Journal articles on the topic 'Molecular Switche'
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1
Burlando, Martina, Gabriella Fabbrocini, Claudio Marasca, Paolo Dapavo, Andrea Chiricozzi, Dalma Malvaso, Valentina Dini, et al. "Adalimumab Originator vs. Biosimilar in Hidradenitis Suppurativa: A Multicentric Retrospective Study." Biomedicines 10, no. 10 (October 9, 2022): 2522. http://dx.doi.org/10.3390/biomedicines10102522.
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This study aimed to compare adalimumab originator vs. biosimilar in HS patients, and to evaluate the effect of a switch to a biosimilar, or a switch back to the originator, in terms of treatment ineffectiveness. Patients with a diagnosis of HS were enrolled from 14 Italian sites. Treatment ineffectiveness was measured using Hurley score. The major analyses were 1) comparison between the two treatment groups (non-switcher analysis), and 2) the cross-over trend of Hurley score between treatment switchers (switcher analysis). Cox and Poisson regression models were used to compare the treatment ineffectiveness between groups. A total of 326 patients were divided into four groups: 171 (52.5%) taking originator; 61 (18.7%) patients taking biosimilar; 66 (20.2%) switchers; 28 (8.6%) switchers from originator to biosimilar and switched. A greater loss of efficacy was observed in the group allocated to the biosimilar than the originator group. The switcher analysis showed an effectiveness loss in the biosimilar compared to the originator. These results seem to indicate that a switch from one drug to the other may lead to a greater risk of inefficacy. A return to the previous treatment also does not ensure efficaciousness.
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Ho, P. Joy, Ross D. Brown, Gregory J. Pelka, Antony Basten, John Gibson, and Douglas E. Joshua. "Illegitimate switch recombinations are present in approximately half of primary myeloma tumors, but do not relate to known prognostic indicators or survival." Blood 97, no. 2 (January 15, 2001): 490–95. http://dx.doi.org/10.1182/blood.v97.2.490.
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Abstract The myeloma plasma cell is a postgerminal center, isotype-switched B cell. Chromosomal translocations into immunoglobulin heavy chain (IgH) switch regions, recombination sites in isotype switching, were initially demonstrated in myeloma cell lines but only a limited number of primary tumors. Molecular cytogenetics have since been applied to a series of primary tumors, in which IgH translocations accounted for many recurrent aberrations, among numerous nonrecurrent changes of unknown significance. This study, therefore, examined primary myeloma for IgH switch translocations using an established Southern blot assay that detected illegitimate switch recombinations. Sensitivity of the method was established by confining the analysis to 21 samples (4 stable, 17 progressive disease) with demonstrable legitimate isotype switches, of a total of 60 samples. Illegitimate recombinations were found in 12 or 57% (1 stable, 11 progressive) of 21 samples, comparable with estimates by molecular cytogenetics. The presence of switch translocations was supported by demonstrating up-regulated expression in myeloma marrow of cyclin D1 and fibroblast growth factor receptor 3 (FGFR3), candidate oncogenes on chromosomes 11q13 and 4p16, respectively. Illegitimate switches were detected most frequently in Sμ, with more than one region involved in 6 cases. Although these results confirmed the presence of switch translocations in primary myeloma, their absence in 43% of cases may imply heterogeneity of pathogenesis. In progressive disease, there was no significant difference between patients with and without illegitimate switches in survival, nor the prognostic indicators of β2microglobulin (β2m) and serum thymidine kinase (STK). Hence IgH switch translocations as a single entity are unlikely to be a feature of disease progression or have prognostic significance.
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Scognamiglio, Viviana, and Amina Antonacci. "Structural Changes as a Tool for Affinity Recognition: Conformational Switch Biosensing." Crystals 12, no. 9 (August 27, 2022): 1209. http://dx.doi.org/10.3390/cryst12091209.
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Biosensors draw inspiration from natural chemosensing based on molecular switches between different bond-induced conformational states. Proteins and nucleic acids can be adapted into switch-based biosensors with a wide plethora of different configurations, taking advantage of the variety of transduction systems, from optical to electrochemical or electrochemiluminescence, as well as from nanomaterials for signal augmentation. This review reports the latest trends in conformational switch biosensors reported in the literature in the last 10 years, focusing on the main representative and recent examples of protein-based switching biosensors, DNA nanomachines, and structure-switched aptamers being applied for the detection of a wide range of target analytes with interest in biomedical and agro-environmental sectors.
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Glintborg, Bente, Anne Gitte Loft, Emina Omerovic, Oliver Hendricks, Asta Linauskas, Jakob Espesen, Kamilla Danebod, et al. "To switch or not to switch: results of a nationwide guideline of mandatory switching from originator to biosimilar etanercept. One-year treatment outcomes in 2061 patients with inflammatory arthritis from the DANBIO registry." Annals of the Rheumatic Diseases 78, no. 2 (November 5, 2018): 192–200. http://dx.doi.org/10.1136/annrheumdis-2018-213474.
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ObjectivesReal-world evidence on effectiveness of switching to biosimila r etanercept is scarce. In Denmark, a nationwide guideline of mandatory switch from 50 mg originator (ETA) to biosimilar (SB4) etanercept was issued for patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA) in 2016. Clinical characteristics and treatment outcomes were studied in ETA-treated patients, who switched to SB4 (switchers) or maintained ETA (non-switchers). Retention rates were compared with that of a historic cohort of ETA-treated patients. Switchers who resumed ETA treatment (back-switchers) were characterised.MethodsObservational cohort study based on the DANBIO registry. Treatment retention was explored by Kaplan-Meier plots and Cox regression (crude, adjusted).Results1621 (79%) of 2061 ETA-treated patients switched to SB4. Disease activity was unchanged 3 months’ preswitch/postswitch. Non-switchers often received 25 mg ETA (ETA 25 mg pens/syringes and powder solution were still available). One-year adjusted retention rates were: non-switchers: 77% (95% CI: 72% to 82%)/switchers: 83% (79% to 87%)/historic cohort: 90% (88% to 92%). Patients not in remission had lower retention rates than patients in remission, both in switchers (crude HR 1.7 (1.3 to 2.2)) and non-switchers (2.4 (1.7 to 3.6)). During follow-up, 120 patients (7% of switchers) back-switched to ETA. Back-switchers’ clinical characteristics were similar to switchers, and reasons for SB4 withdrawal were mainly subjective.ConclusionSeventy-nine per cent of patients switched from ETA to SB4. After 1 year, adjusted treatment retention rates were lower in switchers versus the historic ETA cohort, but higher than in non-switchers. Withdrawal was more common in patients not in remission. The results suggest that switch outcomes in routine care are affected by patient-related factors and non-specific drug effects.
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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 (May 19, 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., and Darerca Owen. "Allostery and dynamics in small G proteins." Biochemical Society Transactions 46, no. 5 (October 9, 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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Harris, Jared D., Mark J. Moran, and Ivan Aprahamian. "New molecular switch architectures." Proceedings of the National Academy of Sciences 115, no. 38 (July 16, 2018): 9414–22. http://dx.doi.org/10.1073/pnas.1714499115.
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In this paper we elaborate on recently developed molecular switch architectures and how these new systems can help with the realization of new functions and advancement of artificial molecular machines. Progress in chemically and photoinduced switches and motors is summarized and contextualized such that the reader may gain an appreciation for the novel tools that have come about in the past decade. Many of these systems offer distinct advantages over commonly employed switches, including improved fidelity, addressability, and robustness. Thus, this paper serves as a jumping-off point for researchers seeking new switching motifs for specific applications, or ones that address the limitations of presently available systems.
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Rowe, Helen. "Satellite DNA arrays barcode chromosomes to regulate genes." Open Access Government 36, no. 1 (October 5, 2022): 138–39. http://dx.doi.org/10.56367/oag-036-10174.
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Satellite DNA arrays barcode chromosomes to regulate genes In this piece, Dr Helen Rowe summarizes how arrays or strings of multi-copy satellite DNAs can barcode chromosomes to regulate cell fate, by acting as molecular switches. Rowe explores Dark matter in relation to DNA and its unknown function and that makes up a huge 98% of our genome. Intense research in this area has revealed that dark matter contributes to gene-regulatory networks that serve to control where and when sets of genes are switched ON or OFF. Specialised cell types work by each expressing a unique set of genes: for example, a cell that functions in the adaptive immune system, such as an activated T cell, will switch on a different subset of genes than a neuron in the brain. Likewise, development is a highly regulated process, whereby different sets of genes are progressively switched on in different tissues. Thus, the dark matter within our genome contributes to the control of gene regulatory networks and biological systems.
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Li, Ming. "Delay Analysis of Networked Control Systems Based on 100 M Switched Ethernet." Scientific World Journal 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/751491.
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For the delay may degrade the performance of networked control systems, networked control systems based on 100 M switched Ethernet are proposed in this paper. According to the working principle of Ethernet switch, the formulas of the upper bound delay of the single-level switched Ethernet and the multiple-level switched Ethernet are deduced by the timing diagram method, and the values of the upper bound delay are also given. The key factors that influence the upper bound delay of switched Ethernet are analyzed; then, the characteristics of the upper bound delay are presented, which show that the delay induced by the single-level 100 M switched Ethernet has little effect on the performance of control systems, while the delay induced by the multiple-level 100 M switched Ethernet may meet the time requirements of all classes of control systems if the numbers of levels and the numbers of nodes connecting to switches are set properly. Finally, the performance of networked control systems is simulated by TrueTime, and the results further show the feasibility and superiority of 100 M switched Ethernet based networked control systems without modification of the network protocols.
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Pokhilko, Alexandra, Oliver Ebenhöh, W. Marshall Stark, and Sean D. Colloms. "Mathematical model of a serine integrase-controlled toggle switch with a single input." Journal of The Royal Society Interface 15, no. 143 (June 2018): 20180160. http://dx.doi.org/10.1098/rsif.2018.0160.
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Dual-state genetic switches that can change their state in response to input signals can be used in synthetic biology to encode memory and control gene expression. A transcriptional toggle switch (TTS), with two mutually repressing transcription regulators, was previously used for switching between two expression states. In other studies, serine integrases have been used to control DNA inversion switches that can alternate between two different states. Both of these switches use two different inputs to switch ON or OFF. Here, we use mathematical modelling to design a robust one-input binary switch, which combines a TTS with a DNA inversion switch. This combined circuit switches between the two states every time it receives a pulse of a single-input signal. The robustness of the switch is based on the bistability of its TTS, while integrase recombination allows single-input control. Unidirectional integrase-RDF-mediated recombination is provided by a recently developed integrase-RDF fusion protein. We show that the switch is stable against parameter variations and molecular noise, making it a promising candidate for further use as a basic element of binary counting devices.
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Su, Xing, Qi Yu, Ting Zhang, Yu-Mo Zhang, Lin Yu, Ivan Zhang, Minjie Li, Yifei Liu, and Sean Xiao-An Zhang. "A fluorescence molecular switch with high contrast multi-emissions and ON/OFF states." RSC Advances 6, no. 93 (2016): 90305–9. http://dx.doi.org/10.1039/c6ra21639k.
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Moehring, Rebekah W., Eric T. Lofgren, and Deverick J. Anderson. "Impact of Change to Molecular Testing for Clostridium difficile Infection on Healthcare Facility–Associated Incidence Rates." Infection Control & Hospital Epidemiology 34, no. 10 (October 2013): 1055–61. http://dx.doi.org/10.1086/673144.
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Background.Change from nonmolecular to molecular testing techniques is thought to contribute to the increasing trend in incidence of Clostridium difficile infection (CDI); however the degree of effect attributed to this versus other time-related epidemiologic factors is unclear.Methods.We compared the relative change in incidence rate (IRR) of healthcare facility–associated (HCFA) CDI among hospitals in the Duke Infection Control Outreach Network before and after the date of switch from nonmolecular tests to polymerase chain reaction (PCR) using prospectively collected surveillance data from July 2009 to December 2011. Data from 10 hospitals that switched and 22 control hospitals were included. Individual hospital estimates were determined using Poisson regression. We used an interrupted time series approach to develop a Poisson mixed-effects model. Additional regression adjustments were made for clustering and proportion of intensive care unit patient-days. The variable for PCR was treated as a fixed effect; other modeled variables were random effects.Results.For those hospitals that switched to PCR, mean incidence rate of HCFA CDI before the switch was 6.0 CDIs per 10,000 patient-days compared with 9.6 CDIs per 10,000 patient-days after the switch. Estimates of hospital-specific IRR that compared after the switch with before the switch ranged from 0.89 (95% confidence interval [CI], 0.32–2.44) to 6.91 (95% CI, 1.12–42.54). After adjustment in the mixed-effects model, the overall IRR comparing CDI incidence after the switch to before the switch was 1.56 (95% CI, 1.28–1.90). Time-trend variables did not reach statistical significance.Conclusion.Hospitals that switched from nonmolecular to molecular tests experienced an approximate 56% increase in the rate of HCFA CDI after testing change.
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Dunnick, W., M. Wilson, and J. Stavnezer. "Mutations, duplication, and deletion of recombined switch regions suggest a role for DNA replication in the immunoglobulin heavy-chain switch." Molecular and Cellular Biology 9, no. 5 (May 1989): 1850–56. http://dx.doi.org/10.1128/mcb.9.5.1850-1856.1989.
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The heavy-chain switch from immunoglobulin M (IgM) expression to IgA expression is mediated by a recombination event between segments of DNA called switch regions. The switch regions lie two to six kilobases upstream of the mu and alpha constant region coding segments. Switch recombination to IgA expression results in a recombinant mu-alpha switch region upstream of the expressed alpha constant region gene. We have characterized the products of switch recombination by a lymphoma cell line, I.29. Two sets of molecular clones represent the expected products of simple mu to alpha switches. Five members of a third set of molecular clones share the same recombination site in both the mu and the alpha switch regions, implying that the five molecular clones were derived from a single switch recombination event. Surprisingly, the five clones fall into two sets of sequences, which differ from each other by several point mutations and small deletions. Duplication of switch region sequences are also found in these five molecular clones. An explanation for these data is that switch recombination involves DNA synthesis, which results in nucleotide substitutions, small deletions, and duplications.
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Dunnick, W., M. Wilson, and J. Stavnezer. "Mutations, duplication, and deletion of recombined switch regions suggest a role for DNA replication in the immunoglobulin heavy-chain switch." Molecular and Cellular Biology 9, no. 5 (May 1989): 1850–56. http://dx.doi.org/10.1128/mcb.9.5.1850.
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The heavy-chain switch from immunoglobulin M (IgM) expression to IgA expression is mediated by a recombination event between segments of DNA called switch regions. The switch regions lie two to six kilobases upstream of the mu and alpha constant region coding segments. Switch recombination to IgA expression results in a recombinant mu-alpha switch region upstream of the expressed alpha constant region gene. We have characterized the products of switch recombination by a lymphoma cell line, I.29. Two sets of molecular clones represent the expected products of simple mu to alpha switches. Five members of a third set of molecular clones share the same recombination site in both the mu and the alpha switch regions, implying that the five molecular clones were derived from a single switch recombination event. Surprisingly, the five clones fall into two sets of sequences, which differ from each other by several point mutations and small deletions. Duplication of switch region sequences are also found in these five molecular clones. An explanation for these data is that switch recombination involves DNA synthesis, which results in nucleotide substitutions, small deletions, and duplications.
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Muraoka, Aoyama, Fujihara, Yamane, Hisaki, Miyata, Murata, and Nakatsuji. "Template-Free Synthesis of a Phenanthroline-Containing [2]Rotaxane: A Reversible pH-Controllable Molecular Switch." Symmetry 11, no. 9 (September 6, 2019): 1137. http://dx.doi.org/10.3390/sym11091137.
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The synthesis of symmetric and asymmetric rotaxanes consisting of neutral axle and ring components without ionic templates is necessary for applications in molecular sensors and molecular switches. A phenanthroline-containing symmetric [2]rotaxane was newly synthesized by inducing hydrogen bonding and π-interaction using a template-free threading-followed-by-stoppering method. The obtained rotaxane serves as a reversible pH-controllable molecular switch.
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Paulish, Andrey G., Oleg V. Minin, Yuri E. Geints, and Igor V. Minin. "Experimental Proof-of-Concept of a Spatial Photonic Switch Based on an Off-Axis Zone Plate in Millimeter Wavelength Range." Photonics 9, no. 10 (September 20, 2022): 670. http://dx.doi.org/10.3390/photonics9100670.
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Optical switches are key elements in modern network communications. We present the results of the experimental verification of a new theoretical concept proposed earlier for a full-optical wavelength-selective dual-channel switch based on the photonic hook effect, which is free from using any micro-mechanical devices or nonlinear materials. A large-scale laboratory prototype of such a device based on an off-axis Wood zone plate is considered, and its main parameters in the millimeter wavelength range are investigated. On the basis of the experiments, we show that the optical isolation of switched channels for a switch based on an off-axis zone plate can achieve 15 dB at a frequency difference of 25 GHz in a frequency range of 93 to 136 GHz. Given the scaling, these results can be transferred to another range, including the optical one.
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Heath, James R. "Wires, switches, and wiring. A route toward a chemically assembled electronic nanocomputer." Pure and Applied Chemistry 72, no. 1-2 (January 1, 2000): 11–20. http://dx.doi.org/10.1351/pac200072010011.
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A Boolean logic, nonreversible computing machine should, in principle, be capable of 10 18 bit operations per second at a power consumption of 1 W. In order to build such a machine that can even approach this benchmark for efficiency, the development of a robust quantum-state switch capable of ambient operation, as well as a bottom–up manufacturing technology, will be necessary. My group, in collaboration with Hewlett Packard, has developed much of the architecture for such a machine, which we call a chemically assembled electronic nanocomputer (CAEN). More recently, in a collaborative effort with Fraser Stoddart's group at UCLA, we have begun to build it. The fundamental unit of the machine is a field-programmable molecular switch, and the fundamental architecture is a hierarchical organization of wire/switch lattices called crossbars. Electronically, singly configurable molecular-based switch devices based on rotaxane molecular compounds have been fabricated in high yield. These switches were used to construct simple molecular-based logic structures and read-only memory elements.
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White, Deborah L., Verity A. Saunders, Amity Frede, Kelvin GrootObbink, Cassandra Slader, David T. Yeung, Michael Osborn, Anthony K. Mills, Andrew Grigg, and Timothy P. Hughes. "The Strategy of Early Nilotinib Switch Based on Failure to Achieve Optimal Molecular Targets on Imatinib May Not Overcome the Negative Impact of a Low OCT-1 Activity in De-Novo CP-CML Patients." Blood 118, no. 21 (November 18, 2011): 1690. http://dx.doi.org/10.1182/blood.v118.21.1690.1690.
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Abstract Abstract 1690 Background: We have previously identified that low OCT-1 activity (OA) is a poor prognostic indicator in CP-CML patients treated with imatinib (IM). Importantly, a very low OA (OA≤4ng/200,000 cells) is associated with a significant risk of poor molecular response, kinase domain mutations and transformation. The TIDEL II strategy of early intervention, via dose escalation and/or switch to nilotinib (NIL) may reduce the incidence of poor response/therapeutic failure in CP-CML patients, particularly those with very low OA. Methods: Patients in Cohort I (n=105) of the TIDEL II trial were switched to NIL for either IM intolerance, or failure to demonstrate a clinical benefit from IM dose escalation which was triggered by failure to achieve time dependent molecular targets: ≤10% BCR-ABL by 3 m, ≤1% BCR-ABL by 6 m or ≤0.1% BCR-ABL by 12 m. In Cohort II (n=105) patients failing to achieve these molecular targets were switched directly to NIL without prior IM dose intensification. All patients, where possible, had OA measured at diagnosis. Only therapeutic changes prior to 24 months, and patients with a minimum of 6 months exposure to NIL are considered in this analysis. Results: (Table 1) Cohort I: Median follow-up 30 months. The overall rate of major molecular response (MMR) by 12 months was 66%. There was a significant difference in the rate of MMR between patients with low OA (n=49) compared to those with higher OA (n= 54): 49% vs 76%, p=0.007. The overall rate of MMR by 24 months was 81%. Again, patients with low OA (n=46) achieved MMR at a significantly lower rate compared to those with higher OA (n=54): 65% vs 91%, p= 0.003. Thirty patients have switched to NIL, 19/30 because of IM intolerance (av. time on IM 8.5m.) and 11/30 because of molecular target failure (av. time on IM 12.8m). 14/14 intolerant patients not in MMR at the time of switch have achieved MMR on NIL with an average log reduction of 2.8, and 9/18 have achieved CMR. In contrast, 1/9 patients switched for molecular target failure has achieved MMR on NIL, with an average log reduction of 0.65. Importantly, 3/19 withdrew from study due to CML related events. Cohort II: Median follow-up 12 months. To date, 22/105 patients have switched to NIL and have a minimum of 6 months follow-up: 11 for intolerance and 11 for molecular target failure. All patients switched for intolerance achieved and/or maintained MMR on nilotinib, with an average log reduction of 2.89. In contrast, 1/11 patients switched for molecular target failure achieved MMR, with an average log reduction of 0.95 and CCyR has been achieved in 5/10 patients not previously in CCyR. 2/11 of these patients have withdrawn from study. There was a significant difference in the time of switch to NIL, and the length of imatinib exposure between the 2 cohorts for intolerance, and a significant difference between the cohorts in the length of IM exposure for patients with target failure. However, this did not translate to a significant difference in molecular response between the 2 cohorts, suggesting the length of prior IM exposure is not a determinant of subsequent NIL response. Importantly in both cohorts, the OA of those patients switched to NIL based on molecular target failure was significantly lower than that of those who switched for intolerance (p=0.007 and p=0.003) and those patients remaining on IM (p=0.004). Conclusion: Switch to NIL significantly improves response in IM intolerant patients. The majority of patients who switch for molecular target failure on IM do not subsequently achieve MMR on NIL. This suggests that a low OA may delineate a group of CP-CML patients intrinsically insensitive to TKI therapy, for whom switch to NIL either following IM dose intensification (Cohort 1) or as a primary strategy (Cohort II) may not result in an improvement in response. A different first-line strategy may be more effective for this poor risk subgroup. Disclosures: White: Novartis Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Slader:Novartis Pharmaceuticals: Employment, Equity Ownership. Yeung:Novartis Pharmaceuticals: Research Funding; BMS Oncology: Research Funding. Osborn:Novartis Pharmaceuticals: Research Funding; BMS Oncology: Research Funding. Mills:Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Sponsorship to professional meetings; BMS Oncology:. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ARIAD: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Wang, Cong, Lingfeng Gao, Hualong Chen, Yiquan Xu, Chunyang Ma, Haizi Yao, Yufeng Song, and Han Zhang. "Broadband and ultrafast all-optical switching based on transition metal carbide." Nanophotonics 10, no. 10 (June 25, 2021): 2617–23. http://dx.doi.org/10.1515/nanoph-2021-0066.
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Abstract Ultrafast all-optical switches have attracted considerable attention for breaking through the speed limitation of electric devices. However, ultrafast and high-efficiency all-optical switches based on two-dimensional (2D) materials can be achieved due to their strong nonlinear optical response and ultrafast carrier dynamic. For this reason, we propose the pump-probe method to achieve an ultrafast optical switcher with a response time of 192 fs and a switching energy of 800 nJ by using transition metal carbide (Nb2C). The response time and switching energy are far smaller than that of the all-optical device based on the saturable absorption effect of 2D materials. It is believed that the Nb2C-based all-optical switch provides a novel idea to achieve a high-performance all-optical device and has the potential for application in high-speed photonics processing.
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Xia, Cai Juan, Han Chen Liu, and Chang Feng Fang. "The I-V Characteristics of the 3,3',5',5-Tetra-Tert-Butyl-Azobenzene Optical Molecular Switch: A First-Principles Study." Advanced Materials Research 152-153 (October 2010): 839–42. http://dx.doi.org/10.4028/www.scientific.net/amr.152-153.839.
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By applying nonequilibrium Green’s function formalism combined first-principles density functional theory, we investigate the electronic transport properties of 3,3′,5,5′-Tetra-tert-butyl-azobenzene(meta-TBA) optical molecular switch. This molecular switch comprises a meta-TBA molecule with the trans and cis forms, which can be reversed from one structure to another one upon photoexcitation. The influence of HOMO-LUMO gaps and the spatial distributions of molecular orbitals on the electronic transport through the molecular device are discussed in detail. Theoretical results show that there is a large current ratio in bias window, which suggests that this system can be one of good candidates for optical switches due to this unique advantage, and have real applications in the molecular circuit.
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Ilieş, Iulian, James C. Benneyan, Tiago Barbieri Couto Jabur, Arthur W. Baker, and Deverick J. Anderson. "Impact of molecular testing on reported Clostridoides difficile infection rates." Infection Control & Hospital Epidemiology 41, no. 3 (December 19, 2019): 306–12. http://dx.doi.org/10.1017/ice.2019.327.
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AbstractBackground:The reported incidence of Clostridoides difficile infection (CDI) has increased in recent years, partly due to broadening adoption of nucleic acid amplification tests (NAATs) replacing enzyme immunoassay (EIA) methods. Our aim was to quantify the impact of this switch on reported CDI rates using a large, multihospital, empirical dataset.Methods:We analyzed 9 years of retrospective CDI data (2009–2017) from 47 hospitals in the southeastern United States; 37 hospitals switched to NAAT during this period, including 24 with sufficient pre- and post-switch data for statistical analyses. Poisson regression was used to quantify the NAAT-over-EIA incidence rate ratio (IRR) at hospital and network levels while controlling for longitudinal trends, the proportion of intensive care unit patient days, changes in surveillance methodology, and previously detected infection cluster periods. We additionally used change-point detection methods to identify shifts in the mean and/or slope of hospital-level CDI rates, and we compared results to recorded switch dates.Results:For hospitals that transitioned to NAAT, average unadjusted CDI rates increased substantially after the test switch from 10.9 to 23.9 per 10,000 patient days. Individual hospital IRRs ranged from 0.75 to 5.47, with a network-wide IRR of 1.75 (95% confidence interval, 1.62–1.89). Reported CDI rates significantly changed 1.6 months on average after switching to NAAT testing (standard deviation, 1.9 months).Conclusion:Hospitals that switched from EIA to NAAT testing experienced an average postswitch increase of 75% in reported CDI rates after adjusting for other factors, and this increase was often gradual or delayed.
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Zajc, Charlotte U., Markus Dobersberger, Irene Schaffner, Georg Mlynek, Dominic Pühringer, Benjamin Salzer, Kristina Djinović-Carugo, et al. "A conformation-specific ON-switch for controlling CAR T cells with an orally available drug." Proceedings of the National Academy of Sciences 117, no. 26 (June 17, 2020): 14926–35. http://dx.doi.org/10.1073/pnas.1911154117.
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Molecular ON-switches in which a chemical compound induces protein–protein interactions can allow cellular function to be controlled with small molecules. ON-switches based on clinically applicable compounds and human proteins would greatly facilitate their therapeutic use. Here, we developed an ON-switch system in which the human retinol binding protein 4 (hRBP4) of the lipocalin family interacts with engineered hRBP4 binders in a small molecule-dependent manner. Two different protein scaffolds were engineered to bind to hRBP4 when loaded with the orally available small molecule A1120. The crystal structure of an assembled ON-switch shows that the engineered binder specifically recognizes the conformational changes induced by A1120 in two loop regions of hRBP4. We demonstrate that this conformation-specific ON-switch is highly dependent on the presence of A1120, as demonstrated by an ∼500-fold increase in affinity upon addition of the small molecule drug. Furthermore, the ON-switch successfully regulated the activity of primary human CAR T cells in vitro. We anticipate that lipocalin-based ON-switches have the potential to be broadly applied for the safe pharmacological control of cellular therapeutics.
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Kiltz, U., S. Tsiami, X. Baraliakos, and J. Braun. "AB1171 Effects of successive switches of two different biosimilars of etanercept on outcomes in inflammatory rheumatic diseases in daily practice." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1876.1–1876. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3640.
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Background:A single switch from an originator to a biosimilar product has been shown to be safe and effective in the treatment of rheumatic musculoskeletal diseases (RMDs). The availability of biosimilars has created a financial incentive to encourage switching to cheaper products (“non-medical switch”). This is naturally associated with multiple switches. However, the effect of multiple switching between biosimilars of the same reference product has not been thoroughly investigated to date.Objectives:To assess the effectiveness and safety of systematic non-medical switching from innovator etanercept (ETN) to biosimilar ETN (SB4) and successive to another biosimilar ETN (GP2015) in adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) in a real-life setting.Methods:This retrospective study was performed in a tertiary center in adult patients with RA, PsA or axSpA who had been treated with the innovator ETN and who had been switched to two ETN biosimilars for economic reasons thereafter. The first switch from innovator ETN to the first biosimilar ETN occurred between February-May 2017 and the second switch from the first to the second biosimilar ETN occurred between September-December 2017. The end of the observation period was October 2019. Disease activity, function and adverse events (AE) were regularly assessed, and any changes in outcome were recorded during the follow-up period. The scores documented at week 12 week after the second switch were taken as primary outcome.A total of 100 patients (54 RA, 27 axSpA, 19 PsA, mean age 54.3±15.1, 46% male) who switched twice to those ETN biosimilars over a follow-up period of 21.1±7.4 months were included. The retention rate after the second ETN biosimilar switch was 89% about 6 months after the second switch. While 2 patients were lost to follow-up and 1 patient died (cardiac arrest), 7 patients discontinued due to inefficacy or AE, including one pancreatic cancer. One patient was withdrawn due to pregnancy. Overall, 14 AEs were reported in 8 patients. Among them, 4 patients switched back to originator etanercept in month 6, 1 patient re-administered GP2015 successfully in month 3 after suffering from mucosal erosions and in 3 patients another mode of action was prescribed. The scores at week 12 of both, disease activity and function, remained unchanged (Table 1).Table 1.Patient characteristicsAssessmentBaseline(n=100)SB4 Follow-up 12 weeks(n=100)SB 4 Follow-up 24 weeks(n=100)Second switch to GP2015(n=100)GP2015 Follow-up 12 weeks(n=97)GP2015 Follow-up 24 weeks(n=89)RADAS283,0 (1,2)2,9 (1,4)3,1 (1,2)2,8 (1,4)3,4 (2,5)3,0 (1,4)HAQ1,4 (0,8)1,6 (0,9)1,0 (0,9)1,5 (0,8)1,5 (0,8)1,6 (0,9)PsADAS283,8 (1,4)1,9 (1,4)2,8 (1,5)3,1 (1,1)4,5 (2,6)3,6 (2,6)HAQ1,2 (0,9)1,0 (0,9)0,9 (0,9)1,0 (0,8)1,0 (0,9)1,2 (0,8)axSpABASDAI5,1 (2,7)4,5 (2,6)5,1 (3,8)4,1 (2,2)4,6 (2,5)4,3 (2,4)ASDAS3,4 (0,8)2,5 (0,8)2,7 (0,8)3,2 (1,8)2,7 (1,2)2,5 (0,9)BASFI4,4 (2,7)4,3 (2,7)4,3 (3,2)4,6 (2,6)4,5 (2,7)4,8 (3,0)*Values are mean ± standard deviationDisclosure: Hexal funded this researchConclusion:The retention rate after multiple switches from innovator ETN to two ETN biosimilars was close to 90%. No major changes in disease activity and function were observed in all three indications.
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Ren, Yue, Yanan Liu, Kaiyang Liu, Xiaoqian Huo, Chaoqun Liu, and Yanling Zhang. "Discovery of Therapeutic Candidates for Diabetic Retinopathy Based on Molecular Switch Analysis: Application of a Systematic Process." Oxidative Medicine and Cellular Longevity 2022 (January 6, 2022): 1–20. http://dx.doi.org/10.1155/2022/3412032.
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The pathogenesis of diabetic retinopathy (DR) is complicated, and there is no effective drug. Oxidative stress-induced human retinal microvascular endothelial cells (HRMECs) injury is one of the pathogenic factors for DR. Molecular switches are considered high-risk targets in disease progression. Identification of molecular switch is crucial to interpret the pathogenesis of disease and screen effective ingredients. In this study, a systematic process was executed to discover therapeutic candidates for DR based on HRMECs injury. First of all, the molecular mechanism of HRMECs oxidative stress injury was revealed by transcriptomics and network pharmacology. We found that oxidative stress was one of the pivotal pathogenic factors, which interfered with vascular system development, inflammation, cell adhesion, and cytoskeleton damaged HRMECs through crosstalk. Then, network topology analysis was used to recognize molecular switches. The results indicated that the Keap1-Nrf2-ARE signaling pathway was the molecular switch in HRMECs oxidative stress injury. On this basis, the HEK293-ARE overexpression cell line was applied to obtain 18 active traditional Chinese medicine (TCM) ingredients. Furthermore, andrographolide, one of the 18 candidates, was applied in the HRMECs oxidative stress model to evaluate the accuracy of the systematic process. The efficacy evaluation results showed that andrographolide could regulate oxidative stress, vascular system development, inflammation, adhesion, and skeleton tissue to inhibit HRMECs injury cooperatively. And its mechanism was related to the Nrf2 signaling pathway. Overall, our data suggest that the Nrf2 signaling pathway is the molecular switch in the HRMECs oxidative stress injury. 18 potential Nrf2 agonists are likely to be promising DR candidates.
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Shendrikov, Valeriy P., Anna S. Alekseeva, Erik F. Kot, Konstantin S. Mineev, Daria S. Tretiakova, Abdulilah Ece, and Ivan A. Boldyrev. "Indane Based Molecular Motors: UV-Switching Increases Number of Isomers." Molecules 27, no. 19 (October 9, 2022): 6716. http://dx.doi.org/10.3390/molecules27196716.
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We describe azophenylindane based molecular motors (aphin-switches) which have two different rotamers of trans-configuration and four different rotamers of cis-configuration. The behaviors of these motors were investigated both experimentally and computationally. The conversion of aphin-switch does not yield single isomer but a mixture of these. Although the trans to cis conversion leads to the increase of the system entropy some of the cis-rotamers can directly convert to each other while others should convert via trans-configuration. The motion of aphin-switches resembles the work of a mixing machine with indane group serving as a base and phenol group serving as a beater. The aphin-switches presented herein may provide a basis for promising applications in advanced biological systems or particularly in cases where on demand disordering of molecular packing has value, such as lipid bilayers.
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Dequesnes, Marc, Zhi Tang, and N. R. Aluru. "Static and Dynamic Analysis of Carbon Nanotube-Based Switches." Journal of Engineering Materials and Technology 126, no. 3 (June 29, 2004): 230–37. http://dx.doi.org/10.1115/1.1751180.
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In this paper, we report on molecular dynamics (MD), continuum (based on linear and nonlinear beam theories) and combined molecular dynamics/continuum simulation of carbon nanotube based nanoelectromechanical switches. As a prototype device, we study the pull-in voltage characteristics of a nanoelectromechanical switch made of a suspended single wall nanotube over a ground plane. The various simulations (MD, continuum and combined MD/continuum) have been performed accounting for the electrostatic and van der Waals forces between the nanotube and the ground plane. The results from the nonlinear continuum theory compared well with the results from MD, except, for cases, where nanotube buckling was observed. When buckling occurs, the electromechanical behavior of the switch is simulated by employing a combined MD/continuum approach. The combined MD/continuum approach is computationally more efficient compared to the MD simulation of the entire device. Static and dynamic pull-in, pull-in time and fundamental frequency analysis is presented for fixed-fixed and cantilever carbon nanotube switches.
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Löfås, H., B. O. Jahn, J. Wärnå, R. Emanuelsson, R. Ahuja, A. Grigoriev, and H. Ottosson. "A computational study of potential molecular switches that exploit Baird's rule on excited-state aromaticity and antiaromaticity." Faraday Discuss. 174 (2014): 105–24. http://dx.doi.org/10.1039/c4fd00084f.
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A series of tentative single-molecule conductance switches which could be triggered by light were examined by computational means using density functional theory (DFT) with non-equilibrium Green's functions (NEGF). The switches exploit the reversal in electron counting rules for aromaticity and antiaromaticity upon excitation from the electronic ground state (S0) to the lowest ππ* excited singlet and triplet states (S1 or T1), as described by Hückel's and Baird's rules, respectively. Four different switches and one antifuse were designed which rely on various photoreactions that either lead from the OFF to the ON states (switches 1, 2 and 4, and antifuse 5) or from the ON to the OFF state (switch 3). The highest and lowest ideal calculated switching ratios are 1175 and 5, respectively, observed for switches 1 and 4. Increased thermal stability of the 1-ON isomer is achieved by benzannulation (switch 1B-OFF/ON). The effects of constrained electrode–electrode distances on activation energies for thermal hydrogen back-transfer from 1-ON to 1-OFF and the relative energies of 1-ON and 1-OFF at constrained geometries were also studied. The switching ratio is strongly distance-dependent as revealed for 1B-ON/OFF where it equals 711 and 148 when the ON and OFF isomers are calculated in electrode gaps with distances confined to either that of the OFF isomer or to that of the ON isomer, respectively.
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Merkx, Maarten, Misha V. Golynskiy, Laurens H. Lindenburg, and Jan L. Vinkenborg. "Rational design of FRET sensor proteins based on mutually exclusive domain interactions." Biochemical Society Transactions 41, no. 5 (September 23, 2013): 1201–5. http://dx.doi.org/10.1042/bst20130128.
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Proteins that switch between distinct conformational states are ideal to monitor and control molecular processes within the complexity of biological systems. Inspired by the modular architecture of natural signalling proteins, our group explores generic design strategies for the construction of FRET-based sensor proteins and other protein switches. In the present article, I show that designing FRET sensors based on mutually exclusive domain interactions provides a robust method to engineer sensors with predictable properties and an inherently large change in emission ratio. The modularity of this approach should make it easily transferable to other applications of protein switches in fields ranging from synthetic biology, optogenetics and molecular diagnostics.
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Imen, Hnid, Sun Xiaonan, Frath Denis, Lafolet Frédéric, and Lacroix Jean-Christophe. "Multi-functional switches of ditopic ligands with azobenzene central bridges at a molecular scale." Nanoscale 11, no. 47 (2019): 23042–48. http://dx.doi.org/10.1039/c9nr06350a.
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This paper reports multi-functional switches from a ditopic ligand bpy-azo-bpy. The molecule can adopt a cis-to-trans isomerization at the bipyridine terminals and can switch between their TRANS and CIS configurations at the central azobenzene unit by protonation or by light irradiation.
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Feng, Hongbo, Jiabin Zhao, Chengsi Zhou, and Mingxin Song. "Design and Analysis of the Capacitive RF MEMS Switches with Support Pillars." Sensors 22, no. 22 (November 16, 2022): 8864. http://dx.doi.org/10.3390/s22228864.
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Conventional parallel capacitive RF MEMS switches have a large impact during the suction phase. In general, RF MEMS switches have to be switched on and off in a considerably fast manner. Increasing the driving voltage enables fast switching but also increases the impact force, which causes the beam membrane to be prone to failure. In the present study, the addition of two support pillars was proposed for slowing down the fall of the beam membrane based on the conventional RF MEMS parallel switch, so as to reduce the impact velocity. As such, a novel RF MEMS switch was designed. Further, simulation software was used to scan and analyze the positioning and height of the support pillars with respect to electromechanical and electromagnetic performance. The simulation results show that the optimal balance of impact velocity and pull-in time was achieved at a height of 0.8 um, a distance of 10 um from the signal line, and an applied voltage of 50 V. The impact velocity was reduced from 1.8 m/s to 1.1 m/s, decreasing by nearly 40%. The turn off time increased from 3.9 us to 4.2 us, representing an increase of only 0.05%. The insertion loss was less than 0.5 dB at 32 GHz, and the isolation was greater than 50 dB at 40 GHz.
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Astorri, D., F. Ometto, L. Friso, B. Raffeiner, C. Botsios, and A. Doria. "AB0274 USE OF TNF-INHIBITORS BIOSIMILARS IN CHRONIC INFLAMMATORY ARTHRITIDES: A THREE-YEAR EXPERIENCE IN A LARGE MONOCENTRIC COHORT OF PATIENTS FROM THE NORTH-EAST ITALY." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1435.2–1436. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4898.
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Background::In recent years several biosimilars (BS) of tumour necrosis factor inhibitors (TNF-i) were introduced. At the Padova University Hospital the first BS of etanercept (bsETN) was available in October 2016 and the BS of adalimumab (bsADA) was available in November 2018.Objectives:The objectives of the study were to evaluate the rate of bioriginator-biosimilar (BO-BS) switch in all patients with rheumatoid arthritis (RA), psoriatic arthritis (PSA) and axial spondiloarthritis (axSpA) in the cohort of the Padova University Hospital and to examine factors favouring BO-BS switch. Secondly, we investigated survival of BO-BS switch and BO treatment and factors associated with longer treatment survival.Methods:We considered all patients on ETN originator (boETN) treatment when the first bsETN was available (1st October 2016) and all patients on ADA originator (boADA) when bsADA was available (1st November 2018). Patients were followed until 30 August 2019 and were classified as BO-BS switchers if they underwent a switch from either boETN or boADA to BS during the follow-up, otherwise they were considered as continuing BO treatment. Factors associated with BO-BS switch were tested with a multivariable regression analysis. To test the survival of the BO-BS switch and of the BO treatment, Cox regression analysis was used including all variables achiving a p<0.10 in univariate analysis tested with Log-rank test and Kaplan-Meier curves.Results:Among 1208 patients (553 RA, 433 PSA, 215 axSpA), 560 (46.3%) patients switched to bsETN (391) or bsADA (169). Mean disease duration was 16 (14.2) years and mean duration of the bDMARD treatment was 96.3 (56.8) months. After adjustment for potential confounders, factors associated with BO-BS switch were a longer disease duration, a shorter duration of previous bDMARD treatments and diagnosis (Tab.1) RA patients had almost a 3 fold increased likelihood of being switched to BS compared to PSA and axSPA, while difference between PSA and axSPA was not significant.Following Cox regression analysis we observed a longer drug survival in BO-BS switchers compared to those continuing with BO (HR 1.38; 95% C.I. 1.2-1.58; p<0.001) (Fig. 1). A longer drug survival was also associated with a longer disease duration (.15years: HR 1.75; 95% C.I. 1.5-2; p<0.001), longer mean duration of previous bDMARDs (.5years: HR 4.1; 95% C.I. 3.5-4.7; p<0.001), and diagnosis (RA vs PSA: HR 1.22; 95% C.I. 1.02-1.47; p=0.030; RA vs axSpA: HR 0.89 95% C.I. 0.067-0.97; p=0.023; PSA vs axSpA: HR 0.66; 95% C.I. 0.57-0.77; p<0.001) (Fig 2).Figure 1.Kaplan-Meier curves for treatment survival, Log-rank test.Figure 2.Kaplan-Meier curves for treatment survival in all patients, Log-rank tesConclusion:BO-BS switch was undertaken in almost half of the patients. Patients with longer disease duration and longer bDMARD duration, were the most likely to be switched successfully to BS. BO-BS switching does not affect the survival of the treatment, indeed, it provides sustained effectiveness particularly if undertaken in patients with stable disease activity.Table 1.Factors associated with BO-BS switch, multivariate regression analysis.Disclosure of Interests:DAVIDE ASTORRI: None declared, Francesca Ometto: None declared, LARA FRISO: None declared, BERND RAFFEINER: None declared, Costantino Botsios: None declared, Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS
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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 (June 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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Lin, Shu-Kun. "Molecular Switches." Molecules 6, no. 12 (December 31, 2001): 1017–18. http://dx.doi.org/10.3390/61201017.
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Semchenkova, Alexandra, Ekaterina Mikhailova, Alexander Komkov, Marina Gaskova, Ruslan Abasov, Evgenii Matveev, Marat Kazanov, et al. "Lineage Conversion in Pediatric B-Cell Precursor Acute Leukemia under Blinatumomab Therapy." International Journal of Molecular Sciences 23, no. 7 (April 5, 2022): 4019. http://dx.doi.org/10.3390/ijms23074019.
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We report incidence and deep molecular characteristics of lineage switch in 182 pediatric patients affected by B-cell precursor acute lymphoblastic leukemia (BCP-ALL), who were treated with blinatumomab. We documented six cases of lineage switch that occurred after or during blinatumomab exposure. Therefore, lineage conversion was found in 17.4% of all resistance cases (4/27) and 3.2% of relapses (2/63). Half of patients switched completely from BCP-ALL to CD19-negative acute myeloid leukemia, others retained CD19-positive B-blasts and acquired an additional CD19-negative blast population: myeloid or unclassifiable. Five patients had KMT2A gene rearrangements; one had TCF3::ZNF384 translocation. The presented cases showed consistency of gene rearrangements and fusion transcripts across initially diagnosed leukemia and lineage switch. In two of six patients, the clonal architecture assessed by IG/TR gene rearrangements was stable, while in others, loss of clones or gain of new clones was noted. KMT2A-r patients demonstrated very few additional mutations, while in the TCF3::ZNF384 case, lineage switch was accompanied by a large set of additional mutations. The immunophenotype of an existing leukemia sometimes changes via different mechanisms and with different additional molecular changes. Careful investigation of all BM compartments together with all molecular –minimal residual disease studies can lead to reliable identification of lineage switch.
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Romero, Andrés, Vicente Rojas, Verónica Delgado, Francisco Salinas, and Luis F. Larrondo. "Modular and Molecular Optimization of a LOV (Light–Oxygen–Voltage)-Based Optogenetic Switch in Yeast." International Journal of Molecular Sciences 22, no. 16 (August 9, 2021): 8538. http://dx.doi.org/10.3390/ijms22168538.
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Optogenetic switches allow light-controlled gene expression with reversible and spatiotemporal resolution. In Saccharomyces cerevisiae, optogenetic tools hold great potential for a variety of metabolic engineering and biotechnology applications. In this work, we report on the modular optimization of the fungal light–oxygen–voltage (FUN-LOV) system, an optogenetic switch based on photoreceptors from the fungus Neurospora crassa. We also describe new switch variants obtained by replacing the Gal4 DNA-binding domain (DBD) of FUN-LOV with nine different DBDs from yeast transcription factors of the zinc cluster family. Among the tested modules, the variant carrying the Hap1p DBD, which we call “HAP-LOV”, displayed higher levels of luciferase expression upon induction compared to FUN-LOV. Further, the combination of the Hap1p DBD with either p65 or VP16 activation domains also resulted in higher levels of reporter expression compared to the original switch. Finally, we assessed the effects of the plasmid copy number and promoter strength controlling the expression of the FUN-LOV and HAP-LOV components, and observed that when low-copy plasmids and strong promoters were used, a stronger response was achieved in both systems. Altogether, we describe a new set of blue-light optogenetic switches carrying different protein modules, which expands the available suite of optogenetic tools in yeast and can additionally be applied to other systems.
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Yarnall, M., P. C. Taylor, P. Pouliot, E. Hettel, and K. Murray. "AB0419 RHEUMATOID ARTHRITIS SWITCHING PATTERNS AND THE GROWTH OF SMALL MOLECULE TREATMENT IN THE EU5." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1337.2–1338. http://dx.doi.org/10.1136/annrheumdis-2022-eular.5091.
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BackgroundTNF-α inhibitor therapy has long been the standard of care for adult patients diagnosed with moderate to severe rheumatoid arthritis (RA) across the EU5, though several new biologics, biosimilars, and small molecules have become available for the treatment of RA.ObjectivesThis research sought to understand the factors influencing treatment changes when patients are switched from one biologic or small molecule to another, including the reason(s) for their treatment selection.MethodsAn independent market analytics firm collaborated with EU5 rheumatologists (n=250 across France, Germany, Italy, Spain, and the UK) to conduct a retrospective chart review of patients diagnosed with RA (n=1,268) who had switched from one biologic therapy or small molecule agent to another in the prior twelve weeks. Data were collected in August and September 2021 and included clinical and non-clinical patient demographics as well as physician demographics and attitudinal survey responses. This study was a non-longitudinal trending analysis to 2020 (n=1,288), 2019 (n=1,294), 2018 (n=1,312) and 2017 (n=1,235) audits following the same methodology.Results70% of surveyed rheumatologists reported recent changes to the management of their RA patients, with the most recalled treatment shift being an increased use of small molecule agents (JAK inhibitors, 30%), attributable to the introduction of upadacitinib and filgotinib in December 2019 and September 2020, respectively. Despite a plethora of RA treatment options in the EU5, annual physician-reported rates of RA patient switching have remained stable since 2017, with 25% of biologic/small molecule-treated patients switching brands within a given year.There has been a steady increase in switches from TNF inhibitors to JAK inhibitors over the last few years (2% in 2017 to 19% in 2021). At the same time, the rates of TNF cycling have been on a downward trend (43% in 2017, 40% in 2018, 39% in 2019, 34% in 2020, and 32% in 2021). Rheumatologists indicate 44% of their RA switch patients were switched from a TNF to a JAK inhibitor due to secondary efficacy failure, and their primary reason for selecting a JAK was due to the specific MOA (40%) and dosing delivery (19%).TNF cycling (both branded and biosimilar) represent one-third of all switches in the EU, making it the most common switch pattern. TNF cycling remains most common in Germany and Spain, while France observes the lowest switch rates between TNFs. The incidence of switches from TNFs to JAK inhibitors is more consistent across countries but remains highest in Germany.Figure 1.ConclusionThe introduction of small molecule agents in the EU over recent years (upadacitinib and filgotinib) has provided new options for the treatment of RA, creating a shift in the switching arena from TNF cycling to more utilization of alternate mechanisms of action post first line therapy in favor of JAK inhibitors.ReferencesNoneDisclosure of InterestsMaxine Yarnall: None declared, Peter C. Taylor Consultant of: Received consulting fees from AbbVie, Biogen, Eli Lilly, Fresenius, Galapagos, Gilead Sciences, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Inc, Roche, and Sanofi., Grant/research support from: Received research grants from Celgene and Galapagos., Phil Pouliot: None declared, Emily Hettel: None declared, Kara Murray: None declared
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Hart, K., and M. Bienz. "A test for cell autonomy, based on di-cistronic messenger translation." Development 122, no. 3 (March 1, 1996): 747–51. http://dx.doi.org/10.1242/dev.122.3.747.
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We have devised a test for cell autonomy of a gene that is switched on ectopically in a clone of cells, allowing us to ask whether the wild-type activity of this gene can influence neighbouring cells. To switch on the test gene, we used the yeast FRT system, and marked the FRT-generated cell clone by co-expressing beta-galactosidase. Co-expression is achieved by a stretch of 5′ untranslated mRNA from the homeotic gene Ultrabithorax (Ubx), which is inserted between the two coding sequences. We show that this Ubx sequence mediates efficient and reliable di-cistronic mRNA translation in wing imaginal discs of Drosophila. Applying our test to Ubx, we find that ectopic Ubx in wing discs strictly coincides with beta-galactosidase expression. Consequently, wing cells are transformed into cells that appear to be intermediates between wing and haltere cells, contesting the view that homeotic genes act as binary switches.
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Seppa, Nathan. "Molecular Switch." Science News 167, no. 15 (April 9, 2005): 227. http://dx.doi.org/10.2307/4016288.
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Ribeiro, Lucas F., Vanesa Amarelle, Liliane F. C. Ribeiro, and María-Eugenia Guazzaroni. "Converting a Periplasmic Binding Protein into a Synthetic Biosensing Switch through Domain Insertion." BioMed Research International 2019 (January 3, 2019): 1–15. http://dx.doi.org/10.1155/2019/4798793.
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All biosensing platforms rest on two pillars: specific biochemical recognition of a particular analyte and transduction of that recognition into a readily detectable signal. Most existing biosensing technologies utilize proteins that passively bind to their analytes and therefore require wasteful washing steps, specialized reagents, and expensive instruments for detection. To overcome these limitations, protein engineering strategies have been applied to develop new classes of protein-based sensor/actuators, known as protein switches, responding to small molecules. Protein switches change their active state (output) in response to a binding event or physical signal (input) and therefore show a tremendous potential to work as a biosensor. Synthetic protein switches can be created by the fusion between two genes, one coding for a sensor protein (input domain) and the other coding for an actuator protein (output domain) by domain insertion. The binding of a signal molecule to the engineered protein will switch the protein function from an “off” to an “on” state (or vice versa) as desired. The molecular switch could, for example, sense the presence of a metabolite, pollutant, or a biomarker and trigger a cellular response. The potential sensing and response capabilities are enormous; however, the recognition repertoire of natural switches is limited. Thereby, bioengineers have been struggling to expand the toolkit of molecular switches recognition repertoire utilizing periplasmic binding proteins (PBPs) as protein-sensing components. PBPs are a superfamily of bacterial proteins that provide interesting features to engineer biosensors, for instance, immense ligand-binding diversity and high affinity, and undergo large conformational changes in response to ligand binding. The development of these protein switches has yielded insights into the design of protein-based biosensors, particularly in the area of allosteric domain fusions. Here, recent protein engineering approaches for expanding the versatility of protein switches are reviewed, with an emphasis on studies that used PBPs to generate novel switches through protein domain insertion.
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Kessler, Peter S., Catherine Daniel, and John A. Leigh. "Ammonia Switch-Off of Nitrogen Fixation in the Methanogenic Archaeon Methanococcus maripaludis: Mechanistic Features and Requirement for the Novel GlnB Homologues, NifI1 and NifI2." Journal of Bacteriology 183, no. 3 (February 1, 2001): 882–89. http://dx.doi.org/10.1128/jb.183.3.882-889.2001.
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ABSTRACT Ammonia switch-off is the immediate inactivation of nitrogen fixation that occurs when a superior nitrogen source is encountered. In certain bacteria switch-off occurs by reversible covalent ADP-ribosylation of the dinitrogenase reductase protein, NifH. Ammonia switch-off occurs in diazotrophic species of the methanogenicArchaea as well. We showed previously that inMethanococcus maripaludis switch-off requires at least one of two novel homologues of glnB, a family of genes whose products play a central role in nitrogen sensing and regulation in bacteria. The novel glnB homologues have recently been named nifI 1 and nifI 2. Here we use in-frame deletions and genetic complementation analysis inM. maripaludis to show that thenifI 1 and nifI 2 genes are both required for switch-off. We could not detect ADP-ribosylation or any other covalent modification of dinitrogenase reductase during switch-off, suggesting that the mechanism differs from the well-studied bacterial system. Furthermore, switch-off did not affectnif gene transcription, nifH mRNA stability, or NifH protein stability. Nitrogenase activity resumed within a short time after ammonia was removed from a switched-off culture, suggesting that whatever the mechanism, it is reversible. We demonstrate the physiological importance of switch-off by showing that it allows growth to accelerate substantially when a diazotrophic culture is switched to ammonia.
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Xia, Cai Juan, Han Chen Liu, and Ji Xin Yin. "First-Principles Study of Triangle Terarylene as a Possible Optical Molecular Switch." Advanced Materials Research 311-313 (August 2011): 526–29. http://dx.doi.org/10.4028/www.scientific.net/amr.311-313.526.
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Using non-equilibrium Green’s function formalism combined with first-principles density functional theory, we investigate the electronic transport properties of a triangle terarylene(open- and closed-ring forms) optical molecular switch. The influence of the HOMO-LUMO gaps and the spatial distributions of molecular orbitals on the quantum transport through the molecular device is discussed. Theoretical results show that the conductance of the closed-ring is 3-8 times larger than that of open-ring, which expect that this system can be one of good candidates for optical switches due to this unique advantage, and may have some potential applications in future molecular circuit.
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Wilhelm, Daniel, Jehoshua Bruck, and Lulu Qian. "Probabilistic switching circuits in DNA." Proceedings of the National Academy of Sciences 115, no. 5 (January 16, 2018): 903–8. http://dx.doi.org/10.1073/pnas.1715926115.
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A natural feature of molecular systems is their inherent stochastic behavior. A fundamental challenge related to the programming of molecular information processing systems is to develop a circuit architecture that controls the stochastic states of individual molecular events. Here we present a systematic implementation of probabilistic switching circuits, using DNA strand displacement reactions. Exploiting the intrinsic stochasticity of molecular interactions, we developed a simple, unbiased DNA switch: An input signal strand binds to the switch and releases an output signal strand with probability one-half. Using this unbiased switch as a molecular building block, we designed DNA circuits that convert an input signal to an output signal with any desired probability. Further, this probability can be switched between 2n different values by simply varying the presence or absence of n distinct DNA molecules. We demonstrated several DNA circuits that have multiple layers and feedback, including a circuit that converts an input strand to an output strand with eight different probabilities, controlled by the combination of three DNA molecules. These circuits combine the advantages of digital and analog computation: They allow a small number of distinct input molecules to control a diverse signal range of output molecules, while keeping the inputs robust to noise and the outputs at precise values. Moreover, arbitrarily complex circuit behaviors can be implemented with just a single type of molecular building block.
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Selvarajan, A., and J. E. Midwinter. "Photonic switches and switch arrays on LiNbO3." Optical and Quantum Electronics 21, no. 1 (January 1989): 1–15. http://dx.doi.org/10.1007/bf02199462.
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Singh, Tejinder, and Navjot Khaira. "High Isolation Single-Pole Four-Throw RF MEMS Switch Based on Series-Shunt Configuration." Scientific World Journal 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/605894.
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This paper presents a novel design of single-pole four-throw (SP4T) RF-MEMS switch employing both capacitive and ohmic switches. It is designed on high-resistivity silicon substrate and has a compact area of 1.06 mm2. The series or ohmic switches have been designed to provide low insertion loss with good ohmic contact. The pull-in voltage for ohmic switches is calculated to be 7.19 V. Shunt or capacitive switches have been used in each port to improve the isolation for higher frequencies. The proposed SP4T switch provides excellent RF performances with isolation better than 70.64 dB and insertion loss less than 0.72 dB for X-band between the input port and each output port.
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Liu, Jiangtao, Shaofei Wang, Tiefan Huang, Priyanka Manchanda, Edy Abou-Hamad, and Suzana P. Nunes. "Smart covalent organic networks (CONs) with “on-off-on” light-switchable pores for molecular separation." Science Advances 6, no. 34 (August 2020): eabb3188. http://dx.doi.org/10.1126/sciadv.abb3188.
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Development of the new-generation membranes for tunable molecular separation requires materials with abilities beyond strict separation. Stimuli response could remotely adjust the membrane selectivity. Azobenzene derivatives can be photo-switched between trans and cis isomers under ultraviolet or visible light. Here, the azobenzenes were implanted as light switches to bridge the flexible cyclen building blocks. The smart covalent organic network membranes fold and unfold as origami that can be photo-switched between on-state (large) and off-state (small) pores. The cis membranes with off state under ultraviolet (UV) light have higher dye rejection than trans membranes with on-state channels. By controlling the trans-to-cis azobenzene isomerization via UV/Vis light, the pore size can be remotely controlled at the molecular level and the solvent permeance and dye rejection can be dynamically tuned.
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Zhang, Liang, Vanesa Marcos, and David A. Leigh. "Molecular machines with bio-inspired mechanisms." Proceedings of the National Academy of Sciences 115, no. 38 (February 26, 2018): 9397–404. http://dx.doi.org/10.1073/pnas.1712788115.
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The widespread use of molecular-level motion in key natural processes suggests that great rewards could come from bridging the gap between the present generation of synthetic molecular machines—which by and large function as switches—and the machines of the macroscopic world, which utilize the synchronized behavior of integrated components to perform more sophisticated tasks than is possible with any individual switch. Should we try to make molecular machines of greater complexity by trying to mimic machines from the macroscopic world or instead apply unfamiliar (and no doubt have to discover or invent currently unknown) mechanisms utilized by biological machines? Here we try to answer that question by exploring some of the advances made to date using bio-inspired machine mechanisms.
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Anannya, Orchi, and Avery August. "Interleukin-2 inducible T cell kinase functions as a molecular switch to fine tune differentiation of naive T helper cells in pro/anti-inflammatory effector T cell lineages." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 98.04. http://dx.doi.org/10.4049/jimmunol.206.supp.98.04.
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Abstract Naïve CD4+ T helper cells differentiate into effector CD4+ T cells with pro/anti-inflammatory functions upon receipt of signals from the T cell receptor (TCR) in presence of cytokines in the environment. Interleukin-2 inducible T cell kinase (ITK) has been shown to control the strength of signals downstream of the TCR. Here we have investigated the potential of ITK to act as a molecular switch in controlling T cell differentiation fate. Our results demonstrate in the absence of ITK expression/activity, naïve CD4+ T cells activated under conditions that promote differentiation into pro-inflammatory T helper type-17 (Th17) cells fail to differentiate into Th17 cells and instead switch into T cells expressing the T regulatory (Treg) lineage specific transcription factor Forkhead Box P3 (FoxP3). Similarly, we found that naïve CD4+ T cells activated to differentiate into anti-inflammatory Type 1 regulatory (Tr1) cells in the absence of ITK expression/activity fail to differentiate into Tr1 cells and instead switch into expressing the T helper type-1 (Th1) lineage specific T-box transcription factor (T-Bet). The switched FoxP3 expressing T cells resemble Tregs by their expression of Treg specific markers and have anti-inflammatory properties in suppressing effector T cell proliferation. In addition the switched T-Bet expressing T cells resemble Th1 cells by their expression of Th1 specific markers and the Th1 effector cytokine Interferon γ (IFNγ). This work suggest that signals regulated by ITK may function as a molecular switch to control Th17/Treg and Tr1/Th1 axes, highlighting the potential of manipulating ITK to control the balance of pro/anti-inflammatory T cells in immune disorders.
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Boldyrev, Ivan. "Optical Switches for Lipid Membranes: Computed Molecular Projection Area as a Switch Selection Criterion." Colloids and Interfaces 6, no. 2 (May 9, 2022): 30. http://dx.doi.org/10.3390/colloids6020030.
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Optical switches in lipid membranes are an emerging tool to tune the properties of the bilayer or membrane protein integrated therein. Here, we use simple geometry and physics considerations to deduce structural criteria to design efficient photoactivated switches for lipid membranes. We compare how the area of projection on the bilayer of various classes of photoswitches changes upon the trans/cis or open/closed transition and show that azobenzene and stilbene should distort the bilayer structure the most. We also conclude that planar-elongated molecules, in which atoms of isomerizable double bond have no additional substituents, while substituents of the fragments adjacent to the double bond prevent formation of the planar molecule in cis configuration, are to be the best photoswitches for lipid membranes.
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Koeditz, Dominik, Juergen Frensch, Martin Bierbaum, Nils-Henning Ness, Benjamin Ettle, Umakanth Vudumula, Kapil Gudala, Nicholas Adlard, Santosh Tiwari, and Tjalf Ziemssen. "Comparing the long-term clinical and economic impact of ofatumumab versus dimethyl fumarate and glatiramer acetate in patients with relapsing multiple sclerosis: A cost-consequence analysis from a societal perspective in Germany." Multiple Sclerosis Journal - Experimental, Translational and Clinical 8, no. 1 (January 2022): 205521732210857. http://dx.doi.org/10.1177/20552173221085741.
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Background Evidence suggests that early highly efficacious therapy in relapsing multiple sclerosis is superior to escalation strategies. Objective A cost-consequence analysis simulated different treatment scenarios with ofatumumab (OMB), dimethyl fumarate (DMF) and glatiramer acetate (GA): immediate OMB initiation as first treatment, early switch to OMB after 1 year on DMF/GA, late switch after 5 years or no switch. Methods An EDSS-based Markov model with a 10-year time horizon was applied. Cycle transitions included EDSS progression, improvement or stabilization, treatment discontinuation, relapse or death. Input data were extracted from OMB trials, a network meta-analysis, published literature, and publicly available sources. Results The late switch compared to the immediate OMB scenario resulted in a lower proportion of patients with EDSS 0–3 (Δ − 7.5% DMF; Δ − 10.3% GA), more relapses (Δ + 0.72 DMF; Δ + 1.23 GA) and lower employment rates (Δ − 4.0% DMF; Δ − 5.6% GA). The same applies to late versus early switches. No switch scenarios resulted in worse outcomes. Higher drug acquisition costs in the immediate OMB and early switch scenarios were almost compensated by lower costs for patient care and productivity loss. Conclusion Immediate OMB treatment and an early switch improves clinical and productivity outcomes while remaining almost cost neutral compared to late or no switches.
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Čavlović, Daniel, and Michal Juríček. "Molecular Magnetic Switches." CHIMIA International Journal for Chemistry 73, no. 4 (April 24, 2019): 313–16. http://dx.doi.org/10.2533/chimia.2019.313.
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