolution drove the G clustering and G density on the nontemplate strand of mammalian switch regions. This provides an independent basis for concluding that the primary function of G clustering, in the context of high G density, is R-loop formation.

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Mcgrory, L., C. Goess i K. Lynch. "P613 Switch from intravenous to subcutaneous maintenance infliximab in real world IBD cohort". Journal of Crohn's and Colitis 17, Supplement_1 (30.01.2023): i741—i743. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0743.

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Abstract Background During the COVID-19 pandemic, there has been concern regarding patients attending hospitals for intravenous (IV) infusions due to increased COVID-19 exposure risk and demand on hospital resources. Data on switching patients from escalated dosing of IV infliximab (IFX) are limited. We describe a real-world experience of electively switching a cohort of patients on maintenance IV IFX for inflammatory bowel disease (IBD), at both standard and escalated dosing, to subcutaneous CT-P13 (Remsima®). Methods Adult patients with IBD on IV IFX at Royal Adelaide Hospital were invited to switch to fortnightly dosing of subcutaneous IFX. We collected demographic data using medical records, and prospectively measured clinical assessment scores (CDAI/HBI for Crohn's disease (CD) and partial Mayo/SCCAI for Ulcerative Colitis (UC)), faecal calprotectin (FCal), CRP and trough IFX levels prior to switching to subcutaneous IFX, and at 6 months post switch. Clinical remission was defined as CDAI≤150/HBI≤4 (CD) or partial Mayo≤3 (no subscore>1)/SCCAI≤2 (UC). Results 29 patients were switched from IV IFX to subcutaneous CT-P13 between March 2021 and May 2022 (see Table 1 for baseline demographics). 23 had Crohn's disease (79%). 10/29 patients (31%) were on intensified IV dosing at baseline prior to switch. The majority of patients, 25/29 (86%) were in remission pre-switch. Of 19 patients with paired trough IFX levels, these increased significantly from baseline to 6 months post-switch (5.9mg/ml to 13.9mg/ml, respectively (p=0.0003), see Fig 1). The median FCal did not change pre- vs post switch (73mcg/g vs 80mcg/g, p=0.540), see Fig 2). Median CRP did not change pre- vs. post switch (1 µg/ml vs 2 µg/ml). Clinical assessment scores remained stable pre- vs. post-switch (CDAI 31 vs 31, (p=0.316) see Fig 3; HBI. 1 vs 2 (p=0.940); partial Mayo 0 vs 0, (p>0.999); and SCCAI 1 vs 2 (p=0.5000)). Regarding the subset of patients on escalated dosing at baseline, all patients were in clinical remission at 6 months post-switch. There was no significant change in IFX levels (8.4 vs 13.3, p=0.253). FCal did not significantly change (76mcg/g vs 79mcg/g (p=0.563), nor did median CDAI (37 vs 21 (p=0.5312) and median HBI (2 vs 2 (p=0.750)). Overall, only 1/29 (3%) patients were not in remission at 6 month follow-up. No patients in required steroids or surgery. Of the 9 patients with perianal disease, none had a flare. All patients with weight>100kg (n=4) remained in remission. Conclusion Switching patients from IV to subcutaneous IFX delivered stable clinical outcomes in this real world cohort, with no change in disease biomarkers and clinical indices. IFX levels increased overall and all patients on escalated IV dosing were in clinical remission at 6 months post-switch.

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Dudin, Alexander N., i Shoichi Nishimura. "Optimal control for a BMAP/G/1 queue with two service modes". Mathematical Problems in Engineering 5, nr 3 (1999): 255–73. http://dx.doi.org/10.1155/s1024123x99001088.

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Queueing models with controllable service rate play an important role in telecommunication systems. This paper deals with a single-server model with a batch Markovian arrival process (BMAP) and two service modes, where switch-over times are involved when changing the service mode. The embedded stationary queue length distribution and the explicit dependence of operation criteria on switch-over levels and derived.

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Rosborough, K., G. Yu, C. Barker, K. Jacobson i S. Lawrence. "A56 CLINICAL AND BIOCHEMICAL EFFICACY ARE NOT AFFECTED BY SWITCH FROM INFLIXIMAB ORIGINATOR TO RENFLEXIS IN PEDIATRIC INFLAMMATORY BOWEL DISEASE PATIENTS." Journal of the Canadian Association of Gastroenterology 4, Supplement_1 (1.03.2021): 13–14. http://dx.doi.org/10.1093/jcag/gwab002.054.

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Abstract Background Increased infliximab (IFX) utilization has generated higher drug expenditures and cost burden to the healthcare system. The expiration of the IFX originator Remicade patent led to the addition of biosimilar agents to the drug market that may reduce drug expenditures. In British Columbia, Pharmacare’s 2019 biosimilar initiative mandated all pediatric inflammatory bowel disease (IBD) patients on Remicade to switch to the biosimilar Renflexis. To date, there is limited pediatric IBD data demonstrating that switching from IFX originator to IFX biosimilar CT-P13 is safe and effective, and no data on switching to Renflexis. Aims To determine the proportion of patients remaining on Renflexis 6 months after switch from originator IFX. The secondary aims are to determine the proportion of patients remaining in clinical and biochemical remission after switch. Methods In this prospective, longitudinal observation single-center study, all children with Crohn’s disease and ulcerative colitis receiving maintenance IFX originator therapy were switched to Renflexis by May 15th 2020. Baseline demographics, concomitant therapy, clinical disease indices (wPCDAI, PUCAI), growth data, blood work, fecal calprotectin and IFX drug levels were collected at baseline and prospectively from 6 months after the switch. All data are presented as median and interquartile range. Results A total of 139 children (110 CD, 25 UC and 4 IBDU; Median age 16.2 (3.7) years) with a median IFX originator duration of 42.7 (35.1) months before switching to Renflexis were included. 137/139 (99%) of patients remained on Renflexis at study end. The proportion of children in clinical remission from baseline to 6 months post switch was unchanged (133/139 (95.7%) vs. 130/132 (98.5%), p=0.17). There was no significant change pre and post switch in median CRP (<5 (0) mg/L vs <5 (0) mg/L, p=0.26) or fecal calprotectin (72.5 (144.2) ug/g vs. 65.5 (140.0) ug/g, p=0.87). There was no significant change pre and post switch in the proportion of patients with normal CRP (<5 mg/L) (89/103 (86.4%) vs 89/98 (90.8%), p=0.33) or normal fecal calprotectin (<250 ug/g)(91/112 (81.2%) vs 51/63 (80.9%), p=0.60). There was no significant change pre and post switch in IFX trough level (15.5 (12.3) ug/mL vs 17.5 (12.9) ug/mL, p=0.42). 2 patients had antibodies to IFX after switching. Safety profile is improved with adverse events in 38/139 (27.3%) children on IFX originator vs. 11/139 (7.91%) children on Renflexis for 6 months. Conclusions Pediatric IBD patients can be successfully switched from IFX originator to biosimilar Renflexis during maintenance without affecting efficacy, immunogenicity or safety in the short term. Funding Agencies None

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Lin, Yi, Tao Yang, Ting Ting Liu, Guang Yan Chen i Chao Wang. "Analysis and Simulation of Micro-Fluidic Inertial Switch". Key Engineering Materials 503 (luty 2012): 348–53. http://dx.doi.org/10.4028/www.scientific.net/kem.503.348.

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This paper presents a micro-fluidic inertial switch with varying rectangular cross section, which employs the moving mercury droplet in the micro-channel to close a switch. Combining the Young-Laplace formula with the structure, the formula of the threshold g-value is derived. The influence of design parameters of microchannel on the threshold g-value is analyzed. Based on the VOF approach containing contact angle effects, the dynamic behavior of mercury droplet in the microchannel is simulated using Fluent. The response time is predicted through simulation with the contact angles ranging from 130° to 170°. In addition, the dynamic process of inertial switch is simulated, and the result indicates that the selected design parameters can achieve reliable switching under given threshold g-value.

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Vasiljević, D. M. "Nonlinear analysis of a quartz multivibrator with a complementary switch". IEE Proceedings G (Electronic Circuits and Systems) 132, nr 2 (1985): 33. http://dx.doi.org/10.1049/ip-g-1.1985.0006.

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Yang, H. G., i D. M. Holburn. "Switch-level timing verification for CMOS circuits: a semianalytic approach". IEE Proceedings G Circuits, Devices and Systems 137, nr 6 (1990): 405. http://dx.doi.org/10.1049/ip-g-2.1990.0062.

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Chen, Wenguo, Rui Wang, Huiying Wang i Shulei Sun. "The Design, Simulation and Fabrication of an Omnidirectional Inertial Switch with Rectangular Suspension Spring". Micromachines 12, nr 4 (15.04.2021): 440. http://dx.doi.org/10.3390/mi12040440.

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An omnidirectional inertial switch with rectangular spring is proposed in this paper, and the prototype has been fabricated by surface micromachining technology. To evaluate the threshold consistency and stability of omnidirectional inertia switch, the stiffness of rectangular suspension springs is analyzed. The simulation result shows that the coupling stiffness of the rectangular spring suspension system in the non-sensitive direction is a little more than that in the sensitive direction, which indicated that the omnidirectional switching system’s stability is reinforced, attributed to the design of rectangular springs. The dynamic response simulation shows that the threshold of the omnidirectional inertial switch using the rectangular suspension spring has high consistency in the horizontal direction. The prototype of an inertial switch is fabricated and tested successfully. The testing results indicate even threshold distribution in the horizontal direction. The threshold acceleration of the designed inertial switch is about 58 g in the X direction and 37 g in the Z direction; the contact time is about 18 μs.

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34

Yadegari, Farzad, Ali Mahdianikhotbesara i M. Hossein Sehhat. "Design and Modeling of a High-Acceleration MEMS G-Switch". COMPUTATIONAL RESEARCH PROGRESS IN APPLIED SCIENCE & ENGINEERING 8, nr 2 (2022): 1–5. http://dx.doi.org/10.52547/crpase.8.2.2783.

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Stouten, Pieter F. W., Chris Sander, Alfred Wittinghofer i Alfonso Valencia. "How does the switch II region of G-domains work?" FEBS Letters 320, nr 1 (29.03.1993): 1–6. http://dx.doi.org/10.1016/0014-5793(93)81644-f.

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Monchaud, David, Peng Yang, Laurent Lacroix, Marie-Paule Teulade-Fichou i Jean-Louis Mergny. "A Metal-Mediated Conformational Switch Controls G-Quadruplex Binding Affinity". Angewandte Chemie International Edition 47, nr 26 (16.06.2008): 4858–61. http://dx.doi.org/10.1002/anie.200800468.

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Monchaud, David, Peng Yang, Laurent Lacroix, Marie-Paule Teulade-Fichou i Jean-Louis Mergny. "A Metal-Mediated Conformational Switch Controls G-Quadruplex Binding Affinity". Angewandte Chemie 120, nr 26 (16.06.2008): 4936–39. http://dx.doi.org/10.1002/ange.200800468.

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Juji, Takeo, Nobuhiro Wakimoto, Yoichi Kagawa i Seiichi Ono. "5098371 Switch bag type blood gathering set". Transfusion Science 13, nr 4 (październik 1992): ii—iii. http://dx.doi.org/10.1016/0955-3886(92)90043-g.

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Ash, Miriam-Rose, Megan J. Maher, J. Mitchell Guss i Mika Jormakka. "A suite of Switch I and Switch II mutant structures from the G-protein domain of FeoB". Acta Crystallographica Section D Biological Crystallography 67, nr 11 (19.10.2011): 973–80. http://dx.doi.org/10.1107/s0907444911039461.

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Sun, Yutong, Jianyun Huang, Yang Xiang, Murat Bastepe, Harald Jüppner, Brian K. Kobilka, J. Jillian Zhang i Xin-Yun Huang. "Dosage-dependent switch from G protein-coupled to G protein-independent signaling by a GPCR". EMBO Journal 26, nr 1 (14.12.2006): 53–64. http://dx.doi.org/10.1038/sj.emboj.7601502.

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Mao, Jianbin, Micheal Johnson, Jeffrey Mcpheeters, Girish Prajapati i Andrew Beyer. "Healthcare Resource Utilization and Costs Associated with Switching First-line Antiretroviral Therapy among HIV-infected Patients in the United States". Open Forum Infectious Diseases 4, suppl_1 (2017): S435—S436. http://dx.doi.org/10.1093/ofid/ofx163.1101.

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Abstract Background Initial antiretroviral therapy (ART) is modified for non-virologic failure reasons in many patients, and the healthcare resource utilization (HRU) and costs associated with these switches in the real world is not well understood. Methods Administrative claims data from the Optum Research and Impact National Benchmark Databases were utilized. Adult patients (≥18 years) with HIV-1 diagnosis code, and claim for an anchor agent of the protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) class in first-line ART between July 1, 2006 and December 31, 2015 were identified (see Figure 1 for addl. criteria). Patients with a claim for an anchor agent (PI or NNRTI) different from that in first-line ART were defined as switchers, with index date as date of first claim for new anchor agent. Switchers were matched to patients who did not switch (non-switchers) at 1:3 ratio using propensity score matching on patient and first-line ART characteristics. For non-switchers, date following corresponding duration of first-line ART in matched switcher was assigned as index date. Per-patient-per-month (PPPM) all-cause HRU and costs (US$) during switch period (±15 days of index date) were compared descriptively. Results 11,302 patients met study criteria. After matching, switcher (1,204) and non-switcher (3,612) groups were comparable on mean age (41.9 vs. 41.7 years), percent male (85.8% vs. 82.6%), percent commercial enrollee (96.0% vs. 95.8%), mean Quan-Charlson comorbidity index score (both 0.4), and mean ART pill burden (both 2.2) with standard difference less than absolute value of 10%. During switch period, switchers had higher mean PPPM ambulatory visits (2.30 vs. 1.26), emergency room visits (0.12 vs. 0.06), inpatient stays (0.04 vs. 0.01), and pharmacy fills (4.52 vs. 3.01) than non-switchers (all P < 0.001). Switchers also incurred greater mean PPPM costs during switch than non-switchers, with an additional $2,261/month total cost, and $1,031/month pharmacy cost (Figure 2). Conclusion The study gives a more complete view of the burden of switching initial ART with pharmacy costs driving this burden. Assuming some patients will switch regardless of the regimen selected, less expensive initial ART could reduce this burden further. Disclosures M. Johnson, Merk & Co: Research Contractor, research funded by Merk; J. Mcpheeters, Merck & Co.: Research Contractor, Sarary from Optum; G. Prajapati, Merck & Co., Inc.: Employee, Salary; A. Beyer, Merck & Co., Inc: Employee and Shareholder, Salary

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Pan, Q., H. Rabbani, F. C. Mills, E. Severinson i L. Hammarström. "Allotype-associated variation in the human gamma3 switch region as a basis for differences in IgG3 production." Journal of Immunology 158, nr 12 (15.06.1997): 5849–59. http://dx.doi.org/10.4049/jimmunol.158.12.5849.

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Abstract High and low serum concentrations of IgG3 are associated with the human G3 m(b) and G3 m(g) allotypes, respectively. We previously hypothesized that a low frequency of switching is the most likely defect in (g) allotype-positive individuals, and therefore analyzed the structure, recombination breakpoints, and binding of nuclear proteins to the switch (S)gamma3 regions of these two allotypes. There are no allotype-associated differences in the length and basic structure of the Sgamma3, since both contain eighteen 79-bp repeats. However, we found a number of allotype-associated nucleotide changes. As in the mouse system, there is a preferential switching to the B site, or switch nuclear protein/nuclear factor-kappaB motif, with a clustering of switch breakpoints at the most 5' residue of the B site. The B site sequence used most frequently in switching was found to be mutated at this nucleotide in the (g) allotype-associated Sgamma3. This change was shown by electrophoretic mobility shift assay to alter the binding of the switch nuclear protein/nuclear factor-kappaB protein to the B site. Taken together, these data suggest that polymorphism within Sgamma3 may contribute to allotype-associated differences in IgG3 switching, and that specific sequences within the Sgamma3 79-bp repeats could be mechanistically important for switch recombination.

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Xu, Huiying, Fenghua Geng, Yongxiang Wang, Maotian Xu, Xinhe Lai, Peng Qu, Yintang Zhang i Baohong Liu. "A label-free fluorescent molecular switch for a DNA hybridization assay utilizing a G-quadruplex-selective auramine O". Chemical Communications 51, nr 41 (2015): 8622–25. http://dx.doi.org/10.1039/c5cc02624e.

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Thalluri, Lakshmi, K. V. V. Kumar, Konari Sekhar, Bhushana Babu, S. S. Kiran i Koushik Guha. "Damping analysis to improve the performance of shunt capacitive RF MEMS switch". Facta universitatis - series: Electronics and Energetics 34, nr 3 (2021): 381–92. http://dx.doi.org/10.2298/fuee2103381t.

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This paper describes the significance of the iterative approach and the structure damping analysis which help to get better the performance and validation of shunt capacitive RF MEMS switch. The micro-cantilever based electrostatic ally actuated shunt capacitive RF MEMS switch is designed and after multiple iterations on cantilever structure a modification of the structure is obtained that requires low actuation voltage of 7.3 V for 3 ?m deformation. To validate the structure we have performed the damping analysis for each iteration. The low actuation voltage is a consequence of identifying the critical membrane thickness of 0.7 ?m, and incorporating two slots and holes into the membrane. The holes to the membrane help in stress distribution. We performed the Eigen frequency analysis of the membrane. The RF MEMS switch is micro machined on a CPW transmission line with Gap- Strip-Gap (G-S-G) of 85 ?m - 70 ?m - 85 ?m. The switch RF isolation properties are analyzed with high dielectric constant thin films i.e., AlN, GaAs, and HfO2. For all the dielectric thin films the RF MEMS switch shows a high isolation of -63.2 dB, but there is shift in the radio frequency. Because of presence of the holes in the membrane the switch exhibits a very low insertion loss of -0.12 dB.

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Kalogriopoulos, Nicholas A., Steven D. Rees, Tony Ngo, Noah J. Kopcho, Andrey V. Ilatovskiy, Nina Sun, Elizabeth A. Komives, Geoffrey Chang, Pradipta Ghosh i Irina Kufareva. "Structural basis for GPCR-independent activation of heterotrimeric Gi proteins". Proceedings of the National Academy of Sciences 116, nr 33 (30.07.2019): 16394–403. http://dx.doi.org/10.1073/pnas.1906658116.

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Heterotrimeric G proteins are key molecular switches that control cell behavior. The canonical activation of G proteins by agonist-occupied G protein-coupled receptors (GPCRs) has recently been elucidated from the structural perspective. In contrast, the structural basis for GPCR-independent G protein activation by a novel family of guanine-nucleotide exchange modulators (GEMs) remains unknown. Here, we present a 2.0-Å crystal structure of Gαi in complex with the GEM motif of GIV/Girdin. Nucleotide exchange assays, molecular dynamics simulations, and hydrogen–deuterium exchange experiments demonstrate that GEM binding to the conformational switch II causes structural changes that allosterically propagate to the hydrophobic core of the Gαi GTPase domain. Rearrangement of the hydrophobic core appears to be a common mechanism by which GPCRs and GEMs activate G proteins, although with different efficiency. Atomic-level insights presented here will aid structure-based efforts to selectively target the noncanonical G protein activation.

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Jiang, Xi, i James S. Meditch. "A high-speed integrated services ATM/STM switch". Computer Networks and ISDN Systems 26, nr 4 (grudzień 1993): 459–77. http://dx.doi.org/10.1016/0169-7552(93)90083-g.

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Gerwert, Klaus, Daniel Mann i Carsten Kötting. "Common mechanisms of catalysis in small and heterotrimeric GTPases and their respective GAPs". Biological Chemistry 398, nr 5-6 (1.05.2017): 523–33. http://dx.doi.org/10.1515/hsz-2016-0314.

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Abstract GTPases are central switches in cells. Their dysfunctions are involved in severe diseases. The small GTPase Ras regulates cell growth, differentiation and apoptosis by transmitting external signals to the nucleus. In one group of oncogenic mutations, the ‘switch-off’ reaction is inhibited, leading to persistent activation of the signaling pathway. The switch reaction is regulated by GTPase-activating proteins (GAPs), which catalyze GTP hydrolysis in Ras, and by guanine nucleotide exchange factors, which catalyze the exchange of GDP for GTP. Heterotrimeric G-proteins are activated by G-protein coupled receptors and are inactivated by GTP hydrolysis in the Gα subunit. Their GAPs are called regulators of G-protein signaling. In the same way that Ras serves as a prototype for small GTPases, Gαi1 is the most well-studied Gα subunit. By utilizing X-ray structural models, time-resolved infrared-difference spectroscopy, and biomolecular simulations, we elucidated the detailed molecular reaction mechanism of the GTP hydrolysis in Ras and Gαi1. In both proteins, the charge distribution of GTP is driven towards the transition state, and an arginine is precisely positioned to facilitate nucleophilic attack of water. In addition to these mechanistic details of GTP hydrolysis, Ras dimerization as an emerging factor in signal transduction is discussed in this review.

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Xu, Jian, Vijay G. Sankaran, Yuko Fujiwara i Stuart H. Orkin. "Control of Hemoglobin Switching by BCL11A." Blood 114, nr 22 (20.11.2009): 5. http://dx.doi.org/10.1182/blood.v114.22.5.5.

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Abstract Abstract 5 All vertebrates switch expression of globin chains during development. In humans b-like globins switch from embryonic to fetal to adult, whereas in the mouse a single switch from embryonic to adult occurs. The switch from human fetal (g) to adult (b) expression is especially critical in the b-hemoglobin disorders, such as sickle cell anemia and the b-thalassemias. Delay of the switch or reactivation of the fetal gene in the adult stage greatly ameliorates clinical severity. Despite intensive molecular studies of the human b-globin cluster over more than two decades, the proteins regulating the switch, and the mechanisms controlling the process, have been largely elusive. Recently, genome-wide association studies identified genetic variation at a chromosome 2 locus that correlates with the level of HbF in different populations. The most highly associated single nucleotide polymorphisms (SNPs) reside in an intron of the BCL11A gene, which encodes a zinc-finger repressor protein. Previously we showed that shRNA-mediated ex vivo knockdown of BCL11A in cultured human CD34-derived erythroid precursors leads to robust HbF expression, consistent with a role for BCL11A in maintaining g-genes in a silenced state in adult cells. To address in vivo roles of BCL11A either in development or in globin gene silencing in an intact individual, we have employed stringent genetic tests of function in mice that carry a complete human b-globin gene cluster as a yeast artificial chromosome transgene (b-locus mice). Knockout of BCL11A in mice leads to failure to silence the endogenous b-like embryonic genes in adult erythroid cells of the fetal liver (>2500-fold derepression). The ratio of human g to b globin RNA in the fetal liver of BCL11A knockout mice is inverted compared to controls, such that g constitutes >90% of the b-like human expression at embryonic day (E)14.5 and >75% at E18.5. These quantitatively striking findings indicate that BCL11A controls developmental silencing of g-globin gene expression. To address by formal genetics the contribution of BCL11A to g silencing in adult animals we have employed conditional inactivation of BCL11A through hematopoietic- and erythroid-specific Cre-alleles. These experiments reveal that BCL11A is also required in vivo for g-gene silencing in adults. We observed that human g-globin expression is persistently derepressed >2000-fold (as compared to littermate controls) in bone marrow erythroblasts of 15-20 week old b-locus mice upon erythroid-specific deletion of BCL11A. Taken together, these findings establish BCL11A as the first genetically validated transcriptional regulator of both developmental control of globin switching and silencing of g-globin expression in adults. The recognition of these roles for BCL11A now permits focused mechanistic studies of the switch. In human erythroid cells, BCL11A physically interacts with at least two corepressor complexes, Mi-2/NuRD and LSD1/CoREST, as well as the erythroid transcription factor GATA-1 and the HMG-box protein SOX6. Rather than binding to the promoters of the g- or b-globin genes as do these latter factors, BCL11A protein occupies the upstream locus control and g-d-intergenic regions of the b-globin cluster (as determined by high resolution ChIP-Chip analysis), suggesting that BCL11A mediates long-range interactions and/or reconfigures the locus during different stages. An in-depth mechanistic understanding of globin switching offers the prospect for design of target-based activation of HbF in adult erythroid cells of patients with hemoglobin disorders. Disclosures: No relevant conflicts of interest to declare.

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Ma, Dik-Lung, Lihua Lu, Sheng Lin, Bingyong He i Chung-Hang Leung. "A G-triplex luminescent switch-on probe for the detection of mung bean nuclease activity". Journal of Materials Chemistry B 3, nr 3 (2015): 348–52. http://dx.doi.org/10.1039/c4tb01569j.

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Malisan, F., F. Brière, J. M. Bridon, N. Harindranath, F. C. Mills, E. E. Max, J. Banchereau i H. Martinez-Valdez. "Interleukin-10 induces immunoglobulin G isotype switch recombination in human CD40-activated naive B lymphocytes." Journal of Experimental Medicine 183, nr 3 (1.03.1996): 937–47. http://dx.doi.org/10.1084/jem.183.3.937.

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Upon activation, B lymphocytes can change the isotype of the antibody they express by immunoglobulin (Ig) isotype switch recombination. In previous studies on the regulation of human IgG expression, we demonstrated that interleukin 10 (IL-10) could stimulate IgG1 and IgG3 secretion by human CD40-activated naive (sIgD+) tonsillar B cells. To assess whether IL-10 actually promotes the DNA recombination underlying switching to these isotypes, we examined the effect of IL-10 on the generation of reciprocal products that form DNA circles as by-products of switch recombination. The content of reciprocal products characteristic of mu-gamma recombination was elevated after culture of CD40-activated tonsillar sIgD+ B cells with either IL-4 or IL-10, although high levels of IgG secretion were observed only with IL-10. Unlike IL-4, IL-10 did not induce reciprocal products of mu-epsilon and gamma-epsilon switch recombination. These results demonstrate that IL-10 promotes both switching to gamma and IgG secretion.

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