Journal articles on the topic 'Bennet's doubler'

Abraham Bennet was a clergyman and electrical experimenter who invented the gold-leaf electroscope and the doubler of electricity. He used a mechanical revolving version of the latter to devise a concept of ‘adhesive electricity’, which had an important influence on Volta in the formulation of his contact theory of electromotivity. Bennet managed to balance his clerical position, obtained by patronage, with the friendship and assistance of the local philosophical community, which included Erasmus Darwin, White Watson and the members of the Lunar and Derby Philosophical Societies. The Lunar members helped him to publish his research and supported his nomination as F.R.S. in 1789; however, the relative harmony of the philosophical community represented by the Royal Society, which temporarily united provinces and metropolis, was shattered by the political turbulence of the revolutionary era. The delicate balancing act that allowed Bennet to claim support from Banks and Kaye at the same time as from Priestley and Darwin became more difficult and Bennet's research activity foundered due to ill health and political division.

The many facets of Bennett's investigation into his skew four-bar linkage and its several extensions have given rise to an abundance of studies by other workers. Among his imaginative endeavours was the deployment of a double helix to convert his planar 12-bar network into a spatial counterpart. A geometrically attractive idea, its algebraic equivalent had been difficult to realize because of a lack of underlying analytical relationships. As well, recent papers have revealed apparent shortcomings in Bennett's representation. The present work is an attempt to provide a complete algebraic treatment of Bennett's novel device.

AbstractThis article explores Alan Bennett’s Single Spies (1988), an espionage double bill comprising “An Englishman Abroad” and “A Question of Attribution,” proposing that the personalizing of social, political, and historical themes, as well as the astute documentation of a decaying Englishness and its class system in both plays, are representative of the work of a playwright whose output deserves serious critical attention. The study focuses on how Bennett historicizes the actions of his infamous protagonists (Guy Burgess and Anthony Blunt) while challenging assumptions regarding patriotism. Single Spies is a Cambridge Five franchise, demonstrating the playwright’s characteristic wit, irony, and reflection on personal and national identity, illusion, and sacrifice. The one-act plays each deal with a key figure in the notorious Cambridge spy ring, enhancing the dramatic effect through the use of onstage theatrical and visual allusions. In the first play, references to William Shakespeare’s Hamlet (c 1599), together with English music, highlight Burgess’s duality and the bitter reality of his post-defection life in Russia, while the second play is notable for its use of two paintings (Titian and a Venetian Senator and Allegory of Prudence) as key images and conceits suggesting the gradual uncovering of the Cambridge Five. The paper therefore suggests that Bennett’s ability to lift the veil of personal and institutional secrecy, while airing his own ambivalence, confirms him as a skillful, if academically undervalued, commentator on Englishness.

Alan Bennett is one of the most popular mainstream dramatists working in Britain today, his canon now a mainstay of regional and amateur theatre companies. Yet for a writer who was once compared to John Osborne as taking ‘the moral temperature of the nation’, his output is widely regarded as apolitical and, at worst, ‘safe’. In the following article, Richard Scarr suggests that this viewpoint is misleading, and argues that Bennett is not only one of the most politically contentious playwrights in dominant theatre, but that the ideological viewpoints he has supported have changed as his career has progressed. Richard Scarr is an English graduate of the University of North London, and has recently completed an MA in Renaissance Studies at Queen Mary and Westfield College. He is currently researching a PhD on the rhetoric of Renaissance comedy, with particular emphasis on the double-entendre.

I argue that the Doctrine of Double Effect is accepted because of unreliable processes of belief-formation, making it unacceptably likely to be mistaken. We accept the doctrine because we more vividly imagine intended consequences of our actions than merely foreseen ones, making our aversions to the intended harms more violent, and making us judge that producing the intended harms is morally worse. This explanation fits psychological evidence from Schnall and others, and recent neuroscientific research from Greene, Klein, Kahane and Schaich Borg. It explains Mikhail and Hauser's ‘universal moral grammar’ and an interesting phenomenon about Double Effect cases noted by Bennett. When unequally vivid representations determine our decisions, we typically misjudge the merits of our options and make mistakes. So if Double Effect is a product of unequal vividness, it is likely to be mistaken. This argument, I claim, fits Berker's specifications for good empirically grounded arguments in ethics.

This paper investigates the lateral pull-in effect of an in-plane overlap-varying transducer. The instability is induced by the translational and rotational displacements. Based on the principle of virtual work, the equilibrium conditions of force and moment in lateral directions are derived. The analytical solutions of the critical voltage, at which the pull-in phenomenon occurs, are developed when considering only the translational stiffness or only the rotational stiffness of the mechanical spring. The critical voltage in a general case is numerically determined by using nonlinear optimization techniques, taking into account the combined effect of translation and rotation. The influences of possible translational offsets and angular deviations to the critical voltage are modeled and numerically analyzed. The investigation is then expanded for the first time to anti-phase operation mode and Bennet’s doubler configuration of the two transducers.

A complete family of double-Goldberg 6 R linkages is reported in this article by combining a subtractive Goldberg 5 R linkage and a Goldberg 5 R linkage through the common link-pair or common Bennett-linkage method. A number of distinct types of overconstrained linkages are built, namely the mixed double-Goldberg 6 R linkages. They all have one degree of freedom and their closure equations are derived in detail. One of them degenerates into a Goldberg 5 R linkage. From the construction process and geometry conditions, the corresponding relationship between the newly found 6 R linkages and the double-Goldberg 6 R linkages, constructed from two Goldberg 5 R linkages or two subtractive Goldberg 5 R linkages, has been established.

We introduce a new integral method for Quantum Key Distribution to perform sifting, reconciliation and amplification processes to establish a cryptographic key through the use of binary matrices called frames which are capable to increase quadratically the secret key rate. Since the eavesdropper has no control on Bob’s double matching detection events, our protocol is not vulnerable to the Intercept and Resend (IR) attack nor the Photon Number Splitting (PNS) attack. The method can be implemented with the usual optical Bennett–Brassard ( B B 84 ) equipment allowing strong pulses in the quantum regime.

We provide the first comprehensive estimates of the size of the for-profit higher education sector and evaluate whether for-profits increase tuition in response to federal subsidies. By using state administrative data we include institutions that do not participate in federal student aid programs and are missed in official counts. Including these institutions doubles the number of for-profits and increases students by one-third compared with official counts. Aid-eligible institutions charge tuition for sub-baccalaureate (mainly certificate) programs that is about 78 percent higher than that charged by comparable programs in nonparticipating institutions, lending some credence to the “Bennett hypothesis” of federal aid capture. (JEL H52, I22, I23, I28)

Mechanisms of rare transitions between long-lived stable states are often analyzed in terms of commitment probabilities, determined from swarms of short molecular dynamics trajectories. Here, we present a computer simulation method to determine rate constants from such short trajectories combined with free energy calculations. The method, akin to the Bennett–Chandler approach for the calculation of reaction rate constants, requires the definition of a valid reaction coordinate and can be applied to both under- and overdamped dynamics. We verify the correctness of the algorithm using a one-dimensional random walker in a double-well potential and demonstrate its applicability to complex transitions in condensed systems by calculating cavitation rates for water at negative pressures.

Cet article se veut un examen critique de la première collaboration entre Robert Lepage et le Cirque du Soleil, qualifiés par Susan Bennett comme deux des « plus précieux produits (culturels) d’exportation » du Québec. KÀ, qui a débuté au MGM Grand Hotel de Las Vegas en 2005, est considéré comme la production la plus onéreuse jamais montée en Amérique du Nord. Elle constitue une tentative pour mélanger le théâtre avec quelques-unes des tropes de la performance aérienne qui ont fait la réputation du Cirque. Cet article traite de la production de KÀ dans le double parcours du Cirque et de Lepage et défend la thèse suivant laquelle ses créateurs, en dépit d’avoir formulé une proposition scénique visuellement époustouflante et techniquement innovante, n’ont sans doute pas totalement saisi les défis esthétiques que représentait l’union de leur entreprise créative respective.

The copepod Nemesis santhadevii sp. nov. (Siphonostomatoida: Eudactylinidae), which is parasitizing the gill filaments of the Coral catshark Atelomycterus marmoratus (Anonymous (Bennett), 1830) off Kota Kinabalu waters, Malaysia, is described and illustrated in this article. The new species Nemesis santhadevii prominently differs from its congeners in the following features: (1) the cephalothorax sub-circular is 1.3 times as wide as long and overlapping the second pedigerous somite; (2) the fifth somite is 0.4 times the width of the fourth; (3) the genital double somite is slightly narrower than the fifth; (4) the lowest cephalothoracic shield’s body length (0.20:1) proportion; (5) the caudal rami is ovate, it has two large and three small setae; (6) and the second somite has antenna with a patch of 34–38 spinules. It is the first record of parasitic eudactilinid copepod from Sabah, East Malaysia. A checklist of global valid species of Nemesis Risso, 1826, is provided.

L’auteur s’attache à une série de films mettant en scène des musiciens classiques dont la carrière est traversée par leurs problèmes sentimentaux ou leurs névroses ; il s’intéresse particulièrement au mélodrame The Seventh Veil (Robert Compton-Bennett, 1945) dont l’action conjugue les motifs du pianiste ténébreux et de la pianiste-victime. Analysant le montage des corps des interprètes (celui de l’actrice, celui de sa doublure), il montre comment ce film dit le faux quand il fait croire par des inserts de mains d’une virtuose que c’est l’actrice qui joue du piano, et comment, en même temps, il dit le vrai par le faux quand il illustre métaphoriquement que les mains de quelqu’un ne lui appartiennent pas complètement : elles sont dressées, menées, mais aussi tentées, happées, entraînées par une autre force dont le reste du corps ne trahit rien.

The problems associated with hazardous materials control are numerous and complex. One of these problems involves selecting hand protection which will resist permeation for the duration of the exposure while maintaining sufficient levels of dexterity and tactility so that the worker can safely and efficiently perform the required task. This study investigated the effect of nine glove combinations on manual dexterity. These included three single glove and six double glove combinations plus the bare hand condition. The subjects performed a nut-bolt-washer assembly-dissassembly task using the Bennett Hand Tool Dexterity Test apparatus. The task required the use of a screw driver, two sizes of open-end wrenches, and an adjustable wrench, along with handling the bolt, nut, and washer while performing the assembly-disassembly task for three different bolt, nut, and washer sizes (1/2″, 5/16″, 1/4″). The response variables measured in the experiment were the time to complete each task and number of errors committed during each task. An error was defined as a drop of any of the items handled. The data was analyzed using a fixed effects randomized ANOVA model and the Duncan's Multiple Range Test. An alpha level of 5 per cent was used in the analysis. The results of the analyses showed that gloves increased the average completion time by 15 to 37%. Several double gloving combinations had significantly longer task completion times compared to single gloves.

DNA origami enables the precise fabrication of nanoscale geometries. We demonstrate an approach to engineer complex and reversible motion of nanoscale DNA origami machine elements. We first design, fabricate, and characterize the mechanical behavior of flexible DNA origami rotational and linear joints that integrate stiff double-stranded DNA components and flexible single-stranded DNA components to constrain motion along a single degree of freedom and demonstrate the ability to tune the flexibility and range of motion. Multiple joints with simple 1D motion were then integrated into higher order mechanisms. One mechanism is a crank–slider that couples rotational and linear motion, and the other is a Bennett linkage that moves between a compacted bundle and an expanded frame configuration with a constrained 3D motion path. Finally, we demonstrate distributed actuation of the linkage using DNA input strands to achieve reversible conformational changes of the entire structure on ∼minute timescales. Our results demonstrate programmable motion of 2D and 3D DNA origami mechanisms constructed following a macroscopic machine design approach.

Human chromosomal DNA contains many repeats which might provide opportunities for DNA repair. We have examined the consequences of a single double-strand break (DSB) within a 360-kb dispensable yeast artificial chromosome (YAC) containing human DNA (YAC12). An Alu-URA3-YZ sequence was targeted to several Alu sites within the YAC in strains of the yeast Saccharomyces cerevisiae; the strains contained a galactose-inducible HO endonuclease that cut the YAC at the YZ site. The presence of a DSB in most YACs led to deletion of the URA3 cassette, with retention of the telomeric markers, through recombination between surrounding Alus. For two YACs, the DSBs were not repaired and there was a G2 delay associated with the persistent DSBs. The presence of persistent DSBs resulted in cell death even though the YACs were dispensable. Among the survivors of the persistent DSBs, most had lost the YAC. By a pullback procedure, cell death was observed to begin at least 6 h after induction of a break. For YACs in which the DSB was rapidly repaired, the breaks did not cause cell cycle delay or lead to cell death. These results are consistent with our previous conclusion that a persistent DSB in a plasmid (YZ-CEN) also caused lethality (C. B. Bennett, A. L. Lewis, K. K. Baldwin, and M. A. Resnick, Proc. Natl. Acad. Sci. USA 90:5613-5617, 1993). However, a break in the YZ-CEN plasmid did not induce lethality in the strain (CBY) background used in the present study. The differences in survival levels appear to be due to the rapid degradation of the plasmid in the CBY strain. We, therefore, propose that for a DSB to cause cell cycle delay and death by means other than the loss of essential genetic material, it must remain unrepaired and be long-lived.

Abstract Apoptosis, the main cell death mechanism triggered by double strand breaks (DSBs), occurs as quickly as 2-3 hours, or 6-24 hours in vivo. However, when we transduced Cas9-expressing pancreatic cancer (PC) cell lines with multi-target sgRNAs, in which each sgRNA contains 2-16 target sites in the human genome, we found that most of the reduction in sgRNA tag counts did not occur in the first 7 days post transduction, but rather occurred between days 7 and 21. We demonstrated that CRISPR-Cas9 scission occurs over the course of days in our PC cells and peaked at days 3-5, consistent with another recent observation. Thus, we hypothesized that the mechanism of cell death was likely not due to DNA damage response pathways that were immediately and directly triggered by the multiple scission events, but rather was caused by a slower process. To test this, we treated the Cas9-expressing TS0111 PC cell line with a 14-target sgRNA and performed cytogenetic analysis on cells harvested from 0-21 days after transduction at 3-4 day intervals using a chromosome breakage assay. We observed various karyotypic abnormalities, such as formations of ring, dicentric, and tricentric chromosomes. These abnormalities accumulated over time and peaked at day 14, except for the chromatid and chromosome breaks in which the frequency was maintained through day 21, suggesting ongoing occurrence of breakage events. Analysis of breakpoints on dicentric and tricentric chromosomes showed that although breakpoints at sgRNA targeted regions predominated at early time points and decreased over time, non-targeted regions increased and peaked at day 14. A break-apart FISH assay was also implemented to confirm that these structural variants (SVs) were a direct result of CRISPR-Cas9 cuts, in which the number of cells with abnormal FISH patterns increased over time and also peaked at day 14. Additionally, we performed bioinformatics analyses on the whole genome sequencing data of surviving colonies post treatment of multi-target sgRNAs to identify novel SVs. We found that novel SVs increased as a function of the number of sgRNA target sites, and majority of the SVs were found at non-targeted sites, consistent with ongoing genomic instability. Interestingly, we found that cells responded to the 14-cutter by becoming polyploid, manifesting as extremely large nuclei or multinucleated giant cells. XY FISH showed that polyploidy peaked at day 10 and decreased by day 21. Finally, we assayed for apoptosis, which increased on days 7 and 14 but decreased by day 21. We concluded that cytotoxicity occurred following the induction of multiple DSBs that resulted in ongoing chromosomal rearrangements and polyploidization, ultimately leading to cell death via apoptosis and possibly other mechanisms. Citation Format: Selina Shiqing K. Teh, Eitan Halper-Stromberg, Laura Morsberger, Kirsten Bowland, Alexis Bennett, Robert B. Scharpf, Ying S. Zou, James R. Eshleman. Genomic instability delays cell death in PDAC after simultaneous double strand breaks. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6103.

A DNA-binding nonhistone protein, protein BA, was previously demonstrated to co-localize with U-snRNPs within discrete nuclear domains (Bennett, F. C., and L. C. Yeoman, 1985, Exp. Cell Res., 157:379-386). To further define the association of protein BA and U-snRNPs within these discrete nuclear domains, cells were fractionated in situ and the localization of the antigens determined by double-labeled immunofluorescence. Protein BA was extracted from the nucleus with the 2.0 M NaCl soluble chromatin fraction, while U-snRNPs were only partially extracted from the 2.0 M NaCl-resistant nuclear structures. U-snRNPs were extracted from the residual nuclear material by combined DNase I/RNase A digestions. Using an indirect immunoperoxidase technique and electron microscopy, protein BA was localized to interchromatinic regions of the cell nucleus. Protein BA was noted to share a number of chemical and physical properties with a family of cytoplasmic enzymes, the glutathione S-transferases. Comparison of the published amino acid composition of protein BA and glutathione S-transferases showed marked similarities. Nonhistone protein BA isolated from saline-EDTA nuclear extracts exhibited glutathione S-transferase activity with a variety of substrates. Substrate specificity and subunit analysis by SDS polyacrylamide gel electrophoresis revealed that it was a mixture of several glutathione S-transferase isoenzymes. Protein BA isolated from rat liver chromatin was shown by immunoblotting and peptide mapping techniques to be two glutathione S-transferase isoenzymes composed of the Yb and Yb' subunits. Glutathione S-transferase Yb subunits were demonstrated to be both nuclear and cytoplasmic proteins by indirect immunolocalization on rat liver cryosections. The identification of protein BA as glutathione S-transferase suggests that this family of multifunctional enzymes may play an important role in those nuclear domains containing U-snRNPs.

In recent years, a low-grade vanadiferous titanomagnetite concentrate (LVTC) produced in the northwest area of Liaoning has attracted more and more attention. However, it is difficult to recover and utilize valuable minerals such as iron, titanium, and vanadium, due to their special physical and chemical properties and complex mineral composition. Grinding and magnetic separation are two important operational units for recovering valuable metal components from vanadiferous titanomagnetite. Therefore, the grinding kinetics of the LVTC in northwestern Liaoning were first studied by means of grinding kinetics equations in this paper. The results show that the grinding process of LVTC is consistent with the grinding kinetics equation, and the sieve residues of particles approached a constant value after grinding for 30 min, resulting from equilibrium between the fragmentation and agglomeration processes. In addition, equivalent particle size (EPS) and specific surface area (SSA) were linearly proportional to the double logarithm of grinding time, and the correlation coefficients for fitted data by the Rosin–Rammler–Bennet (RRB) model were slightly higher than those by the Swebrec model, and could reflect the dispersibility and uniformity of particle size distribution (PSD) quantitatively. Then, the grinding products were separated by magnetic separation, and the influence of grinding conditions on the grade and recovery ratio of Fe and TiO2 in the LVTC was analyzed. As a result, grinding time has a significant impact on the recovery ratio and grade of Fe and TiO2 during the magnetic separation process, and the LVTC grinding duration is not as prolonged as it might be, as the optimal grinding time is 20 min. Titanomagnetite, ilmenite, and titanite are still the predominant phases in all magnetic separation products at optimal grinding time, but the intensity or content of these three minerals varies between magnetic separation products, and 232 kA/m magnetic field intensity has a higher separation efficiency than 134 kA/m magnetic field intensity.

Abstract Abstract 70 Introduction: Chronic ITP is characterized by decreased platelet counts resulting from autoantibody-mediated peripheral platelet destruction and suboptimal platelet production. Eltrombopag is an oral, thrombopoietin receptor agonist approved for the treatment of ITP in the USA and elsewhere. Thromboembolic events (TEEs) can occur in patients with ITP; it has been speculated that ITP has prothrombotic characteristics and that low platelet counts may prevent a higher incidence of TEEs (Sarpatwari, 2010; Aledort, 2004; Zelcer, 2003). In the UK General Practice Research Database, incidence rates for TEEs were 1.35/100 patient years (PYs) (95% CI [0.99, 1.79]) for patients with ITP vs 1.16/100 PYs (95% CI [0.99, 1.35]) in patients without ITP (Sarpatwari, 2010). Similar results were found in a US claims database study (Bennett, 2008) and in romiplostim studies (Bussel, 2009). In this study we evaluated the incidence of TEEs in patients with chronic ITP treated with eltrombopag. Methods: Data from 446 patients with chronic ITP exposed to eltrombopag were analyzed from 5 eltrombopag clinical trials: two 6-week, randomized, double-blind, phase 2 and 3 studies, with patients on eltrombopag (n=164) or placebo (n=67) (Bussel, 2007; Bussel, 2009); RAISE, a 6-month, randomized, double-blind, phase 3 study, with 135 patients on eltrombopag and 62 on placebo (Cheng, 2010); REPEAT, a phase 2 study with 66 patients on eltrombopag for 3 cycles of 6 weeks on-therapy followed by up to 4 weeks off therapy (Psaila, 2008); and EXTEND, an ongoing extension study with 299 of the same patients on eltrombopag for at least 2 years (Cheng, 2008). The first occurrence of a TEE was used in the calculation of the incidence rates across the ITP program. Confirmed or suspected cases of TEEs were either reported by investigators or identified after sponsor evaluation based on symptoms reported as adverse events (AEs) that were potentially compatible with a TEE. In an additional analysis, the odds ratio for a TEE at different platelet thresholds was investigated to assess if a direct relationship could be established. Results: Across the ITP program, 20 patients (4.5%, 20/446) exposed to eltrombopag have experienced 27 TEEs. The TEEs were DVT (12), pulmonary embolism (6), MI (4), ischemic stroke (3), suspected prolonged reversible ischemic neurologic deficit (1), and transient ischemic attack (1). No placebo-treated patient experienced a TEE. The PYs of exposure to study medication was approximately 17 times greater than PYs of exposure to placebo (eltrombopag 584.4 PYs; placebo 35.4 PYs). Despite the increased exposure to eltrombopag in the EXTEND study, the incidence of TEEs (3.14/100 PYs, 95% CI [1.92, 4.85]) decreased compared to previously reported data (4.04/100 PYs, 95% CI [2.35, 6.46], Bussel, 2009). There was no clear pattern observed with regard to time to TEE onset; events were reported as early as day 1 and up to day 981 (median time to onset 229 days). The platelet counts most proximal to the events ranged between 14,000/μ L and 482,000/μ L (median 143,000/μ L). The majority of patients (55%, 11) had platelet counts below the normal range at the time of the TEE (<150,000/μ L). 4/20 patients experienced the TEE closest to their maximum platelet count achieved on study, whereas the majority (80%, 16/20) experienced the TEE at a lower platelet count than their maximum platelet count during treatment with eltrombopag. As seen in the Table, no changes in the odds ratio for a TEE at different platelet thresholds were observed. All patients experiencing a TEE had at least one risk factor for TEE; analysis did not reveal any one risk factor that was associated with the majority of cases. Two of 15 patients with TEEs tested had positive results for heterozygous Factor V Leiden mutation. Conclusions: There is no increase in the incidence rate of TEEs across the ITP program despite longer duration of eltrombopag treatment. The data presented here confirm previous observations that there is no evidence of a correlation between platelet count increases and the occurrence of TEEs in patients with chronic ITP on eltrombopag. Disclosures: Bussel: GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cheng:GlaxoSmithKline: Consultancy, Honoraria, Speakers Bureau. Saleh:GlaxoSmithKline, Novartis, Imcoline, Celgene: Honoraria, Speakers Bureau. Mayer:GlaxoSmithKline: Employment, Equity Ownership. Vasey:GlaxoSmithKline: Employment. Brainsky:GlaxoSmithKline: Employment.

Abstract We have previously described a novel compound, BTM-3566, that exhibits robust single agent activity in xenograft and PDX models of DLBCL. BTM-3566 is effective on all types of DLBCL, independent of cell of origin (COO) or genotype. Drug activity depends on activation of the mitochondrial protease OMA1 followed by activation of HRI and induction of the ATF4 ISR. To ascertain whether ATF4 ISR induction occurs in vivo, we determined the pharmacokinetics (PK) and pharmacodynamic (PD) responses of BTM-3566 in mouse xenograft models of DLBCL using the double hit lymphoma SU-DHL-10. To establish PK parameters, tumor bearing mice were dosed orally for 1 or 5 consecutive days with 20 mg/kg BTM-3566 and blood sampled over 28 hours. Plasma levels of BTM-3566 were determined and analyzed using a non-compartment model. Half-life in blood plasma was 5.4 and 4.5 hours on days 1 and 5 respectively. Total exposure (AUCinf) was 524164 and 429485 hr*nM on day 1 and day 5 respectively. Drug AUCinf in tumor after a single oral dose of BTM-3566 was 151260 hr*nM. Free drug was estimated to be above the free IC90 for approximately 16 hours post-dose in both plasma and tumor. PD responses to BTM-3566 treatment were determined by measuring biomarkers of the therapeutic cascade: OPA1 cleavage is used as a surrogate for target engagement and activation of OMA1; increased phosphorylation of eIF2α represents pathway activation; induction of ATF4 regulated transcripts and the decrease in the anti-apoptotic protein MCL1 represent pathway effect. A single 20/mg/kg dose of BTM-3566 on day 1 resulted in cleavage of OPA1 by 0.5 hour, with maximal cleavage seen by 12 hours. Phosho-eIF2α was observed by 0.5 hours, peaking at 6 hours. Induction of the ATF4 transcripts ATF4, DDIT3, TRIB3, and CDKN1A was observed within 2 hours with a maximum at 6-12 hours followed by a reduction in transcript levels. MCL1 protein levels were reduced consistent with suppression of translation and protein turnover. By day 5, repeat dosing shows evidence of cumulative pathway effects: OPA1 is extensively cleaved; despite generally depressed levels, phosphorylation of eIF2α remains dynamic and MCL1 levels are markedly suppressed. Induction of ATF4 transcripts, however, follow largely the same kinetics as seen on day 1. The data suggests that in vivo anti-tumor activity of BTM-3566 is associated with activation of the mitochondrial protease OMA1 and induction of the ATF4 ISR. Robust tumor regression is correlated with both blood plasma levels of BTM-3566 and induction of the ATF4 ISR pathway. The data support the use of both ATF4 transcripts and OPA1 cleavage as robust PD markers of target engagement and pathway effect in human clinical trials. An Investigational New Drug application for BTM3566 in B-cell malignancies has been approved with initiation of first in human clinical trials planned for spring 2023. Citation Format: Azadeh Bagherzadeh, Jennifer Baker, Charlotte Bennett, Mi-Young Lee, Natalia Pacheco, Bhavisha Patel, Kevin Stewart, Jon Travers, Michael Stocum, Todd Hembrough, Matthew Kostura. Pharmacokinetics and pharmacodynamics of the novel OMA1 activator BTM 3566 in a mouse model of diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2803.

Background:Current treatments for PsA have proven effective in reducing patient (pt)-reported pain;1,2however, residual pain often remains. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA.Objectives:This descriptive analysis evaluated the effect of tofacitinib, adalimumab and placebo on residual pain in pts with PsA whose inflammation was attenuated after 3 months of therapy.Methods:Data were included from OPAL Broaden (NCT01877668), a randomised, double-blind, placebo-controlled Phase 3 trial of 12 months’ duration in pts with PsA.3Pts were randomised to receive tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, adalimumab 40 mg subcutaneous injection once every 2 weeks or placebo. This analysis assessed pts with ‘residual pain’ at Month (M)3. Residual pain was considered as pain in pts with complete attenuation of inflammation at M3, defined by a swollen joint count (SJC) of 0 and CRP levels <6 mg/L. Pain was measured by a visual analogue scale (VAS; 0 [“no pain”] – 100 mm [“most severe pain”]). Changes in pain from baseline to M3 and residual pain (VAS pain reported at M3) were assessed.Results:Demographics and baseline disease characteristics have previously been reported in the primary study, and were generally similar between treatment groups.3At M3, 100/422 (23.7%) pts with PsA had achieved SJC of 0 and CRP <6 mg/L. At M3, more tofacitinib-treated (tofacitinib 5 mg BID, n=23/107 [21.5%]; tofacitinib 10 mg BID, n=33/104 [31.7%]) and adalimumab-treated pts (n=31/106 [29.2%]) achieved SJC of 0 and CRP <6 mg/L vs placebo (PsA: n=13/105 [12.4%]). Baseline pain appeared numerically higher in tofacitinib-treated pts (tofacitinib 5 mg BID, 54.7 mm; tofacitinib 10 mg BID, 58.4 mm) vs adalimumab-treated pts (47.7 mm) and placebo (50.4 mm). In pts who achieved SJC of 0 and CRP <6 mg/L at M3, improvements in pain from baseline to M3 appeared numerically greater in pts receiving tofacitinib vs those receiving placebo (Figure 1a). When considering absolute (residual) pain at M3, mean residual pain was similar across treatment groups (ranging from 22.7–29.2 mm; Figure 1b), despite a higher baseline pain in tofacitinib treatment groups.Conclusion:Changes from baseline in pain and absolute pain at M3 suggest that in pts with PsA whose inflammation has been completely attenuated, tofacitinib might have an effect on residual pain not obviously attributable to inflammation. However, the sample population was small, and there were large standard deviations. To confirm these results and to understand the mechanisms by which tofacitinib may improve residual pain, a meta-analysis will be performed using individual participant data from pts with rheumatic disease who have participated in tofacitinib randomised controlled trials.References:[1]Gladman et al. Ann Rheum Dis 2007;66:163-68.[2]Gladman et al. Arthritis Care Res 2014;66:1085-92.[3]Mease et al. NEJM 2017;377:1537-50.Acknowledgments:Study sponsored by Pfizer Inc. Medical writing support was provided by Mark Bennett of CMC Connect and funded by Pfizer Inc.Disclosure of Interests:Maxime Dougados Grant/research support from: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Consultant of: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Speakers bureau: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV, Clifton Bingham Grant/research support from: Bristol-Myers Squibb, Consultant of: Bristol-Myers Squibb, Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB, Lara Fallon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, John Woolcott Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Yves Brault Shareholder of: Pfizer France, Employee of: Pfizer France, Lisy Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Meriem Kessouri Shareholder of: Pfizer France, Employee of: Pfizer France

Background:Obesity is highly prevalent in PsA (~45%)1and is associated with a reduced response to TNF inhibitors.2Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA.Objectives:This post hoc analysis assessed tofacitinib efficacy and safety in patients (pts) with PsA by baseline (BL) body mass index (BMI) category.Methods:Data were pooled from two placebo (PBO)-controlled, double-blind, Phase 3 studies in pts with active PsA and an inadequate response to ≥1 conventional synthetic DMARD (OPAL Broaden [12 months;NCT01877668]) or to ≥1 TNF inhibitor (OPAL Beyond [6 months;NCT01882439]).3,4This analysis included pts randomised to tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID or PBO, stratified by BL BMI: <25 kg/m2, ≥25–<30 kg/m2, ≥30–<35 kg/m2, or ≥35 kg/m2. Efficacy and safety were reported to Month (M)3. M3 efficacy outcomes included ACR20/50/70 and HAQ-DI responses, dactylitis and enthesitis resolution rates and changes from BL in HAQ-DI, Short Form-36 Version 2 (SF-36v2) Physical (PCS) and Mental Component Summary (MCS) scores, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores. Safety outcomes included adverse events (AEs), such as cardiovascular (CV) events and changes in lipid levels and liver function tests (LFTs).Results:This analysis included 710 pts; 43.8% were obese (BMI ≥30). At BL, 161 (22.7%) pts had a BMI <25, 238 (33.5%) had a BMI ≥25–<30, 186 (26.2%) had a BMI ≥30–<35 and 125 (17.6%) had a BMI ≥35. Most pts were white (92.5–96.8%), middle-aged (mean: 44.5–51.2 yrs) and female (49.5–65.6%). Greater proportions of obese pts were from Russia/Eastern Europe (35.0%) and USA/Canada (31.8%), vs the rest of world. At BL, higher BMI correlated with an increased prevalence of metabolic syndrome (4.3% in BMI <25 to 76.0% in BMI ≥35) and CRP levels >2.87 mg/L (49.1% in BMI <25 to 84.0% in BMI ≥35). Higher proportions of pts (42.5–47.9%) in BL BMI categories <35 reported no prior biologic DMARD use, vs pts with a BL BMI ≥35 (33.6%). At M3, efficacy improvements were greater in tofacitinib-treated pts vs PBO-treated pts (Figure 1). In pts with a BL BMI ≥35, a trend towards fewer pts responding was observed (Figure 1) and mean changes from baseline in SF-36v2 PCS and MCS and FACIT-F generally appeared lower (Figure 2) vs pts in lower BL BMI categories. Up to M3, the proportions of pts with AEs, and percentage change from BL in lipid levels and LFTs, were generally similar across all BL BMI categories. Three CV events were reported: non-fatal cerebrovascular accident, transient ischemic attack (both tofacitinib 5 mg BID, BMI ≥30–<35) and coronary artery revascularisation (PBO; BMI ≥35). Limitations include the 3-month observation time, particularly for safety findings, thus longer observation times are warranted.Conclusion:Regardless of BL BMI, tofacitinib demonstrated greater efficacy than PBO at M3 in pts with PsA. Similar to other advanced therapies,2reduced efficacy was generally observed in tofacitinib and PBO pts with a BL BMI ≥35. Tofacitinib safety appeared consistent across all BL BMI categories.References:[1]Labitigan et al. Arthritis Care Res (Hoboken) 2014;66:600-07.[2]Singh et al. PLoS One 2018;13:e0195123.[3]Mease et al. NEJM 2017;377:1537-50.[4]Gladman et al. NEJM 2017;377:1525-36.Acknowledgments:Medical writing support was provided by Mark Bennett of CMC Connect, McCann Health Medical Communications, and funded by Pfizer Inc.Disclosure of Interests:Christopher T. Ritchlin Grant/research support from: UCB Pharma, AbbVie, Amgen, Consultant of: UCB Pharma, Amgen, AbbVie, Lilly, Pfizer, Novartis, Gilead, Janssen, Alexis Ogdie Shareholder of: Amgen, Novartis, Pfizer Inc, Grant/research support from: Novartis, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Corrona, Eli Lilly, Novartis, Pfizer Inc, Jon T Giles Grant/research support from: Pfizer Inc, Juan Jesus Gomez-Reino Grant/research support from: AbbVie, Novartis, Pfizer Inc, Roche, UCB, Consultant of: Pfizer Inc, Speakers bureau: AbbVie, Bristol-Myers Squibb, Janssen, MSD, Pfizer Inc, Roche, UCB, Philip Helliwell: None declared, Lori Stockert Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Pamela Young Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Wael Joseph Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Rajiv Mundayat Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Daniela Graham Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, John Woolcott Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ana Belen Romero Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Abstract Inhibition of CDK4/6 combined with the estrogen receptor (ER) degrader fulvestrant significantly improves progression free survival and overall survival in advanced hormone receptor positive (HR+) breast cancer patients and is now the standard of care (SOC) in this disease. Up to 40% of HR+ breast cancers harbor PIK3CA mutations leading to activation of phosphoinositide 3-kinase alpha (PI3Kα), which has been associated with resistance to CDK4/6 inhibitors and fulvestrant. Therefore, PI3Kα inhibitor combinations with CDK4/6 inhibitors and/or fulvestrant are of high interest in HR+, PIK3CA mutant breast cancer. The therapeutic index of active site (orthosteric) inhibitors of PI3Kα has been limited by the dual issues of no clinically meaningful selectivity for mutant versus wild-type (WT) PI3Kα and off-isoform inhibitory activity. Alpelisib, the only approved orthosteric PI3Kα inhibitor, is emblematic of the class with toxicity related to inhibition of wild type PI3Kα and other PI3K isoforms resulting in sub-optimal inhibition of mutant PI3Kα, frequent discontinuation, and challenges in combining with CDK4/6 inhibitors. To overcome these limitations, we designed RLY-2608, the first allosteric, mutant, and isoform-selective inhibitor of PI3Kα. We solved the full-length cryo-EM structure of PI3Kα, performed long time-scale molecular dynamic simulations to elucidate conformational differences between WT and mutant PI3Kα, and leveraged these insights to enable the design of RLY-2608. RLY-2608 does not compete with orthosteric inhibitors for binding and associates 8x faster with mutant PI3Kα relative to WT PI3Kα. In biochemical assays, RLY-2608 inhibits kinase domain (H1047R) and helical domain (E542K, and E545K) mutant PI3Kα activity, demonstrating &lt;10nM potency with 8-12x selectivity relative to WT. RLY-2608 is &gt; 1000-fold selective over the β, δ, and γ PI3K isoforms in biochemical assays and demonstrates exquisite selectivity across a panel of 322 kinases, with no other kinases showing &gt;50% inhibition. We performed in vitro combinations in two HR+ PIK3CA mutant cell lines (MCF7: E545K; T47D: H1047R) and observed synergy between RLY-2608 and fulvestrant or CDK4/6 inhibitors. In vivo, we tested combinations of RLY-2608 with fulvestrant and/or the CDK4/6 inhibitor abemaciclib in the MCF7 xenograft model. Oral administration of RLY-2608 in combination with fulvestrant led to improved efficacy compared to either agent alone in a dose-dependent manner, with regressions observed in the combination arms at all doses. Furthermore, the triple combination of RLY-2608, fulvestrant, and abemaciclib resulted in superior efficacy compared to either the RLY-2608 + fulvestrant or RLY-2608 + abemaciclib doublets, with deep regressions observed in the triple combination arm. In addition, in vivo combination efficacy with fulvestrant and CDK4/6 inhibitors (palbociclib or abemaciclib) was assessed in patient-derived xenografts harboring the PIK3CA H1047R or E545K mutation along with a second site PIK3CA minor mutation. In these studies, combination benefit was observed with doses of RLY-2608 significantly lower than the dose required for maximum efficacy as a single agent. RLY-2608 synergizes in vitro with both anti-estrogen and CDK4/6 inhibitors in cell models of HR+/PIK3CA mutant breast cancer. RLY-2608 can be combined with fulvestrant and CDK4/6 inhibitors in vivo with tumor regressions observed in both cell- and patient-derived xenograft models. The pre-clinical profile of RLY-2608 supports the clinical development of RLY-2608 both in single agent and combination clinical trials in patients with PIK3CA mutant tumors, including HR+/PIK3CA mutant breast cancer. Citation Format: Ermira Pazolli, Randy Kipp, Alessandro Boezio, Hakan Gunaydin, Amanda Iskandar, Matthew Zubrowski, Bret Williams, Kelley Shortsleeves, Alexandre Larivee, Tom McLean, Klaus Michelsen, Hongtao Zeng, Jonathan LaRochelle, Joe Manna, Lucian DiPietro, Andre Lescarbeau, Mary Mader, Bindu Bennet, Jeremy Wilbur, Qi Wang, Levi Pierce, Iain Martin, James Watters, Pascal Fortin, Donald Bergstrom. RLY-2608: The first allosteric mutant- and isoform-selective inhibitor of PI3Kα, is efficacious as a single agent and drives regressions in combination with standard of care therapies in PIK3CA mutant breast cancer models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-10.

Genotoxic Effects of Radiofrequency-Electromagnetic Fields. IntroductionRadiation is energy emission in the form of electromagnetic waves emitted from the solar system and natural resources on earth. The currents produced by the elementary particles formed by the electric current create the magnetic field. Earth's surface is under the influence of the geomagnetic field emanating from the sun. However, the outer liquid also has a magnetic field created as a result of heat transfer in the core. Therefore, all living organisms on earth live under the influence of electromagnetic fields (EMF). Today, besides these natural energy resources, rapidly developing technological developments provide most of the convenience in our lives and expose people to artificial electromagnetic fields. However, man's magnetic field is also under the influence of other natural and artificial magnetic fields around him. In particular, by ionizing radiation, which carries enough energy to break down the genetic material, die cells as a result of DNA damaging, and other diseases, especially cancer, can develop as a result of tissue damage. Electromagnetic Fields in Our LivesToday, apart from natural geomagnetic fields, radiation is emitted from many technological devices. The spectrum of these fields includes many different types of radiation, from subatomic radiation such as gamma and X-rays to radio waves, depending on their wavelengths. Though, as a result of the rapid increase of technological growth, the duration and amount of exposure to EMF is also steadily increasing. On the other hand, wireless gadgets such as computers, smartphones and medical radiological devices have become a necessity for humans. Almost everyone is exposed to radiofrequency electromagnetic fields (RF-EMF) from cell phone and base station antennas or other sources. Thus, the damage caused by the radiation to the environment affects living organisms even many kilometres away unlimitedly. All organisms in the world live under the influence of these negative environmental changes and a large part of the world population is exposed to radiofrequency (RF) radiation for a long time in their daily lives. So, though we are not aware of it, our organs and tissues are constantly exposed to radiation. Therefore, radiation adversely affects human, animal and plant health and disrupts the environment and ecological balance. An example of negative effects, radiation can cause genetic changes in the body (Figure 1). Radiation is divided into ionizing and non-ionizing. Ionizing radiations cause electron loss or gain in an atom or group of atoms in the medium they pass through. Thus, positively or negatively charged ions are formed. High energy X, gamma, ultraviolet and some visible rays in the ionized region of the electromagnetic spectrum can be counted. Since gamma rays, X rays and ultraviolet rays can ionize the molecules in living things more, they can easily disrupt the chemical structure of tissues, cells and DNA molecules in living organisms. Therefore, they can be very dangerous and deadly to living things. The energy of the waves in the non-ionizing region of the electromagnetic spectrum is low and the energy levels are insufficient for the ionization of molecules. Electricity, radio and TV waves, microwaves, and infrared rays are not ionizing because they have low energy. Waves emitted from electronic devices (cell phones, computers, microwave ovens, etc.) are absorbed by the human and animal body. The amount of energy absorbed by the unit biological tissue mass per unit time is called the specific absorption rate (SAR), and its unit is W/kg. Risks of Electromagnetic Fields on Living ThingsDepending on the structure of the tissues and organs, the radiation must reach a certain threshold dose for the effect to occur. Radiation levels below the threshold dose are not effective. Depending on the structure of the tissues and organs, the radiation must reach a certain threshold dose. The effects of small doses of waves are negligible. However, the clinical effects of waves above a certain threshold may increase. High dose waves can cause cell death in tissues. Damages in the cell may increase the risk of cancer and hereditary damage after a while, and somatic effects in people exposed to radiation may cause cancer to appear years later. There is much research on the effects of RF fields. In vitro and in vivo studies on rats, plants and different tissues of humans; suggests that the RF fields are not genotoxic and the fact that harmful effect is due to the heat effect. The contradictory results on this issue have brought about discussions. Therefore, there are still concerns about the potential adverse effects of RFR on human health. A good understanding of the biological effects of RF radiation will protect against potential damages. Due to these uncertainties, with the electromagnetic field project of the World Health Organization, experimental and modelling studies on the biological effects of RF radiation have been accelerated. In 2011, the International Agency for Research on Cancer decided that RF-EMR waves could be potentially carcinogenic to humans (2). Considering that almost everyone, including young children, uses mobile phones in addition to other technological devices, the danger of electromagnetic waves has increased social interest. Genotoxic Effects of EMFIn addition to stimulating apoptosis and changes in ion channels, RF-EMF waves also have a potential effect on genetic material. The radiation absorbed by organisms causes the ionization of target molecules. In particular, biological damage may occur as a result of stimulation/ionization of atoms and disruption of molecular structures while ionizing radiation passes through tissue. As a result of ionization in the cell, electron increases and free electrons cause damage, especially in macromolecules and DNA. Free electrons move directly or indirectly. Free electrons directly affect the phosphodiester or H-bonds of DNA. As a result, the phosphodiester bonds of DNA in the cell are broken, single or double-stranded breakages and chemical toxins increase. DNA double-strand breaks are the most relevant biologic damage induced by ionizing radiation (3,4). There are no cells that are resistant to radiation. The nucleus of the cell and especially the chromosomes in dividing cells are very sensitive to radiation. One of the most important effects of radiation on the cell is to suppress cell growth. In particular, growth is impaired in cells exposed to radiation during cell division (mitosis). Consequently, cells with a high division rate are more sensitive to radiation. DNA damage in somatic cells can lead to cancer development or cell death. Cell death can occur as a result of breaking down DNA because ionizing radiation has enough energy to break down the cell's genetic material. Thus, tissues are damaged and cancer development may be triggered. DNA damage caused by radiation in cells is repaired by metabolic repair processes. If the breaks in DNA as a result of DNA damage caused by radiation in cells are not too large, they can be repaired by metabolic repair processes. Still, errors may occur during this repair. Chromosomes containing different genetic codes and information may also occur. In the cell, the released electrons interact with water molecules, indirectly causing the water to be reactively divided into two parts. Free radicals carry an electron that is not electrically shared in their orbits. Free radicals can cause genetic damage in DNA such as nucleotide changes, double and single-strand breaks. Radiation can cause chromosomes to break, stick together and rearrange. All these changes can lead to mutations or even further, the death of the cell. However, in addition to ionizing radiation, extracellular genotoxic chemicals and intracellular oxidative metabolic residues can also create stress in cells during DNA replication and cell division. Damage may occur during DNA replication under such environmental stress conditions. To date, conflicting results have been reported regarding the genotoxic effects of RF-EMF waves on genetic material. It has been reported that the energy of low EM fields is not sufficient to break the chemical bonds of DNA, but the increase in exposure time is effective on the formation of oxygen radicals and the disruptions in the DNA repair process. The absorption of microwaves can cause significant local warming in cells. For example, an increase in temperature has been observed in cells in culture media exposed to waves of high SAR levels. However, there is evidence that reactive oxygen species are formed in cells indirectly and experimentally exposed to RF-EMF waves. Free oxygen radicals can create nucleotide entries in DNA as well as bind cellular components to DNA bases (5). The frequency of polymorphisms observed in DNA repair mechanism genes in children with acute leukaemia living close to high energy lines reveals the effect of this energy on the repair process. Significant evidence has been reported that genotoxic effects occur in various cell types when exposed to RF-EMF waves (6-10). Here, it has been reported that cells exposed to RF-EMF waves (1.800 MHz, SAR 2 W/kg) cause oxidative damage in mitochondrial DNA, DNA breaks in neurons and DNA breaks in amniotic cells (6,10). Similarly, the damage has been reported in lymphocytes exposed to various RF-EMF waves (8). However, exposure to RF-EMF waves is known to cause chromosome imbalance, changes in gene expression, and gene mutations. Such deleterious genetic effects have also been reported in neurons, blood lymphocytes, sperm, red blood cells, epithelial cells, hematopoietic tissue, lung cells, and bone marrow (1,11,12). It has been found that exposure to RF-EMF radiation also increases chromosome numerical aberrations (6,13). It has also been reported that increased chromosome separation in mouse oocytes exposed to EM and increased DNA fragmentation and apoptosis in fly egg cells (14,15). However, increased DNA breaks have been reported in the blastomeres of embryos of pregnant mice exposed to a frequency of 50 Hz, and a decrease in the number of blastocysts has been reported (16). Genetic damages to sex cells can lead to persistent genetic diseases in subsequent generations. Today, X-ray devices used for medical diagnosis have become one of the largest sources of radiation. These radiological procedures used for diagnosis constitute an important part of ionizing radiation. During these processes, the human body is visibly or invisibly affected by X-rays. As a matter of fact, X-rays have effects of disrupting the structure and biochemical activities of DNA, RNA, proteins and enzymes that are vital in the organism (17). Many studies on this subject have revealed that radiation has suppressive and mutational effects on DNA synthesis. These effects can cause serious damage to the cell as well as DNA and chromosome damage. In a recent study, chromosome damage was investigated in patients with X-ray angiography and personnel working in radiological procedures (18). Our findings showed that the beams used in interventional radiological procedures caused chromosomal damage and the rate of chromosomal abnormalities (CAs) increased significantly in patients after the procedure and this damage increased with the amount of radiation dose. Therefore, the radiation dose to be given to the patient should be chosen carefully. Besides, our findings showed that the frequency of CA is significantly higher in personnel working in radiological procedures. This reveals that interventional cardiologists are exposed to high radiation exposure. For this reason, we can say that the personnel working in radiological procedures (physician, health technician and nurse) are very likely to get diseases after years because they are exposed to low doses but long-term X-rays. Therefore, both the potential risks and safety of exposure to medical radiological devices must be continuously monitored. Furthermore, the fact that chromatid and chromosome breaks are very common among structural CAs in our findings suggests that they may be the cause of malignancy. Because, there are many cancer genes, tumour suppressor genes, enzyme genes involved in DNA repair and important genes or candidate genes responsible forapoptosis on these chromosomes. All this information shows that patients are more susceptible to DNA damage and inappropriate radiological examinations should be avoided. Therefore, X-ray and other diagnostic imaging techniques should not be applied unless necessary, and physicians and patients should be more careful in this regard. It has been reported that RF-EMR waves emitted from wireless communication device mobile phones have a genotoxic effect on human and mammalian cells (6,19). In a recent study; The effects of 900 and 1800 MHz cell phone frequencies on human chromosomes were investigated in amniotic cell cultures (6). Here, it has been reported that chromosome packing delays, damage and breaks occur in amniotic cells exposed to 900 and 1800 MHz every day at 3, 6 and 12 hours for twelve days. However, it was found that the frequency of 1800 MHz caused more CAs than 900 MHz, and the amount of damage increased with increasing usage time. These results confirm that GSM-like RF-EMR causes direct genotoxic effects in human in vitro cultures and has adverse effects on human chromosomes, and these effects increase in parallel with exposure time. This shows us that the mobile phone carries a risk for human health and these genetic damages can cause cancer. Therefore, necessary precautions should be taken for these harmful effects of mobile phones. Among these measures, the periods of mobile phone use should be kept short, especially the exposure of developing children and infants to mobile phones should be prevented, and avoiding excessive use of mobile phones may be one of the precautions against cancer. However, in order to evaluate it in more detail, the effects of mobile phones with environmental mutagens and/or carcinogens should be considered in subsequent researches. ConclusionToday, in parallel with the increasing technological developments, the demand of the society for electronic devices and phones and the frequency ranges of electronic devices are constantly increasing. Waves emitted from electronic devices are absorbed by human and animal bodies. Especially, the use of phones by contact with our body and the increase in usage time affects not only adults but also young children. Therefore, there is increasing concern in society about the negative biological effects of EM waves emitted from phones and other electronic devices. Results from all studies show that RF-EMF waves may be carcinogenic due to their genotoxic effect. Because cancer is a disease that occurs as a result of genetic damage. Considering these negative and harmful effects, regulations following international standards regarding the use of electronic devices should be made and society should be made aware of the risks.References Kim JH.; Lee K.; Kim HG.; Kim KB.; Kim HR. Possible Effects of Radiofrequency Electromagnetic Field Exposure on Central Nerve System. Biomol Ther. 2019, 27(3), 265-275. Baan R.; Grosse Y.; Lauby-Secretan B.; et al. WHO International Agency for Research on Cancer Monograph Working Group. Carcinogenicity of radiofrequency electromagnetic fields. Lancet Oncol. 2011, 12, 624–626. Berrington De Gonzalez A.; Darby S. Risk of cancer from diagnostic X-rays: estimates for the UK and 14 other countries. Lancet. 2004, 363, 345-351. Löbrich M.; Jeggo PA.The impact of a negligent G2/M checkpoint on genomic instability and cancer induction. Nat Rev Cancer. 2007, 861–869. M Valko.; M Izakovic.; M Mazur.; CJ Rhodes.; J Telser. Role of oxygen radicals in DNA damage and cancer incidence. Cell. Biochem. 2004, 266, 37–56. Uslu N.; Demirhan O.; Emre M.; Seydaoğlu G. The chromosomal effects of GSM-like electromagnetic radiation exposure on human fetal cells. Biomed Res Clin Prac. 2019, 4, 1-6. Lee S.; Johnson D.; Dunbar K Dong H.; Ge X.; Kim YC.; Wing C.; Jayathilaka N.; Emmanuel N.; Zhou CQ.; Gerber HL.; Tseng CC.; Wang SM. 2.45 GHz radiofrequency fields alter gene expression in cultured human cells. FEBS Lett. 2005, 579, 4829-4836. Phillips JL.; Singh NP.; Lai, H. Electromagnetic fields and DNA damage. Pathophysiology. 2009, 16, 79-88. Ruediger HW. Genotoxic effects of radiofrequency electromagnetic fields. Pathophysiology. 2009, 16, 89-102. Xu S.; Zhou Z.; Zhang L.; Yu Z.; Zhang W.; Wang Y.; Wang X.; Li M.; Chen Y.; Chen C.; He M.; Zhang G.; Zhong M. Exposure to 1800 MHz radiofrequency radiation induces oxidative damage to mitochondrial DNA in primary cultured neurons. Brain Res. 2010, 1311, 189-196. Demsia G.; Vlastos D.; Matthopoulos DP. Effect of 910-MHz electromagnetic field on rat bone marrow. 2004, 2, 48-54. Zhao TY.; Zou SP.; Knapp PE. Exposure to cell phone radiation up-regulates apoptosis genes in primary cultures of neurons and astrocytes. Lett. 2007, 412, 34-38. Mashevich M.; Folkman D.; Kesar A.; Barbul A.; Korenstein R.; Jerby E.; Avivi L. Exposure of human peripheral blood lymphocytes to electromagnetic fields associated with cellular phones leads to chromosomal instability. Bioelectromagnetics. 2003, 24, 82-90. Panagopoulos DJ.; Chavdoula ED.; Nezis IP.; Margaritis LH. Cell death induced by GSM 900-MHz and DCS 1800-MHz mobile telephony radiation. Mutat Res. 2007, 626(1–2), 69–78. Sagioglou NE.; Manta AK.; Giannarakis IK.; Skouroliakou AS.; Margaritis LH. Apoptotic cell death during Drosophila oogenesis is differentially increased by electromagnetic radiation depending on modulation, intensity and duration of exposure. Electromagn Biol Med. 2015, 1-14. Borhani N.; Rajaei F.; Salehi Z.; Javadi A. Analysis of DNA fragmentation in mouse embryos exposed to an extremely low-frequency electromagnetic field. Electromagn Biol Med. 2011, 30(4), 246–252. Rowley R.; Phillips EN.; Schroeder AL. Effects of ionizing radiation on DNA synthesis in eukaryotic cells. Int J Radiat Biol. 1999, 75( 3), 267-283. Çetinel N.; Demirhan O.; Demirtaş M.; Çağlıyan ÇE.; Cüreoğlu A.; Uslu IN.; Sertdemir Y. The Genotoxic Effect Of Interventional Cardiac Radiologic Procedures On Human Chromosomes. Clinical Medical Reviews and Reports. 2020, 3(1), 1-10. Aitken RJ.; Bennetts LE.; Sawyer D.; Wiklendt AM.; King BV. Impact of radio frequency electromagnetic radiation on DNA integrity in the male germline. Int J Androl. 2005, 28(3), 171–179.

Abstract Research on piezoelectric energy microgenerators from vibrations led to an abundant literature, with various strategies to optimize the frequency range and output power. In contrast, for very low frequency range (<10Hz) and/or for non harmonic mechanical source, the large majority of the strategies are not adapted. This work deals with a small scale piezoelectric generator where the input mechanical source consists of a single force application in the range of hundreds of Newtons (i.e., typical human weight). Contrary to vibrational mechanical sources, such an application context necessitates harvesting as much as energy as possible in a single cycle. This was achieved by assembling several piezoelectric stacks within a mechanical amplification system, and to use the electric field and stress levels close to the limits of the piezoelectric elements. Ericsson cycle (i.e. thermodynamic cycle comprising two iso-electric field and two iso-stress steps) was applied to the piezoelectric material and later using two device prototypes in order to quantify the harvesting capabilities. Finally, in a realistic application point of view, a passive electrical interface based on Bennet’s doubler was implemented and compared to the Ericsson cycles in terms of output energy. This electrical energy management strategy successfully allowed working at ultra high electrical field (>2kV/mm) enabling a converted energy density close to the ultimate value. An maximal energy density of 320 mJ/cm3 was reached using Ericsson cycles, and 130 mJ/cm3 using Bennet’s doubler (~40% of the ultimate energy density). The device comprising ~2.4 cm3 of piezoelectric material, the net output energy converted and stored per cycle reached 320 mJ. Still, the work presented here can be adapted to other range of forces and displacements for maximizing energy harvesting.

Abstract This paper explores a class of extended double-centered linkages and presents two novel multi-bifurcated double-centered metamorphic and reconfigurable mechanisms. Higher order kinematic analyses and singular value decomposition are combined to demonstrate the characteristics of multi-furcation and to reveal motion-branch transformation. These findings show that the presented double-centered linkages are able to evolve to distinct motion branches including two spherical 4R linkages, linesymmetric Bricard linkage or Bennett linkage. Furthermore, by exploring the local properties of singular configurations on geometric constraints and algebraic relationships, a systematic approach for the synthesis of the singular configurations can be designed to discover more novel multi-bifurcated metamorphic and reconfigurable mechanisms.

This paper explores a class of metamorphic and reconfigurable linkages belonging to both Waldron's double-Bennett hybrid linkage and Bricard linkages, which include three novel symmetric Waldron–Bricard metamorphic and reconfigurable mechanisms, and further presents their three extended isomeric metamorphic linkages. The three novel Waldron–Bricard metamorphic and reconfigurable linkages are distinguished by line-symmetric, plane-symmetric, and line-plane-symmetric characteristics. The novel line-symmetric Waldron–Bricard metamorphic linkage with one Waldron motion branch and two general and three special line-symmetric Bricard motion branches is obtained by integrating two identical general Bennett loops. The novel plane-symmetric Waldron–Bricard reconfigurable linkage with two plane-symmetric motion branches is obtained by coalescing two equilateral Bennett loops. The novel line-plane-symmetric Waldron–Bricard metamorphic linkage with six motion branches is obtained by blending two identical equilateral Bennett loops, including the plane-symmetric Waldron motion branch, the line-plane-symmetric Bricard motion branch, the spherical 4R motion branch, and three special line-symmetric Bricard motion branches. With the isomerization that changes a mechanism structure but keeps all links and joints, each of the three novel Waldron–Bricard linkages results in an extended isomeric metamorphic linkage. This further evolves into the study of the three isomeric mechanisms. The study of these three novel metamorphic and reconfigurable mechanisms and their isomerization are carried out to demonstrate the characteristics of bifurcation and to reveal motion-branch transformation. Furthermore, by exploring the intersection of given motion branches and using the method of isomerization, more metamorphic and reconfigurable linkages can be discovered to usefully deal with transitions among possible submotions.

To discover single-degree-of-freedom (DOF) single-loop overconstrained mechanisms is still an open problem. This paper deals with the type synthesis of single DOF single-loop overconstrained 6RMCTs (6R spatial mechanisms for circular translation). These mechanisms provide alternatives to planar parallelograms and are also associated with self-motion of several translational parallel mechanisms. 6RMCTs are to be obtained using a construction approach in combination with the approaches to the type synthesis of parallel mechanisms. By imposing certain conditions on the hybrid overconstrained 6R (plano-spherical, plano-Bennett, double-spherical, and spherico-Bennett) mechanisms, Bricard plane symmetric mechanism, and Bricard line symmetric mechanism, six special cases of 6RMCTs are obtained. By combining planar parallelograms with these special mechanisms, the general cases of 6RMCTs are then constructed. Finally, 4R2H, 2R4H, and 6H mechanisms for circular translation are obtained from the above 6RMCTs by replacing one or more pairs of R (revolute) joints with parallel axes each with a pair of H (helical) joints with parallel axes and the same pitch. This work contributes to the research on overconstrained six-bar mechanisms and further reveals that the research areas of parallel mechanisms and single-loop overconstrained mechanisms are closely related.