Input: Claim: Disruption of circadian rhythms can lead to health issues. [SEP] Text: Dowse, H; Ringo, JFurther evidence that the circadian clock in Drosophila is a population of coupled ultradian oscillators J 11: 65–76, DOI: [PubMed] Krishnan, B; Levine, J; Sisson, K; Dowse, H; Funes, P; Hall, J; Hardin, P; Dryer, SA new role for cryptochrome in a Drosophila circadian oscillator Nature 11: 313–317, DOI: [PubMed] Plautz, J; Straume, M; Stanewsky, R; Jamison, C; Brandes, C; Dowse, H; Hall, J; Kay, SQuantitative analysis of Drosophila period gene transcription in living animals J 11: 204–217, DOI: [PubMed] Tenriero, S; Dowse, H; D’Souza, S; Minors, DS; Chiswick, M; Simms, D; Waterhouse, JMRhythms of temperature and heart rate in premature babies in intesive care Dev 11: 33–52, DOI: [PubMed] Lindsley, G; Dowse, H; Burgoon, P; Kilka, M; Stephenson, LA persistent circhoral ultradian rhythm is identified in human core temperature 11: 69–78, DOI: [PubMed] Stephenson, R; Joonbum, L; Famina, S; Caron, A; Dowse, HSlep-wake behavior in the rat: ultradian rhythms in a light–dark cycle and continuous bright light J 11: 490–501, DOI: [PubMed] Dowse, H; Umemori, J; Koide, TUltradian components in the locomotor activity rhythms of the genetically normal mouse, Mus musculus J 11: 1788–1795, DOI: [PubMed] Gaten, E; Tarling, G; Dowse, H; Kyriacou, C; Rosato, EIs vertical migration in Antarctic krill (Euphausia superba) influenced by an underlying circadian rhythm?

Output: pass


Input: Claim: 3D printing allows for customized, on-demand manufacturing. [SEP] Text: For producing size- and shape-specific microlens designs parameter mapping is required, for which the matrix printing ability of the glass 3D printer is highly suitable for. The high laser power used during printing caused a small amount of glass to be evaporated from the hot zone, with a subsequent partial redeposit of fumed silica surrounding the microlens and, in some instances, onto nearby microlenses. To remove this unwanted redeposited material, each lens was irradiated using the CO2 laser for a duration of ∼10 s, using the four laser beams with a total power of 5 W. Figure 2a shows the printed and postprocessed MLA. The redeposited fumed silica can be seen here as darker regions between the microlenses. Figure 2b shows a close-up of a single lens from the same MLA, corresponding to the sliced model in Figure 1c. FIG. 2. Top view (a) of the 5 × 5 MLA, and side view (b) of a single microlens. Fabrication of microlenses with different heights was possible simply by varying the number of print layers. Figure 3 shows images of three different microlenses, having a similar convex radius but different thickness, printed with a single layer (shown in Fig. 3a), double layer (Fig. 3b), and five layers (shown in Fig. 3c). Note that within the five-layer microlens, some small voids are visible that likely are formed during layer shifting. Further improvement of the process parameters is needed for printing multilayer MLA (≥5 layers). FIG. 3. Microlenses in different thickness: (a) 1-layer microlens, (b) 2-layer microlens, (c) 5-layer microlens. CharacterizationTo evaluate the reproducibility of the 3D printing technique, the MLA was characterized using optical microscopy (LV100) in combination with image processing (ImageJ). The surface roughness was measured for several microlenses using atomic force microscopy (). The optical properties of the lenses were measured and compared with the lens maker's formula as well as the ray optics model using simulations. Optical microscopyThe plano-convex shape of the printed microlenses, shown in Figure 2, was characterized using an optical microscope in combination with image processing.

Output: corroborate


Input: Claim: Gene editing is completely risk-free with no side effects. [SEP] Text: 16595/fig-2 Figure 3: Phenotypic analysis of gene-edited parasites. In vitro cultures were established for Plasmodium falciparum reference 3D7 parental strain and transgenic parasite strains MS_glmS and DHFR-TS_glmS with edited PF3D7_1233700 (MS) and PF3D7_0417200 (DHFR-TS) genes, respectively. (A) Knockdown of target proteins in transgenic parasites. MS and DHFR-TS % target protein signals were obtained by western blotting (Fig. S3). Boxplots show the data from triplicate experiments. (B) Target vulnerability assay. Parasites were cultured for 96 h at different glucosamine (GlcN) concentrations. The left panel shows all data and model fits (curves). The right panel shows EC_50 values for each transgenic line compared with that of the 3D7 parental strain. The points show the estimated EC_50 ratio (3D7: transgenic parasite) and error bars represent S. E. M. The dashed line indicates the line of no effect. Estimated EC_50 ratios:- 3D7: DHFR-TS_glmS = 11. 25, adjusted P = 7. 9E-6; 3D7: MS_glmS = 0. 89, adjusted P = 0. 84. Download full-size image DOI: 10. 7717/peerj. 16595/fig-3 Next, we assessed the consequences of target protein knockdown in transgenic parasites with respect to proliferation in target vulnerability assay. In previous studies of the acute effect of glmS-ribozyme mediated target knockdown on parasite proliferation, treatment was performed for up to 72 h in which GlcN has a minor inhibitory effect on wild-type strains (Prommana et al. , 2013). By extending the GlcN treatment to 96 h, greater than 50% inhibition of the 3D7 wild-type strain was observed at the highest concentrations such that we could determine the EC50 (8. 0 mM; 95% confidence intervals 5. 9 to 10. 0 mM).

Output: contrast


Input: Claim: Disruption of circadian rhythms can lead to health issues. [SEP] Text: 0 cm) on soft wood chip bedding in a controlled environment of 23 ± 1ºC, 60% humidity, and 12:12 h light/dark cycles (light on at 8:00) in the Multi-chamber System (& Co. , Osaka, Japan). The bedding in each cage was changed and the food and water were refreshed twice a week. For the lighting in each chamber, a high color-rendering cold cathode lamps having a wavelength near-natural light was installed. The light intensity was measured by installing an illuminometer (T-10, Konica Minolta, Tokyo, Japan) on the floor in the cage and set to 250 lux intensity. All animals were provided with MF diet, Co. , Tokyo, Japan) and water ad libitum. Mice were held for 1-week acclimatization period before test initiation and then subjected to experiments at 8 weeks-old. After acclimatization, the light/dark cycle in each experimental group was set as follows: Control, 12:12 h light/dark cycle; Shift, 12:12 light:dark cycle with inverting every two days, which imitated the rotating two-shift work [34] (Figure 2A). Lighting time is denoted as Zeitgeber time (ZT), where ZT0 represents the start of the light period (the light period was from ZT0 to ZT12 and the dark period was from ZT12 to ZT24). During the test period, the general condition and body weight of the animals were observed once a week. All procedures were carried out under protocols approved by of the University of Shizuoka (Approval number: 165149, 175172). 2. 3. anesthesia with isoflurane, a momentum measuring device (nano tag®, Co. , Ltd. Nagano, Japan) was subcutaneously implanted into the necks of mice. During operation, the animals were cared for with a thermal pad to prevent decrease body temperature. After an acclimatization period of one week, animals were randomly assigned to either of the two types of light/dark cycles and kept for 4 weeks. Locomotor activity was measured by 3-axis accelerometer inside the device. The recording of the momentum data was aggregated every 5 minutes, and the threshold was set to 170.

Output: pass


Input: Claim: 3D printing allows for customized, on-demand manufacturing. [SEP] Text: The focal length (fmeasured = 483 ± 40 μm) was obtained by subtracting the average lens height (475 ± 5 μm) from the measured distance ΔL between the two microscope positions (958 ± 40 μm). The homogeneity of the spots was then analyzed by comparing the intensity of the spots along a selected array of spots. The light intensity of the selected array with five spots (indicated by the red box in Fig. 7a) was measured with the results presented in Figure 7b. The intensities were measured across the center of each spot and quantified using image processing software ImageJ. The result from the five selected microlenses shows uniform light intensities for the different lenses with a variation of ±3. 4%, indicating similar focusing performance for each microlens in the glass MLA. FIG. 7. (a) Spot-matrix image captured from the focal plane of the MLA, (b) light intensities of five spots taken from the red box area. Imaging performanceThe imaging performance of the microlens was also evaluated as shown in Figure 8. Here a parallel white light source was projected through a filter (black horse on a white paper), through the MLA with the image captured using the CCD camera of the optical microscope. Each lens provides a clear image with little distortion (see Fig. 8b) indicating reproducible fabrication and homogeneous refractive index of the different lenses with overall good imaging performance of the MLA. FIG. 8. (a) The setup for the MLA imaging performance test, (b) the top view of the 5 × 5 MLA imaging of a horse and the comparison of a lens imaging with the original image outline (red dashed outline). ConclusionsWe present results on a simple and rapid method of 3D printing silica glass MLA using a filament-based laser deposition technology. The microlenses had a hemispherical plano-convex shape. An ultrasmooth lens surface was achieved with a measured roughness of 0. 12 nm. The 5 × 5 MLA displays uniform focusing performance with an average EFL of 483 ± 40 μm across the whole array, in agreement with theoretical values and simulation results. The MLA provides good imaging quality. The capability of creating microlenses in different thickness enables versatile customizations of microlenses and multifocal MLA fabrications for 3D imaging applications. 1.

Output: corroborate


Input: Claim: Gene editing is completely risk-free with no side effects. [SEP] Text: We posited that knockdown of vulnerable target gene expression by the action of the glmS ribozyme enhances the proliferation defect caused by GlcN treatment itself over 96 h manifested as a significantly lower EC50 compared with 3D7 wild-type. The EC50 of the DHFR-TS_glmS parasite, but not that of the MS_glmS parasite, was significantly different from that of the 3D7 wild-type strain (Fig. 3B). Hence, reduction in DHFR-TS, but not MS expression affected parasite sensitivity to GlcN. Based on these results, DHFR-TS is defined as a vulnerable antimalarial target as expected. In contrast, MS is a non-vulnerable target. Discussion PF3D7_1233700 was identified as the only candidate gene encoding MS from a bioinformatic search of the P. falciparum 3D7 genome, suggesting that the parasite possesses a single MS gene. However, P. falciparum MS is not a vulnerable antimalarial target, in contrast to the vulnerability of the downstream SAMS enzyme in the P. falciparum methionine pathway (Musabyimana et al. , 2022). Salvage is the major source of methionine substrate for P. falciparum SAMS because reducing exogenous methionine leads to a concomitant decrease of SAM (Harris et al. , 2023). Hence, methionine synthesized by MS is of minor importance for intra-erythrocytic proliferation under standard in vitro culture conditions. However, methionine synthesis may be more important for P. falciparum proliferation in natural infections, since the methionine concentration in human serum (Barić et al. , 2004) is approximately two to seven times lower than that of parasite culture medium. The other roles of P. falciparum MS besides methionine synthesis should be considered to explain the conservation of MS in Plasmodium and its tentative annotation of essentiality in P. falciparum based on the absence of transposon insertions in the encoding gene (Zhang et al. , 2018). It should be noted that definitive proof of essentiality requires demonstration of a proliferation defect from more complete knockdown using a different tool (e. g.

Output: contrast


Input: Claim: Disruption of circadian rhythms can lead to health issues. [SEP] Text: The recorded locomotor activity data was captured by FeliCa communication, and changes in behavioral rhythms were analyzed with the nanotag/Viewer (Co. , Ltd. Nagano, Japan). 2. 4. acclimatization, mice were randomly divided into Control group and Shift group. BJMC3879Luc2 tumor cells were implanted into the right fourth mammary fat pad of female BALB/c mice by injection of 0. 1 mL PBS containing 5 × 106 cells. Mice were kept for 3, 5, or 8 weeks, either under normal or irregular light/dark cycle conditions. Transplanted tumor size was measured with a caliper once a week, and volume was calculated using the following formula: tumor volume = maximum diameter (mm) × (minimum diameter (mm))2 × 0. 4 [35]. The endpoint for tumor size defined a maximum diameter of 20 mm. Rate of metastasis to lymph node that located distal to the implantation site was calculated as follows: Rate of metastasis (%) = (Number of metastasis to individual lymph node/Total number of mice in each group) × 100. 2. 5. Imaging of Prior examination has shown that the development of peak luciferase activity is strongly influenced by depth of anesthesia and body temperature. The general condition of mice varied in distribution from mild to severe. Therefore, ex vivo imaging was performed to avoid the effects of anesthesia depth and body temperature to luciferase activity. For imaging of tumors and metastatic sites, mice received an intraperitoneal (i. p. ) injection of 120 mg/kg D-luciferin (Wako) dissolved in PBS. 7 minutes post-injection, tissue-specific metastasis in lung, kidney lymph nodes, and axillary lymph nodes were tracked with bioluminescence using the imaging system () by measuring luciferase activity for 50 seconds exposure time. Images were analyzed with software version 3. 0. 2. 6. Determination of NA in To detect intratumoral NA, breast tumors developed in the mammary fat pad were collected. Tumor tissues were homogenized in 0. 01 N HCl (containing: 1% sodium disulfite and 1 mM EDTA) and supernatant was collected. NA was measured using the kit (ImmuSmol, Talence, France) in accordance with the manufacturer’s protocol. 2. 7.

Output: pass


Input: Claim: 3D printing allows for customized, on-demand manufacturing. [SEP] Text: For all specimens, the following design principles are considered:•Continuous toolpath, no start and stop, and no individual printing islands•Blend between individual layers, no straight z movement upwards•No self-intersecting toolpaths•Blend radius for corners/minimal feature sizeVariable cross-sectionThe footprint of the printed samples is 500 × 75 mm and the height of the elements varies; at least seven layers are printed. The single outline toolpath is chosen, as it allows a stable printing process and a fast cooldown (fast fabrication time). Furthermore, the single outline print eliminates interface interactions between different beads within the same layer. The distance between the layers (resolution in Z direction) varies for every print. The experiments start with a layer height of 16 mm and increase in 2 mm steps until a layer height of 32 mm is reached. Although the layer height is not limited to 32 mm, it is beyond the scope of the 3. Close-up of a section, layer height 24mm and diagram of measurement points. c: center point, determined by ImageJ. h(c): height at point c; w(c): width at point c; w(max): maximum width, determined by ImageJ bounding box; r(x): wall thickness at point x. Different nozzles: Internal geometryThe increased dimension of the 3D printable bead offers the opportunity to create subdivided die geometries. Those internal substructures can potentially improve the properties of the printed component in regard to structural, optical, or thermal performance (Fig. 4). FIG. 4. Different nozzles types, prototyped using 3DP of aluminum. a) o24w. b) o24w1Quad. c) o24w1Crosshair. d) o24tubeInTube. Please see Table 1 for more detail regarding the different types. As a first attempt, four different die typologies are designed and fabricated. All nozzles have an outer diameter of 24 mm, (a) is a nozzle with no internal geometry, (b) contains a cross to reinforce the bead, (c) contains a crosshair pattern, and (d) consists of five individual tubes. Table 1 provides a detailed overview of the shape, pocket size, and plastic cross-section for each design. Similar to the experiments described in and Fabrication section, basic rectangular elements are 3D printed and sections of the printed object are analyzed.

Output: corroborate


Input: Claim: Gene editing is completely risk-free with no side effects. [SEP] Text: , the TetR-DOZI system with 5′ and 3′ aptamers installed at the target gene (Polino et al. , 2020)) or from conditional gene knockout mutagenesis. Essential genes are expressed through the life cycle, and P. falciparum MS is detectably expressed by data-independent proteomics throughout the intraerythrocytic stages at a level approximately 40–1000-fold lower than that of DHFR-TS (Siddiqui et al. , 2022). Moreover, single-cell RNA sequencing data indicate that P. falciparum MS is expressed during mosquito stages (Real et al. , 2021), and the P. vivax MS ortholog PVP01_1451800 is expressed in liver stages (Mancio-Silva et al. , 2022). Although malaria parasites possess a mechanism for the efflux of Hcy (Beri et al. , 2017), lack of MS function may lead to increased levels of Hcy and redox stress, which may be important for sporogonic development in the mosquito vector when Plasmodium is more dependent on glutathione (Vega-Rodríguez et al. , 2009) and α-lipoic acid (Biddau et al. , 2021) to mitigate oxidative stress. The conversion of 5-mTHF to THF by MS may be important for recycling folate required for other enzymatic reactions, particularly during the developmental stages with the greatest folate demand. Plasmodium can salvage folates and the folate precursor para-aminobenzoic acid (p ABA), but the levels of folates are too low, or are not in a form capable of being efficiently transported to support intra-erythrocytic development in the absence of de novo synthesis (Salcedo-Sora & Ward, 2013). P. berghei lacking the p ABA synthetic enzyme aminodeoxychorismate synthase cannot develop in p ABA-deficient medium during intraerythrocytic stages; however, the growth of these mutant parasites is unaffected in p ABA-deficient medium during liver stages (Matz et al. , 2019).

Output: contrast


Input: Claim: Disruption of circadian rhythms can lead to health issues. [SEP] Text: Counting and Classification of For counting of peripheral white blood cells (WBCs), blood samples were treated with 10-fold the amount of Tuerk’s solution (Sigma-Aldrich, St. ), and the number of WBCs per 1 mm3 were calculated by hemocytometer. To perform WBC classification, heparinized blood was smeared onto a slide glass and quickly dried with cool air using a blow-dryer. Slides were fixed and stained with May-Gruenwald stain solution (Sigma-Aldrich) for 3 min, and then stained using 1:20 May-Gruenwald stain solution diluted with phosphate buffer (pH 6. 4, M/15, Sigma-Aldrich) for 3 min. Slides were then stained with Giemsa stain solution (Merck, Darmstadt, Germany) diluted 20 times with phosphate buffer for 15 min. Blood smear specimens were inspected (magnification, × 1,000) using immersion oil. One hundred WBCs were counted and classified into five types (i. e. , lymphocyte, monocyte, neutrophil, eosinophil, and basophil). Each WBC count per 1 mm3 was calculated using the following formula: presence ratio of each type of WBCs × total WBC count. 2. 8. Feeding a Quercetin-in the 3879Luc2 cells were transplanted into female BALB/c mice as described above. The mice were provided MF diet or 0. 3% quercetin-containing MF diet. All food was changed three times a week to reduce the effects of deterioration of quercetin in the MF diet. Mice were maintained for 8 weeks in normal light conditions (Control) or light/dark shift environment (Shift). All mice were divided into the following four groups: MF diet (Control) or 0. 3% quercetin-containing MF diet (0. 3%Q-Ctrl) in a normal light/dark environment; MF diet (Shift) or 0. 3% quercetin-containing MF diet (0. 3%Q-Sh) in an irregular light/dark shift environment. The lymph node metastasis inhibition rates in 0. 3% Q-Ctrl and 0.

Output: pass


Input: Claim: 3D printing allows for customized, on-demand manufacturing. [SEP] Text: HC3DP at large dimensions provides the opportunity to create bespoke, noncircular, and such cross-sections that increase the range of possible applications. Adaptive extrusion section control allows the creation of unseen designs, material efficient structures, and significant improvements on fabrication speed. With this 1. . Large-format fused deposition additive manufacturing: A review. J 2020;26(5):793–799;Crossref2. Large-format additive manufacturing of polymer extrusion-based deposition systems: Review and applications. Manuf 2023;8:1257–1280;Crossref3. Designing for big area additive manufacturing. 2019;25:275–285;Crossref4. . Large-scale hollow-core 3D printing (HC3DP): A polymer 3D printing technology for large-scale ultralightweight components. 2023;78:103874;Crossref5. Scott CS. for Three-Dimensional Objects. US5340433A, 8, 1992, and 23, 1994. 6. Barnatt C. 3D Printing: Industrial Revolution. Third edition. United States: ExplainingTheFuture. com, 2013. ISBN: 978-1-5396-5546-6. 7. . A review of melt extrusion additive manufacturing processes: I. Process design and modeling. J 2014;20(3):192–204;Crossref8. Leapfrog XceL. Industrial 3D Printer. 2019. Available from: [Last accessed: October 23, 2023]. 9. Prusa. . 2020. Available from: E3D. SuperVolcano. 2018. Available from: Structure and mechanical behavior of (BAAM) materials. J 2017;23(1):181–189;Crossref12. van der Kooij D. Endless Chair—Kooij; 2011. Available from: [Last accessed: February 1, 2023]. 13. Infrared preheating to improve interlayer strength of big area additive manufacturing (BAAM) components. 2017;14:7–12;Crossref14. Extrusion control for high quality printing on (BAAM) systems. 2019;28:445–455;Crossref15. Determination of the Distance in Additive Manufacturing. In: 4th on 3D Printing (Additive Manufacturing) Technologies and Digital Industry.

Output: corroborate


Input: Claim: Gene editing is completely risk-free with no side effects. [SEP] Text: Despite an inefficient folate transport system for the uptake of 5-mTHF (Salcedo-Sora & Ward, 2013), elevated levels of 5-mTHF in the liver may drive its accumulation and conversion to THF by Plasmodium MS, such that the parasite is less reliant on de novo folate synthesis during this stage of the life cycle. A knockout mutant of the P. berghei orthologous MS gene (_1448300) shows no growth defect during intraerythrocytic stages (Bushell et al. , 2017), but growth of the mutant is reduced during the transition from the sporozoite (through the liver) to the blood stage (Stanway et al. , 2019). Although these data suggest a non-essential role of Plasmodium MS, dispensability in P. falciparum cannot be extrapolated from knockout data in P. berghei because of species-specific differences in Plasmodium host cell tropism. P. berghei preferentially invades reticulocytes, whereas P. falciparum invades mature erythrocytes. The reticulocyte milieu has a greater metabolic complexity than that of erythrocytes, which can support the growth of P. berghei parasites with knockouts of genes functioning in the intermediary carbon metabolic pathway, pyrimidine metabolism, and glutathione biosynthesis that are essential in P. falciparum (Srivastava et al. , 2015). finding that MS is a non-vulnerable antimalarial target raises the question of what other enzymes in the Plasmodium parasite methionine pathway and other pathways related to folate metabolism (Müller & Hyde, 2013) are also non-vulnerable targets. This could be tested by target vulnerability assay of LOF mutants for other genes annotated as essential. Although the role of MS as an antimalarial target is deprioritized, it would be interesting to test whether the roles of P. falciparum MS in Hcy metabolism and folate recycling are more important in mosquito and liver stages.

Output: contrast


Input: Claim: Disruption of circadian rhythms can lead to health issues. [SEP] Text: s1 Abbreviations DMSO, dimethyl sulfoxide; FBS, fetal bovine serum; for Research on Cancer; MMP, matrix metalloproteinase; NA, noradrenaline; NLR, neutrophil-to-lymphocyte ratio; PBS, phosphate buffered saline; Q3G, quercetin-3-o-glucuronide; SAM, sympathetic-adrenal-medullary axis; WBC, white blood cell; ZT, Zeitgeber time. authors thank Dr. Taka-aki Suzuki (Institute of Shizuoka Prefecture, Japan), Mr. Tadakazu Takahashi, Ms. Chika Tokuyama, and Mr. (University of Shizuoka, Japan) for their technical support, and Dr. (of Science, Japan) for helpful advice for leukocytes differentiation on this study. We also thank H. Nikki March, PhD, from (www. edanzediting. com/ac) for editing a draft of this manuscript. This work was supported by grant number 15H02899 and 18H03194(KS). The authors have no competing interests to declare. M. Y. and K. S. designed and directed the project. M. N, A. H. and Y. Y. performed experiment and statistical analyses. N. M. designed light-dark cycle conditions. K. S. and M. S. provided the breast cancer cell line, BJMC3879luc2 cells and instructed implantation experiment. T. A. and N. O. provided bioimaging instruction and analytical equipment, N. M. provided instruction and analytical equipment for the quantitative analysis of quercetin. M. N. and K. S. wrote the manuscript and all authors reviewed and commented on the manuscript. 437. DOI: Blood pressure and heart rate variabilities in normotensive and hypertensive human beings. Circ Res. 1983; 53: 96–104. DOI: Circadian rhythm of leucocytes and lymphocytes subsets and its possible correlation with the function of the autonomic nervous system. Immunol. 1997; 110(3): 500–508. DOI: Okamura H. Clock genes in cell clocks: roles, actions, and mysteries. J Biol Rhythms.

Output: pass


Input: Claim: 3D printing allows for customized, on-demand manufacturing. [SEP] Text: 3D Printing of medicines: Engineering novel oral devices with unique design and drug release characteristics. 2015;12:4077–4084. CrossrefPubMed71. Verstraete G, Samaro A, Grymonpré W, et al. 3D printing of high drug loaded dosage forms using thermoplastic polyurethanes. Pharm 2018;536:318–325. CrossrefPubMed72. 3D printed tablets with internal scaffold structure using ethyl cellulose to achieve sustained ibuprofen release. 2018;115:11–18. CrossrefPubMed73. Immediate release 3D-printed tablets produced via fused deposition modeling of a thermo-sensitive drug. 2018;35:124. CrossrefPubMed74. 3D printing of metformin HCl PVA tablets by fused deposition modeling: Drug loading, tablet design, and dissolution studies. 2019;20:1–11. Crossref75. 3D printed polyvinyl alcohol tablets with multiple release profiles. 2019;9:1–8. PubMed76. Matijašić G, Gretić M, Kezerić K, et al. Preparation of filaments and the 3D printing of dronedarone HCl tablets for treating cardiac arrhythmias. 2019;20:1–13. Crossref77. Customized novel design of 3D printed pregabalin tablets for intra-gastric floating and controlled release using fused deposition modeling. Pharmaceutics 2019;11:1–14. Crossref78. Development of 3D printed tablets by fused deposition modeling using polyvinyl alcohol as polymeric matrix for rapid drug release. J 2020;109:1558–1572. CrossrefPubMed79. Fabrication of taste-masked donut-shaped tablets via fused filament fabrication 3D printing paired with hot-melt extrusion techniques. 2020;21:1–11. Crossref80. Three-dimensional (3D)-printed devices composed of hydrophilic cap and hydrophobic body for improving buoyancy and gastric retention of domperidone tablets. 2020;155:105555. CrossrefPubMed81. . A flexible-dose dispenser for immediate and extended release 3D printed tablets. 2015;96:380–387. CrossrefPubMed82.

Output: corroborate


Input: Claim: Gene editing is completely risk-free with no side effects. [SEP] Text: Sequence alignment of methionine synthases Protein sequences were obtained from UniProt of the cobalamin-dependent methionine synthase (MS) enzymes from human (MTR, Q99707-1) and Escherichia coli K12 (metH, P13009), together with Plasmodium candidate MS from orthologous group 1324at5820 encoded by P. falciparum PF3D7_1233700 (Pf, Q8I585), P. knowlesi PKH_145080 (Pk, A0A384KWI2), P. malariae PmUG01_14067900 (Pm, A0A1A8X239), P. ovale wallikeri PowCR01_140053700 (Pow, A0A1C3L5P3), P. ovale curtisi PocGH01_14059300 (Poc, A0A1D3UAH7), and P. vivax PVX_100640 (Pv, A0A1G4H5F2) genes. Sequences were aligned using the T-Coffee tool with default options in the Expresso web interface (Armougom et al. , 2006). DOI: 10. 7717/peerj. 16595/supp-1 matrix of methionine synthases Percent identity matrix of the protein alignment (Fig. S1) was created using the bio3d R package version 2. 4-4. Cells are shaded according to the percent identity as indicated by the scale bar on the right. DOI: 10. 7717/peerj. 16595/supp-2 blotting of target proteins Clonal lines of transgenic parasites DHFR-TS_glmS and MS_glmS with edited PF3D7_0417200 (DHFR-TS) and PF3D7_1233700 (MS) genes, respectively were cultured for 24 h in the presence or absence of 5 mM glucosamine (GlcN). A sample of parasite protein extract (50, 50, and 2.

Output: contrast


Input: Claim: Disruption of circadian rhythms can lead to health issues. [SEP] Text: Lymphangiogenesis and axillary lymph node metastases correlated with VEGF-C expression in two immunocompetent mouse mammary carcinoma models. Breast Cancer. 2011; 2011: 867152. DOI:. Systemic Immune-inflammation Index, Based on and Neutrophil-Lymphocyte Ratio, for in Lung Cancer. Exp Med. 2015; 236: 297–304. DOI: Neutrophil-to-lymphocyte ratio may be associated with the outcome in patients with prostate cancer. SpringerPlus. 2015; 4: 255. DOI: Grosso G, Godos J, Lamuela- A comprehensive meta-analysis on dietary flavonoid and lignan intake and cancer risk: Level of evidence and limitations. Food Res. 2017; 61(4): DOI: ás-Barberán Flavonoids in food and their health benefits. Hum Nutr. 2004; 59(3): 113–122. DOI:. Dietary antioxidant flavonoids and risk of coronary heart disease: the Study. Lancet. 1993; 342(8878): 1007–1011. DOI: Dihal AA, de Boer VC, van der Quercetin, but not its glycosidated conjugate rutin, inhibits azoxymethane-induced colorectal carcinogenesis in F344 rats. J Nutr. 2006; 136(11): 2862–2867. DOI: An immunocompetent murine model of metastatic mammary cancer accessible to bioluminescence imaging. Anticancer Res. 2009; 29(11): 4389–4395. Combined effect of circadian dysfunction and cadmium on immune suppression. Sci. 2016; 3(5): 237–242. DOI: Synthetic a-mangostin dilaurate strongly suppresses wide-spectrum organ metastasis in a mouse model of mammary cancer. Cancer Sci. 2018; 109(5): 1660–1671. DOI:. the Risks of Cancers in Women: A and Meta-analysis of 61 423. DOI: Morales--Gallego A, Jimenez-Lopez JC, Morell M. of the Polymorphisms of Associated with Endocrine Cancer.

Output: pass


Input: Claim: 3D printing allows for customized, on-demand manufacturing. [SEP] Text: Goyanes A, Kobayashi M, Martínez-Pacheco R, et al. Fused-filament 3D printing of drug products: Microstructure analysis and drug release characteristics of PVA-based caplets. Pharm 2016;514:290–295. CrossrefPubMed83. . Fabrication of extended-release patient-tailored prednisolone tablets via fused deposition modelling (FDM) 3D printing. 2015;68:11–17. CrossrefPubMed84. Fused deposition modeling (FDM) 3D printed tablets for intragastric floating delivery of domperidone. 2017;7:1–9. CrossrefPubMed85. Development of modified release 3D printed tablets (printlets) with pharmaceutical excipients using additive manufacturing. Pharm 2017;527:21–30. CrossrefPubMed86. . Formulation of 3D printed tablet for rapid drug release by fused deposition modeling: Screening polymers for drug release, drug-polymer miscibility and printability. J 2018;107:390–401. CrossrefPubMed87. . 3D printing of vaginal rings with personalized shapes for controlled release of progesterone. Pharm. 2018;539:75–82. CrossrefPubMed88. Defined drug release from 3D-printed composite tablets consisting of drug-loaded polyvinylalcohol and a water-soluble or water-insoluble polymer filler. Pharm 2018;543:361–367. CrossrefPubMed89. Development of customised 3D printed biodegradable projectile for administrating extended-release contraceptive to wildlife. Pharm 2018;548:349–356. CrossrefPubMed90. Development of immediate release (IR) 3D-printed oral dosage forms with focus on industrial relevance. 2020;155:105558. CrossrefPubMed91. . Novel gastroretentive floating pulsatile drug delivery system produced via hot-melt extrusion and fused deposition modeling 3D printing. Pharmaceutics 2020;12:52. CrossrefPubMed92. Investigations of process parameters during dissolution studies of drug loaded 3D printed tablets. J 2021;235:523–529. Crossref93. Development of controlled porosity polymer-ceramic composite scaffolds via fused deposition modeling. 2003;23:611–620.

Output: corroborate


Input: Claim: Gene editing is completely risk-free with no side effects. [SEP] Text: 16595/supp-6 vector sequence for PF3D7_0417200 (DHFR-TS) gene editing Color key:- Yellow: unique 6 bp restriction sites; Cyan: 3x haemagglutinin (HA) epitopes; Gray: RNA spacer; Red: glmS riboswitch (Bacillus subtilis); Dark blue: Plasmodium berghei DHFR-TS terminator; Blue: Plasmodium falciparum histidine-rich protein 2 terminator; Green: Blasticidin-S-deaminase open reading frame; Brown: Plasmodium falciparum calmodulin promoter; Magenta: DHFR-TS 3′homology region; Purple: DHFR-TS 5′homology region; Black: recodonized DHFR-TS. DOI: 10. 7717/peerj. 16595/supp-7 vector sequence for PF3D7_1233700 (MS) gene editing Color key:- Yellow: unique 6 bp restriction sites; Cyan: 3x haemagglutinin (HA) epitopes; Gray: RNA spacer; Red: glmS ribozyme (Bacillus subtilis); Dark blue: Plasmodium berghei DHFR-TS terminator; Blue: Plasmodium falciparum histidine-rich protein 2 terminator; Green: Blasticidin-S-deaminase open reading frame; Brown: Plasmodium falciparum calmodulin promoter; Magenta: MS 3′homology region; Purple: MS 5′homology region; Black: recodonized MS. DOI: 10. 7717/peerj. 16595/supp-8 blot raw data Raw data from western blotting shown in Fig. 3A. DOI: 10. 7717/peerj. 16595/supp-9 assay raw data Raw data from proliferation assay shown in Fig. 3B. DOI: 10. 7717/peerj. 16595/supp-10 We thank Prof. (Chulalongkorn University, Bangkok, Thailand) for the gift of WR99210 and Dr. (Crick Institute, London, UK) for transfection plasmids and protocols. authors declare there are no competing interests.

Output: contrast


Input: Claim: Disruption of circadian rhythms can lead to health issues. [SEP] Text: also measures head movements with solid-state accelerometers to characterize behavioral activity. Detailed information about the Daysimeter is available elsewhere [20]. Figure 1 Daysimeter and functional block diagram. Figure 2 Spectral response graph. Spectral response functions generated from the model of human circadian phototransduction by Rea et al. [22]. The dashed line represents the predicted spectral response function for an equal energy spectrum light source. The continuous line represents the predicted spectral responses to individual, narrow-band light sources. The two sets of symbols represent empirical spectral response data from two independent laboratories [34, 35]. Figure 3 Logistic transfer function graph. Logistic transfer function relating nocturnal melatonin suppression to the rectified circadian light stimulus (CS) from the model of human circadian phototransduction by Rea et al. [22]. Data from several studies using both narrow-band [34, 35] and polychromatic light sources [36–38] to induce nocturnal melatonin suppression were plotted as a function of CS. A logistic function from Zeitzer et al. [23] was used to fit the data yielding a regression coefficient (r2) for the transfer function equal to 0. 82. Figure was adapted from Rea et al. [22]. It should be emphasized that activity as measured by the Daysimeter is not a direct measure of the endogenous clock in the SCN. Like every downstream measure of circadian function, behavior can only yield partial insight into circadian entrainment. It is presently impossible to directly measure SCN activity in vivo, and thus it is impossible to measure entrainment in the purest sense in living and active humans; the term "behavioral entrainment" is used in this paper to describe the observed levels of synchrony between light-dark exposures and activity-rest responses as measured by the Daysimeter. Data collection was sent to nurses throughout the to measure their actual CS exposures and activity for seven consecutive days. Forty-three pre-menopausal female nurses, both day-shift (n = 32) and rotating-shift nurses (n = 11), participated in the study. They wore the Daysimeter for seven consecutive days and were scheduled to work at least two and no more than three consecutive days during that period. was worn while nurses were awake. The nurses were instructed to place the Daysimeter next to them when they slept or bathed.

Output: pass


Input: Claim: 3D printing allows for customized, on-demand manufacturing. [SEP] Text: 3D-printed poly lactic acid scaffolds with tetrapod-interlocked structure containing dipyridamole. 2020;28:5–8. Crossref107. Fused deposition modeling of poly (lactic acid)/macadamia composites-thermal, mechanical properties and scaffolds. Materials (Basel) 2020;13:258. CrossrefPubMed108. . Fabrication and characterization of poly lactic acid scaffolds by fused deposition modeling for bone tissue engineering. 2020;35:248–251. Crossref109. Calcium phosphate-PLA scaffolds fabricated by fused deposition modeling technique for bone tissue applications: Fabrication, characterization and simulation. 2020;46:2447–2456. Crossref110. 3D printed scaffolds with random microarchitecture for bone tissue engineering applications: Manufacturing and characterization. J 2020;103:103583. CrossrefPubMed111. Rapid development of dual porous poly(lactic acid) foam using fused deposition modeling (FDM) 3D printing for medical scaffold application. 2020;110:110693. CrossrefPubMed112. 3D printed Sr-containing composite scaffolds: Effect of structural design and material formulation towards new strategies for bone tissue engineering. Technol 2020;191:108069. Crossref113. Sanz- Fabrication of 3d-printed biodegradable porous scaffolds combining multi-material fused deposition modeling and supercritical CO2 techniques. Nanomaterials 2020;10:1080. CrossrefPubMed114. Preparation and in vitro evaluation of PLA/biphasic calcium phosphate filaments used for fused deposition modelling of scaffolds. 2020;114:111013. CrossrefPubMed115. Fused deposition modeling of patient specific polymethylmethacrylate implants. J 2010;16:164–173. Crossref116. 3D printing of PEEK–cHAp scaffold for medical bone implant. Bio-Design Manuf. Published online 2020. Crossref117. Effect of processing conditions on the bonding quality of FDM polymer filaments. J 2008;14:72–80. Crossref118. Direct ink writing of three-dimensional ceramic structures. J Soc 2006;89:3599–3609. Crossref119. . Fused deposition modeling with polypropylene. 2015;83:768–776. Crossref120.

Output: corroborate


Input: Claim: Gene editing is completely risk-free with no side effects. [SEP] Text: 2021. Plasmodium falciparum LipB mutants display altered redox and carbon metabolism in asexual stages and cannot complete sporogony in Anopheles mosquitoes. for Parasitology 51:441-453. 2017. Functional profiling of a plasmodium genome reveals an abundance of essential genes. Cell 170:260-272. 2011. Methionine transport in the malaria parasite Plasmodium falciparum. for Parasitology 41:125-135. 1985. Nutritional requirements of Plasmodium falciparum in culture. I. Exogenously supplied dialyzable components necessary for continuous growth. of Protozoology 32:59-64 Espino-ía---. 2023. Direct tests of cytochrome c and c1 functions in the electron transport chain of malaria parasites. Proceedings of the of Sciences of the of America 120:e2301047120. 2004. Structures of the N-terminal modules imply large domain motions during catalysis by methionine synthase. Proceedings of the of Sciences of the of America 101:3729-3736 ña. 2021. Prioritization of molecular targets for antimalarial drug discovery. ACS 7:2764-2776 -Rubio J-J. 2014. Genome editing in the human malaria parasite Plasmodium falciparum using the -Cas9 system. 32:819-821 -Luís. 2023. Sexual differentiation in human malaria parasites is regulated by competition between phospholipid metabolism and histone methylation. . 2019. Plasmodium Niemann-Pick type C1-related protein is a druggable target required for parasite membrane homeostasis. ELife 8:e40529. 2017. Generating conditional gene knockouts in Plasmodium—a toolkit to produce stable recombinase-expressing parasite lines usingCas9. 7:3881. 1989. Characterization of cobalamin-dependent methionine synthase purified from the human malarial parasite, Plasmodium Falciparum. 75:512-517. 2023. OrthoDB v11: annotation of orthologs in the widest sampling of organismal diversity. Research 51:D445-D451 Mancio-. 2022.

Output: contrast


Input: Claim: Disruption of circadian rhythms can lead to health issues. [SEP] Text: After the seven-day recording session, they returned the device for data analyses. In addition to wearing the Daysimeter, participating nurses provided urine samples, obtained every four hours, for subsequent melatonin assay and filled out a chronotype questionnaire [Horne-Östberg Morningness-(MEQ)] and a lighting survey. The nurses were also asked to keep a sleep log, writing down the times they went to bed and any other information about their sleep schedules. These sleep logs were used to match the exact time nurses started wearing the device. Presented here are only the Daysimeter data. Measuring and characterizing circadian behavioral entrainment patterns in nocturnal rodents Data collection Forty albino female Sprague-Dawley rats (Rattus norvegicus) were housed in individual cages illuminated by a lighting system previously developed by Bullough et al. [24] to determine the spectral and absolute sensitivities of another nocturnal rodent (murine). Based upon the mouse phase response curve (PRC) obtained in that study, a spectral power distribution (nearly monochromatic green light; λmax = 525 nm, half-bandwidth = 35 nm) and irradiance (approximately 5 μW/cm2 on the cage floor) were selected to provide the light stimulus to the Sprague-Dawley rats. This particular light stimulus for nocturnal rodents was estimated to be above threshold and below saturation for stimulation of the rat circadian system. The light stimulus for the rats was precisely controlled using a light-emitting diode (LED) light-delivery system fabricated and installed in every cage. The light-delivery system provided better controlled and more biologically meaningful circadian light stimulation to the rats than the fluorescent ceiling lighting traditionally used to provide bright, ambient illumination throughout an animal colony [21]. As with the nurse data, the rat data were obtained from two experimental groups: 20 rats were exposed to a consistently repeating pattern of 12 hours of light (12L) followed by 12 hours of darkness (12D), and another 20 rats (the "jet-lagged" group) were exposed to a 12L:12D pattern where the phase of the light-dark cycle was reversed every 48 hours (as if this group of rats instantly travelled back and forth from Asia to the Americas every other day). Animals were housed individually and allowed to eat and drink ad libidum.

Output: pass


Input: Claim: 3D printing allows for customized, on-demand manufacturing. [SEP] Text: Multi-material bio-fabrication of hydrogel cantilevers and actuators with stereolithography. 2012;12(1):88–98;CrossrefPubMed55. Fully 3D-printed soft robots with integrated fluidic circuitry. 2021;7(29):eabe5257;CrossrefPubMed56. 3D printing for soft robotics—A review. 2018;19(1):243–262;CrossrefPubMed57. . 3D printing of soft robotic systems. Mater 2018;3(6):84–100;Crossref58. . A review on stereolithography and its applications in biomedical engineering. Biomaterials 2010;31(24):6121–6130;CrossrefPubMed59. Additive manufacturing with stimuli-responsive materials. J A 2018;6(42):20621–20645;Crossref60. Continuous liquid interface production of 3D objects. Science 2015;347(6228):1349–1352;CrossrefPubMed61. Design and optimization of a light-emitting diode projection micro-stereolithography three-dimensional manufacturing system. Instrum 2012;83(12):125001. CrossrefPubMed62. Two-photon polymerization initiators for three-dimensional optical data storage and microfabrication. Nature 1999;398(6722):51–54;Crossref63. One-step volumetric additive manufacturing of complex polymer structures. 2017;3(12):eaao5496;CrossrefPubMed64. High-precision stereolithography of biomicrofluidic devices. Technol 2019;4(6):1800395;CrossrefPubMed65. Projection micro stereolithography based 3D printing and its applications. 2020;2(2):022004;Crossref66. Li ZX, Diller E. Multi-for. In: 2022 5th on Manipulation, Automation, and Robotics at Small Scales. IEEE: Toronto, ON, Canada; 2022; 6. Crossref67. , Highly stretchable hydrogels for UV curing based high-resolution multimaterial 3D printing. J B 2018;6(20):3246–3253;CrossrefPubMed68. Recent trends and innovation in additive manufacturing of soft functional materials. Materials 2021;14(16):4521;CrossrefPubMed69.

Output: corroborate


Input: Claim: Gene editing is completely risk-free with no side effects. [SEP] Text: is Open Access? is an initiative that aims to make scientific research freely available to all. To date our community has made over 100 million downloads. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. As PhD students, we found it difficult to access the research we needed, so we decided to create a new publisher that levels the playing field for scientists across the world. How? By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers. are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including winners and some of the world’s most-cited researchers. Publishing on IntechOpen allows authors to earn 10. 5772/intechopen. 85499 this 1. Choose citation style Select style to clipboard Get citation 2. Choose citation style Select format Bibtex RIS Download citation Intech by Yuan-From the - Technologies and by Yuan-and Shiu-purchase hard copies of this book, please contact the representative in India: CBS Publishers & Distributors Pvt. Ltd. www. cbspd. com | customercare@cbspd. com 1. Choose citation style Select style to clipboard Get citation 2. Choose citation style Select format Bibtex RIS Download citation Impact of this 1. IntroductionGene editing is a type of genetic engineering in which DNA is inserted, deleted, modified, or replaced in the genome of a living organism. Unlike traditional methods that randomly insert genetic material into a host genome, current gene editing technologies target and change the specific genome locations. Zinc finger nucleases (ZFNs), transcription activator-like effectors nucleases (TALENs), and clustered regularly interspaced short palindromic repeats ()/Cas9 nuclease system are the three common gene editing technologies. These technologies have been widely used in genome engineering to enable a broad range of mutation by inducing DNA breaks that stimulate error-prone repairs such as homologous recombination (HR) or nonhomologous end joining (NHEJ). They successfully make it possible to achieve site-specific editing, modification, and manipulation at specific genomic sites (Table 1) [1].

Output: contrast


Input: Claim: Disruption of circadian rhythms can lead to health issues. [SEP] Text: The activity and the transformed CS data can be considered as two time-varying signals whose time-matched values can be multiplied together and then the products at every time of data acquisition integrated into a single value. This value is proportional to the covariance of the two signals. When normalized by dividing by the number of data samples, subtracting the product of the individual signal means, and dividing by the product of the standard deviations of each signal, the result will always be limited to values between -1 and 1 (i. e. , a correlation coefficient). The multiply-and-integrate operation can be repeated following a small shift in time by one of the signals (e. g. , the activity trace, Figure 4a) with respect to the other (e. g. , the transformed CS trace, Figure 4c) and a new correlation coefficient computed. Continuously repeating this process for the entire recording period yields a new time-varying function, the circular cross-correlation, bounded by -1 and 1, that reveals the degree to which the two signals are systematically related to one another for all possible alignments of phase between the two signals. This operation is adapted from standard signal processing techniques [25], and when performed on the periodic light and activity data, yields what are termed, for the purposes of this paper, behavioral entrainment-correlation functions. Figure 6 shows two behavioral entrainment-correlation functions relating the transformed CS data to the activity data: one for the day-shift nurse (Figure 6a) and one for the rotating-shift nurse (Figure 6b) in Figure 4. As can be readily appreciated from Figure 6a, the activity of the day-shift nurse is highly entrained to her light-dark pattern throughout the seven days, as exhibited by the regularly oscillating, 24-hour period of her behavioral entrainment-correlation function. More specifically, this nurse, typical of almost all day-shift nurses, has a peak correlation near the zero-phase marker and again at every 24-hour multiple. This day-shift pattern is in marked contrast to the behavioral entrainment-correlation pattern for the rotating-shift nurse (Figure 6b). Her pattern is aperiodic, exhibiting minor correlation peaks at times other than at the 24-hour phase markers.

Output: pass


Input: Claim: 3D printing allows for customized, on-demand manufacturing. [SEP] Text: IntroductionConstruction 3D printing has evolved into a comprehensive research field during the last two decades and has started impacting the building industry. What began as an appropriation of rapid prototyping for disaster relief is today a thriving community of academic and commercial actors who advance the technology and materials, achieving new records of printed structures at an accelerating pace. 1,2 The primary motivation behind these efforts relies on the potential offered by construction 3D printing and robotic fabrication to help mitigate the biggest challenges in the building industry and reduce material use, embodied carbon emissions, hazardous labor, and costs. 3,4Concrete 3D printing is a disruptive technology in this context because of the high compressive strength of the resulting prints and the potential to save resources by fabricating geometrically optimized, material-efficient structures that were previously cost-prohibitive with conventional building techniques. 5 Although these are urgent and laudable developments, concrete 3D printing has still not expressed its full potential. In fact, printed structures commonly feature simple geometric shapes that are not optimized for material efficiency, print materials often have a higher carbon footprint than regular concrete, and printing equipment is not readily available or only at a high initial cost. 6In contrast to construction applications requiring pure strength, foam 3D printing (F3DP) enables the automated and moldless fabrication of lightweight and insulating building elements. 7 Using the properties of porous printing materials allows to create novel building components that require fewer materials to make, have a lower embedded carbon footprint and mass, and help to decrease the operational energy for heating and cooling. Therefore, F3DP can contribute to significantly reduce the emissions of both material and energy consumption in the building industry. State-of-the-artAutomated construction techniques involving foamed materials have been documented since the early 1960s. The porous insulating materials used in the field of F3DP can be categorized into two distinct types: organic and inorganic foams. The first is commonly recognized as plastic foams, such as polystyrene (PS) or polyurethane (PU), and the second encompasses various cementitious, clay-based, and geopolymer foams. Regarding environmental sustainability, inorganic foams are regarded as the superior choice due to their reliance on nonpetroleum-based raw materials. In addition, they conventionally do not present any toxic emissions and are inherently nonflammable. Several recent projects explored F3DP in construction with plastic foams.

Output: corroborate


Input: Claim: Gene editing is completely risk-free with no side effects. [SEP] Text: /Cas9SourceExtensively exists in the naturePlant pathogenic bacteria XanthomonasAn adaptive immune system in bacteriaTargeting specificity determinantZinc finger protein9Restriction for a target sequenceRich in cytosineNo special restrictionPAMTarget siteTwo (left and right)Two (left and right)Only oneLength of target gene12–18 bp12–18 bp18–23 bpMode of actionTwo proteins act on two target sitesTwo proteins act on two target sitesRNA and Cas9 act on one target siteCleavage siteDSB with a sticky endDSB with a sticky endDSB with a blunt endEfficiencyMediumMediumHighEase of engineeringLowMediumHighEase of characterizationtargetYesYesYesTable 1. Comparison of different gene editing technologies. Abbreviations: clustered regularly interspaced short palindromic repeat; DSB, double-strand break; Fok, Flavobacterium okeanokoites; PAM, protospacer adjacent motif; TALE, transcription activator-like effector; sgRNA, single guide RNA; and ZFN, zinc finger nuclease. 1. 1 are artificial restriction enzymes generated by fusing a zinc finger-specific DNA-binding domain to a nonspecific DNA cleavage domain. The specific binding domains of individual ZFNs typically contain between three and six individual zinc finger repeats and can each recognize between 12 and 18 base pairs. If the zinc finger domains are specific for their intended target site, then even a pair of three-finger ZFNs that recognize a total of 18 base pairs can target a single locus in a mammalian genome. The nonspecific cleavage domain from the restriction endonucleaseis typically used as the cleavage domain in ZFNs. This cleavage domain must form a dimer in order to cleave DNA, and thus a pair of ZFNs are required to target nonpalindromic DNA sites [2] (Figure 1). Figure 1. ZFNs are chimeric nucleases consisting of specific DNA-binding modules linked to a nonspecific cleavage domain. Right and left ZFNs containing endonucleases link to an array of 3–6 zinc fingers that have been designed to specifically recognize target sequences (12 green and 12 purple boxes), respectively. The ZFN targets are separated by typically 5 or 6 bp.

Output: contrast


Input: Claim: Disruption of circadian rhythms can lead to health issues. [SEP] Text: This shift reflects the expected difference between a diurnal and a nocturnal species; diurnal nurses are active during the day and inactive at night, whereas nocturnal rats are inactive during the light phase and active in the dark. Figure 6d shows a typical behavioral entrainment-correlation function for one rat in the "jet-lagged" group. Again, there is a marked similarity between the entrainment-correlation functions for the rotating-shift nurse in Figure 6b and for the "jet-lagged" rat in Figure 6d. Phasor representations of circadian behavioral entrainment Plots of the behavioral entrainment-correlation functions for the day-shift nurses generally exhibit smooth, oscillating curves whereas those of the rotating-shift nurses exhibit much more irregular patterns. Estimates of the relationship between activity-rest and light-dark in terms of magnitude and phase can be determined for both groups of nurses through Fourier decomposition and spectral analysis of the behavioral entrainment-correlation functions. Phasors represent the magnitude and phase relationship between the activity-rest data and the light-dark data that underlie the entrainment-correlation functions for a particular spectral component obtained from the Fourier decomposition [26]. Since the 24-hour spectral component is of special interest in studies of circadian entrainment, the activity and light data for every nurse were first parsed into seven equal 24-hour periods. The behavioral entrainment-correlation functions were then calculated for each of these seven periods after which the seven corresponding phasors representing the frequency component corresponding to a 24-hour periodicity, f(24) for every one of the 43 nurses were determined. It should be noted that a systematic investigation of periods ranging from 22 to 26 hours in 10-minute increments was conducted for the day-shift nurse data. While the range of peak phasor amplitudes occurred for periods ranging from 23. 7 to 24. 56 hours as determined from quadratic curve-fits to the phasor magnitude versus period data, the mean was 24. 035 hours, supporting the significance of the 24-hour period for this analysis. Complex arithmetic [27] was then used to determine the average (n = 7) phasor for a given nurse and these average phasors for all the nurses are plotted in Figure 7a in polar coordinates.

Output: pass


Input: Claim: 3D printing allows for customized, on-demand manufacturing. [SEP] Text: Researchers developed an autonomous robotic fabrication platform, including a PU spray printing system, and demonstrated the fabrication of an architectural-scale hemi-ellipsoidal dome section spanning 14. 6 m in diameter. 8 In Nantes, researchers of the BatiPrint project printed the stay-in-place molds for concrete casting of a 95 m2 building using automatic spray printing of PU foam. 9 Plastic foams are often used as filler in printed structures such as hollow walls and spatial lattices to increase the thermal resistance of the finished building component. Alternatively, bio-based, renewable alternatives are investigated in research on large-scale F3DP of composite structures and are envisioned to solve the sourcing problem of organic foams. 10Complementary to organic foams, inorganic counterparts have also found their way into large-scale F3DP research. Cement foams are the most commonly investigated material, and their formulations, properties, and applications are extensively explored. 11 Researchers used lightweight cement-based foams to fabricate wall elements with cellular cross-sections to optimize their insulation properties. 12 Functional grading with different densities of cement foams was demonstrated for robotic F3DP with the potential application for ribbed slab and cavity wall elements. 13However, the cement content significantly increases the embedded carbon footprint of these structures, and alternatives could be researched. For example, clay-based foams sintered for consolidation were used with F3DP in another study to produce hierarchical porous ceramic bricks with programmed thermal insulation and evaporative cooling effects. 14 Sintered mineral foams were utilized with F3DP to show their potential combined with concrete for facade and beam structures. 15 The energy-intensive sintering step could be omitted using set-on-demand geopolymer-hardened mineral foam to 3D print the functional stay-in-place formwork of a ribbed concrete slab prototype. 16ContributionThis 2. Consequently, the base slurry can be prepared as a big batch and used gradually for a day-long F3DP experiment. FIG. 1. (a) The effect of retarder addition measured with calorimetry. The FX_ref is the reference slurry without retarders. FX_r1 and FX_r2 mixes contain different amounts of retarder. (b) Slump tests over time of hardening slurries (Representation with lines as visual guides).

Output: corroborate


Input: Claim: Gene editing is completely risk-free with no side effects. [SEP] Text: I work as a homodimer to cleave the sense strand 1 bp and antisense strand 5 bp downstream of the binding site. 1. 2 activator-like effectors (TALEs) are proteins secreted by bacteria Xanthomonas via type III secretion system when they infect various plant species. TALEs are important virulence factors that act as transcriptional activators in the plant cell nucleus [3]. Each TALE contains a central repetitive region consisting of varying numbers of repeat units (about 17. 5 repeats) of 34 amino acids [3, 4]. The DNA-binding domain contains a highly conserved 34 amino acid sequence with the exception of the 12th and 13th amino acids [3]. Only the 12th and 13th amino acids in TALEs are changeable and variable, the other amino acids are constant and stable. These two locations—repeat variable di-residues (RVD) are highly variable and show a strong correlation with a specific nucleotide recognition by different frequency, for example, NI recognize A (55%), NG recognize T (50%), NN recognize G (7%), and HD recognize C(69%) [3]. Two amino acids have known to recognize one nucleotide after the breaking of code of DNA-binding specificity of TALEs [3, 4]. The restriction endonuclease consists of an N-terminal specific DNA-binding domain and a C-terminal nonspecific DNA cleavage domain. The nonspecific DNA cleavage domain of cleaves the double-strand DNA (DSB) at a fixed distance of 9 and 13 nucleotides downstream of the recognition site [5]. TALENs are artificial restriction enzymes generated by fusing the specific -binding domain to a nonspecific DNA cleavage domain [6, 7, 8] (Figure 2). Figure 2. The specific repeat variable Di-residues (RVDs) used to recognize each base are defined in the key (NI:A, NG:T, NN:G, and HD:C). Left and right TALEs recognize their target sequences and allow their associated endonucleases to work as a homodimer to cleave the sense strand 9 bp and antisense strand 13 bp downstream of the binding site.

Output: contrast


Input: Claim: Disruption of circadian rhythms can lead to health issues. [SEP] Text: Phasors compared to other measures of circadian behavioral entrainment Considering only the degree of behavioral entrainment, Figure 9 shows the distribution of the f(24) phasor magnitudes for the two groups of nurses (Figure 9a) and for the two groups of rats (Figure 9b). Figure 9a shows a clear and statistically significant difference between the day-shift and rotating-shift nurse groups with widely separated group means and medians. Nevertheless, there is some overlap of the distributions, perhaps reflecting a true continuum of the degree of circadian behavioral-entrainment among individuals. The data from the rats in Figure 9b also show a clear and statistically significant separation, but undoubtedly because of the two radically different light-dark patterns, there is no overlap in the phasor amplitudes for these two groups of rats. Figure 9 Phasor magnitudes for the day-shift, and rotating-shift nurses (a) and for the two groups of rats (b). The interdaily stability (IS) and the intradaily variability (IV) statistics [29] have been used in numerous studies as measures of behavioral entrainment, or more precisely the coupling between rest-activity rhythms and assumed exogenous zeitgebers, or time givers [30 - 32]. Unlike the phasor analysis, these two statistics are computed based solely on activity and cannot be used to assess the phase relationship between measured activity and the actual light zeitgeber. It is possible, however, to compare phasor magnitudes (Figure 9) and IS values by using the same sets of activity data as estimates of circadian entrainment. The distribution of the IS statistic was calculated from the activity data from nurses (Figure 10a) and from rats (Figure 10b). The two groups of nurses and the two groups of rats were significantly different in terms of their IS values. The ratio of the mean IS values for the two groups of nurses (2. 6) and the ratio of the mean IS values for the two groups of rats (2. 0) are similar to, but smaller than the ratios of the mean phasor magnitudes for the comparable groups shown in Figure 9 (3. 2 for nurses and 4. 9 for rats).

Output: pass


Input: Claim: 3D printing allows for customized, on-demand manufacturing. [SEP] Text: com/25255-3d-printing-made-usa. html (last accessed 10/30/2013). 22. Davidson P. 3D printing could remake U. S. manufacturing. USA Today; July 10, 2012; (last accessed 10/30/2013). 23. “3D Printing and the Future of Manufacturing. ” Forum; Fall 2012; at 10. (last accessed 10/30/2013). 24. Freedman DH. Layer by layer: with 3-D printing, manufacturers can make existing products more efficiently—and create ones that weren't possible before. MIT Technology Review; January/February 2012; (last accessed 10/30/2013). 25. Park R. Going large on 3D printed aerospace parts. 3D Printing Industry; January 24, 2013; (last accessed 10/30/2013). 26. GE Aviation acquires Manufacturing. November 20, 2012; www. geaviation. com/press/other/other_20121120. html (last accessed 10/30/2013). 27. Zelinski P. The future of manufacturing. Shop; July 3, 2012; www. mmsonline. com/28. ; “? ”; Shop; January 2, 2013; www. mmsonline. com/columns/why-did-ge-aviation-acquire-morris-technologies (last accessed 10/30/2013). 29. Peels J. is going to 3D print aircraft engines. i. Materialise; December 24, 2010; (last accessed 10/30/2013). 30. “3D Printing and the Future of Manufacturing. ” Forum; Fall 2012; at 12. (last accessed 10/30/2013). 31. Staff writer. World's first 3D printed Formula race car tested in Hockenheim. 3D Printing Industry; August 31, 2012; (last accessed 10/30/2013). 32. Vesanto J. 3D printed DB5 replicas. 3D Printing Industry; November 16, 2012; (last accessed 10/30/2013). 33. “3D Printing and the Future of Manufacturing. ” Forum; Fall 2012; at 12–13. (last accessed 10/30/2013). 34. Maxie K. Chinese Dr. creates 3D printed skull implant.

Output: corroborate


Input: Claim: Gene editing is completely risk-free with no side effects. [SEP] Text: Binding of TALEs to the target sites allows to dimerize and create a double-strand break (DSB) with sticky ends within the spacer. 1. 3Cas9/Cas9 system, originally found in the bacteria, functions as an adaptive immune system against foreign virus or plasmid DNA. are DNA loci containing short repetitions of base sequences. Each repetition is followed by short segments of spacer DNA from previous exposures to the foreign DNA. -associated protein (Cas9) is a DNA endonuclease whose structure is bilobed, composed of target recognition domain and nuclease lobes. The nuclease lobe contains nucleases RuvC, HNH, and a carboxyl-terminal domain for the protospacer adjacent motif (PAM) recognition [9]. system is currently limited to target sequences that are N12-20NGG, where NGG represents the PAM sequence [10]. Any potential target sequence must have a specific PAM sequence on its 3′ end. locus consists of Cas9 endonucleases, (crRNAs), trans-activating crRNAs (tracrRNAs), and precursor crRNAs (pre-crRNAs). tracrRNA is partially complementary to and pairs with a pre-crRNA to form an RNA duplex cleaved by RNase III. The crRNA/tracrRNA hybrid acts as a single guide RNA (sgRNA) for the Cas9, which cleaves the invading DNA. The DNA target sites can appear in multiple locations, all of which will be targeted by the Cas9 for cleavage. By delivering the Cas9 protein and appropriate sgRNAs into a cell, the organism’s genome can be cut at most locations with the only limitation of PAM availability (Figure 3). Figure 3. A crRNA/tracrRNA hybrid acts as a single guide RNA (sgRNA) to recognize their target sequences and allow Cas9 endonucleases to cleave the sense strand 3 bp and antisense strand 3 bp upstream of the protospacer adjacent motif (PAM) sequence. Binding of sgRNAs to the target sites makes Cas9 create a double-strand break (DSB) with blunt ends on target sequences. Advertisement 2. Application2. 1 Tools for basic research2. 1.

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: Activity patterns of grass rats were monitored in 12:12 light-dark (LD) conditions (300 lux of white light during the light phase) for at least 10 days prior to surgery. Animals were randomly assigned to either a vSPVZ-lesioned group or a sham control group and allowed to recover from surgery for at least 2 weeks under a 12:12 LD cycle. Animals were then tested for their masking response to light using a previously described procedure (Shuboni et al. , 2012). Briefly, animals were placed in constant darkness (DD) for 2 days and received a 1-h light pulse (LP) on the second day in DD. They were returned to a 12:12 LD cycle for 2 days, and the procedure was repeated for the other 3 LPs. Each animal received a total of 4 LPs at circadian times (CTs, CT0 = activity onset) 6, 14, 18, and 22. The order of LPs was randomized. Next, animals were exposed to an ultradian light-dark cycle, in which they received 3. 5 h of light followed by 3. 5 h of darkness repeatedly for 9 days. Finally, animals were placed back in a 12:12 LD cycle until all animals reentrained. Then, circadian rhythms were examined by placing animals in DD for at least 2 weeks, followed by constant light (LL) for at least 2 weeks. Animals were then sacrificed and brains were collected for histological assessment of the lesions. Surgical ProceduresGrass rats were anesthetized with isoflurane (2. 5%-5%; ) and secured in a stereotaxic apparatus (Stoelting Co. , ) with the tooth bar set to −4. 5 mm. Animals were injected subcutaneously with ketoprofen (5 mg/kg body weight). The top of the head was shaved, disinfected with betadine, and injected subcutaneously with lidocaine (0. 03 mL). An incision was made in the scalp to expose the surface of the skull. Using a surgical drill, 2 small holes were made at the following coordinates: anterior-posterior (AP): +0. 16 mm from bregma; medial-lateral (ML): ±0. 05 mm from the midline; dorsal-ventral (DV): –6. 0 to −6.

Output: pass


Input: Claim: 3D printing allows for customized, on-demand manufacturing. [SEP] Text: Engineering. com 3D Printing; September 9, 2013; www. engineering. com/3DPrinting/3DPrinting35. Staff writer. A custom artificial heart. Maker Faire; 2013; (last accessed 10/30/2013). 36. Heater B. Cornell scientists 3D print ears with help from rat tails and cow ears. Engadget; February 22, 2013; www. engadget. com/2013/02/22/3d-printed-ear/ (last accessed 10/30/2013). 37. Maxie K. Artificial human ear printed from sheep cells. Engineering. com 3D Printing; August 5, 2013; www. engineering. com/3DPrinting/3DPrinting38. Molitch-Hou M. The “six million dollar” ear. 3D Printing Industry; May 6, 2013; (last accessed 10/30/2013). 39. Kuneinen E. Medical application: 3D printing a new nose. 3D Printing Industry; November 12, 2012; (last accessed 10/30/2013). 40. “3D Printing and the Future of Manufacturing. ” Forum; Fall 2012; at 13. (last accessed 10/30/2013). 41. Park R. New micro DSP 3D printing solution for the hearing aid market. 3D Printing Industry; October 27, 2012; (last accessed 10/30/2013). 42. Pirroni R. Clear3D printed digital orthodontics capacity by 30%. 3D Printing Industry; May 10, 2013; (last accessed 10/30/2013). 43. Staff writer. Medical success with 3D printing. 3D Printing Insider; (last accessed 10/30/2013). 44. Clark L. Bioengineers 3D print tiny functioning human liver. Wired. co. uk; April 13, 2013; www. wired. co. uk/news/archive/2013-04/24/3d-printed-liver; www. organovo. com (last accessed 10/30/2013). 45. Molitch-Hou M. 3D bioprinting: now with human embryonic stem cells. 3D Printing Industry; February 6, 2013; (last accessed 10/30/2013). 46. Kuneinen E. 3D printing a vaccine?

Output: corroborate


Input: Claim: Gene editing is completely risk-free with no side effects. [SEP] Text: 1 Genetic cloning of living organismsFor conventional genetic cloning of animals, plants, and microbes, the target genes in the specific genome are cut using restriction enzymes. It usually takes lots of work and long time to clone and screen for the desired ones. Current gene editing technologies can be used to achieve the desired clones both quickly and accurately, without the limitation of restriction site availability [11]. 2. 1. 2 Establishment of animal modelsGenetic cloning, gene knock-in, and gene knockout are the most common methods to make induced or experimental animal models. The efficient approaches include andCas9. By these new gene editing technologies, specific animal models of many diseases for which there are no animal models available previously have been established with unprecedented efficiency and precision [12, 13, 14]. 2. 1. 3 Development of testing tools and reagents/Cas9 can be optimized by bacterial genotypes to be more adaptive to the variation of food pathogens, compared with traditional methods. locus of different bacterial species show high variance to be an ideal basis for genotyping [15]. /Cas12a(Cpf1) (DNA endonuclease targeted trans reporter) system can be used to diagnose gene mutations, cancers, and microbial infections and test microbial antibiotic resistance by analyzing specimens [16]. 2. 1. 4 Discovery of drugsThe screening and identification of target sites are critical to drug discovery; thus, excellent and suitable platforms are needed. Gene editing technologies can work for the editing of functional genes and the screening of target sites. For example,Cas9 was used to target the exons encoding functional protein domains. A screen of 192 chromatin regulatory domains in murine acute myeloid leukemia (AML) cells identified 6 known drug targets and 19 additional dependencies [17]. 2. 2 Nonhuman therapeutics2. 2. 1 Agricultural productsThe gene editing technology can be used to produce agricultural products in accordance with the need of humans. For example, crops were produced with high yield and resistant to diseases, insects, herbicides, and harsh environment [18, 19]; domesticated animals (pig, buffalo) were produced with double muscle phenotype [20]; and aquatic products (catfish) were produced with high level myostatin (MSTN) gene expression [21]. 2. 2. 2 FoodWe can make food more productive or have longer shelf-life by gene editing technologies.

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: 2 mm ventral to the dura. Injections were made using a 0. 5-µL Hamilton syringe () filled with either 0. 3 M NMA (Sigma, St. ) dissolved in 0. 2 M saline or a vehicle control, which consisted of 0. 2 M saline alone. The needle was lowered into the brain slowly until it reached the target coordinates and allowed to rest for 1 min before and after injection. Then, 180 nL of either NMA or saline was injected bilaterally using a manual stereotaxic microinjector (Stoelting Co. ) given over a 5-min period. The incision was closed using autoclips and the animals were injected subcutaneously with 2. 0 mL of 0. 9% sterile saline. At 24 and 48 h following surgery, all animals received Meloxicam (0. 1 mg/kg body weight) orally via a piece of apple. HistologyAt the end of the experiment, animals were euthanized at ZT2 with intraperitoneal injections of sodium pentobarbital () and perfused transcardially with 0. 01 M phosphate-buffered saline (PH), pH 7. 2, followed by 4% paraformaldehyde (PFA; Sigma-Aldrich) with 75 mM lysine (Sigma-Aldrich) and 10 mM sodium periodate (Sigma-Aldrich) in 0. 1 M phosphate buffer to make a periodate-lysine-paraformaldehyde solution (PLP). The brains were postfixed for 4 h in PLP, then transferred to a 20% sucrose solution (J. T. ) and stored at 4 °C for at least 24 h. Brains were sectioned in 30-µm coronal sections using a sliding microtome, separated into 3 series, and stored in cryoprotectant at −20 °C. One series was mounted onto gelatin-coated slides, stained for Nissl using a thionin protocol, and coverslipped with Permount (). The extent of the lesions was determined by 2 experimenters, who independently analyzed the tissue; brain sections were analyzed using a light microscope (Leitz, Wetzlar, Germany) equipped with a drawing tube at 5× magnification.

Output: pass


Input: Claim: 3D printing allows for customized, on-demand manufacturing. [SEP] Text: utm_source=iContact&utm_medium=email&utm_campaign=Hub%20Health&utm_content (last accessed 10/30/2013). 60. Staff writer. 3D printers could create customised drugs on demand. BBC New Technology; April 18, 2012; www. bbc. co. uk/news/technology-17760085 (last accessed 10/30/2013). 61. PARC. Printable and flexible electronics. www. parc. com/services/focus-area/flexible-and-LAE/ (last accessed 10/30/2013). 62. Wilson S. Printing of high quality transistors gets closer thanks to the University of Cambridge. Blorge; November 25, 2011; (last accessed 10/30/2013). 63. Kuneinen E. 3D printing personal electronics in the future with “Carbomorph”? 3D Printing Industry; December 20, 2012; (last accessed 10/30/2013). 64. Park R. The guys behind RepRap—always thinking ahead and now it's graphene. 3D Printing Industry; March 21, 2013; accessed 10/30/2013). 65. Staff writer. First demonstration of inkjet-printed graphene electronics. MIT Technology Review; November 24, 2011; (last accessed 10/30/2013). 66. Park R. Chiplets—3D printed electronic micro materials. 3D Printing Industry; April 10, 2013; accessed 10/30/2013). 67. Somasekharappa M. Additive manufacturing—the voxel method. 3D Printing Industry; April 30, 2013; (last accessed 10/30/2013). 68. Staff writer. Inside 3D brings reality to the hype. 3D Printing Insider; (last accessed 10/30/2013). 69. Anderson G. The future of 3D printing with Terry Wohlers. Engineering. com 3D Printing; September 9, 2013; www. engineering. com/3DPrinting/3DPrinting70. Kirsner S. A 3D printer in every home? BostonGlobe. com; October 20, 2013; www. bostonglobe. com/business/2013/10/19/printer-every-home/ttvYYbjw6zHxb0YrScn6mJ/story.

Output: corroborate


Input: Claim: Gene editing is completely risk-free with no side effects. [SEP] Text: For example,Cas9 was used to edit thermophilic bacteria Streptococcus thermophilus as a bacteriophage-insensitive mutant to improve the product (e. g. , yogurt, cheese) yield by refraining from the infection of phages [22]. The white button mushroom Agaricus bisporus was engineered to resist browning usingCas9. The effect was achieved by targeting to knock out the genes that encodes polyphenol oxidase—an enzyme that causes browning [23]. 2. 2. 3 Industrial products/Cas9 has been used to establish marine algae (e. g. , diatoms) as useful in industrial applications as the carbon neutral synthesis of fuels, pharmaceuticals, health foods, biomolecules, materials related to nanotechnology, and bioremediations of contaminated water [24, 25]. /Cas9 was used to encode the pixel values of black and white images and a short movie into the living bacterial genomes. /Cas9, the technical limits of this information storage system can be optimized to be minimal. /Cas9 can capture and stably store many real data within the genomes of living cells [26]. 2. 2. 4 Environmental protectionMarine microalgae are in charge of about 40% of primary production on earth and capture more CO2 than rain forests. Diatoms are the most important unicellular eukaryotic microalgae and have dominant ecological significance. /Cas9 can be used to modify the diatom genome to achieve more effects in reducing the global warming [25]. 2. 2. 5 Restoration of extinct animalsWoolly mammoths are different from current living elephants by adapting to the extreme cold environment. The mammoth TRPV3 gene, which encodes a temperature-sensitive transient receptor potential (thermoTRP) channel involved in thermal sensation and hair growth, could be achieved by modifying genes of Asian elephants [27]. The mammoth may be restored usingCas9, if the modified embryo can be successfully transferred into the uterus of living elephants. 2. 3 Human therapeutics2. 3. 1 Medicine screeningThe therapeutic strategies of Parkinson’s disease (PD) are quite variable including drug and nondrug treatment. Therefore, it is necessary to find a suitable strategy to treat PD safely, efficiently, and quickly.

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: The lesioned area was drawn by both experimenters in one brain section that was rostral to the SCN; 3 sections that included the rostral, middle, and caudal SCN; and a fifth section caudal to the SCN. These drawings were compared between the 2 independent experimenters, and animals were classified as bilateral lesion, unilateral lesion, or miss. The experimenters were in 100% agreement in the classification of groups. To quantify the extent of the SCN and vSPVZ lesions, the number of Nissl-stained cells was counted bilaterally in the same 3 sections by an experimenter blind to condition using the Plugin in ImageJ software (version 1. 49; of ). The counting box for the vSPVZ (215-µm × 160-µm rectangle) was placed dorsal to the SCN (Shuboni et al. , 2015). The SCN of sham animals was traced and the average size for rostral, middle, and caudal sections was used to delineate the SCN in lesioned animals. We compared the total number of cells that remained in lesioned animals in the vSPVZ and SCN to the average number of cells counted in sham animals in these areas. In addition to the total number of cells, cell size was quantified by randomly selecting 50 cells and measuring the cell size using ImageJ’s Analyze P1. Histology from representative animals with bilateral vSPVZ damage (A), bilateral SCN + vSPVZ damage (B), and sham-operated grass rats (C). Thionin stained coronal sections through the extent of the SCN from rostral (left) to caudal (right). Outlined regions in black indicate the lesioned area. Scale bar represents 1 mm. Abbreviations: ocx = optic chiasm; SCN = suprachiasmatic nucleus; vSPVZ = ventral subparaventricular zone; 3V = third ventricle. Figure 2. Smallest and largest chemical lesions that destroyed the ventral subparaventricular zone bilaterally (A) and misses that left this area intact (B), seen in 4 coronal sections. Gray shaded areas indicate the largest sized lesion in each group; black shaded areas indicate the smallest sized lesion in each group.

Output: pass


Input: Claim: 3D printing allows for customized, on-demand manufacturing. [SEP] Text: (c) Final prototype. ResultsUsing the techniques described above, we successfully fabricated the following prototypes that showcase the type of geometries and print path geometries that can be achieved. The implementation of our work is available in the open-source python package compas_slicer,45 based on the libraries compas46 and libigl. 47 The geometries of the shapes were generated using the Grasshopper48 library Axolotl. 49The single-shell print method with continuous paths that we are using makes sense for printing at a larger scale of furniture or architectural components. The prototypes that we present in this section are scaled studies that address only the geometric aspects of the design of paths. The scale of the prototypes ranges from a height of 10 to 40 cm. The scale indication in the photos of prototypes represents centimeters. The models were sliced with an average layer height of ∼1. 4 mm, considering a constant layer width of 2. 5 mm. The different combination operations were tested on a simple bifurcating shape (Fig. 9). The paths generated using the standard union (Fig. 9a) have an abrupt change in orientation and layer height around the saddle point, which can be realized with significantly slower print speed around that area. The paths generated using the smooth union (Fig. 9b) are a lot easier to fabricate as their orientation and layer height vary smoothly; therefore, constant speed can be kept in the print process. The chamfer union (Fig. 9c) poses challenges due to the risk for collisions, as the almost-straight paths created from the chamfering meet in an extended area around the saddle point, where the tool can collide with paths from the other side. To avoid these collisions, the area around the saddle point was printed with an almost vertical tool orientation. Finally, the stairs' union (Fig. 9d) also poses fabrication challenges due to the nonsmooth changes in orientation and layer height around the peaks of the stair pattern. Another challenge in this union comes from the two additional maxima that appear, which create disconnected islands that need to be printed separately with lower print speed. However, with the correct tuning of print speed and print orientation, all combination operations are feasible, creating an aesthetic result that would not be possible with traditional slicing methods. FIG. 9. Fabrication of paths generated with different union operations. (a) Standard union. (b) Smooth union.

Output: corroborate


Input: Claim: Gene editing is completely risk-free with no side effects. [SEP] Text: A novel tool was established for monitoring endogenous alpha-synuclein (α-SYN) transcription by NanoLuc luciferase tag insertion at the 3′ end usingCas9, and thus making it possible to screen for strategies rapidly that can be used for PD therapy efficiently [28]. 2. 3. 2 Preparation for cell therapy or immunotherapyThe gene-editing technology can be applied to engineer induced pluripotent stem (iPS) cells and chimeric antigen receptor T (CART) cells. /Cas9 has been used to engineer iPS cells to evade immune rejection in full immunocompetent allogeneic recipients [29]. Because the CD19 CAR was successfully used in treatment,Cas9 may further enhance the efficacy and safety of CART cells by engineering therapeutic T cells [30]. 2. 3. 3 Potential application for disease treatment2. 3. 3. 1 Virus latent infectionDiseases caused by viruses are difficult to treat due to their high mutation rates and latent infections. It is almost impossible to eradicate latent viruses in the human host. andCas9 have been found to provide good strategies in targeting viruses and limiting their productive and latent infections ex vivo and/or in vivo, such as herpes simplex virus 1 (HSV-1), Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), human immunodeficiency virus (HIV), and hepatitis B virus (HBV) [31, 32, 33, 34, 35, 36]. 2. 3. 3. 2 Genetic diseaseGenetic diseases can be cured by gene therapies such as sickle cell anemia, β-thalassemia, muscular dystrophy, α1-antitrypsin deficiency, Leber congenital amaurosis, and cystic fibrosis [37]. The gene editing technologies (e. g. ,Cas9) potentially facilitate the progress of gene therapy, because many experiments have been successful ex vivo and in vivo, and some of them are being under clinical trials. 2. 3. 3. 3 Neurodegenerative diseaseBy applying the Interactions by (PRISM) to a yeast model of PD, sgRNAs were identified to modulate transcriptional networks and protect cells from α-Syn toxicity [38]. The APPswe (Swedish) mutation in the amyloid precursor protein (APP) gene causes Alzheimer’s disease (AD).

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: Abbreviations: f = fornix; ocx = optic chiasm; ot = optic tract; PVN = paraventricular nucleus; SCN = suprachiasmatic nucleus. Statistical AnalysisActivity data from VitalView software (Mini-Mitter) were viewed in (Microsoft Corp. , ) and analyzed statistically with SPSS (version 21; SPSS, Inc. , an ). To evaluate the effects of light pulses, activity counts from the same 1-h interval from the pulse day and preceding baseline day in DD were compared. A 3-way analysis of variance (ANOVA) was used to analyze the data with a 2 × 2 × 4 factorial design (surgical condition [sham vs. bilateral lesion] × lighting condition [baseline vs. 1-h pulse] × time of day [CT6, 14, 18, and 22]; surgical condition as the between-group factor and both lighting condition and time of day the within-group factors). This was followed up by analyzing each surgical group separately using 2-way repeated-measures ANOVAs to assess within-subject effects of lighting condition (darkness vs. light pulse) and time-of-day (CT6, 14, 18, and 22). Significant interactions were followed by evaluation of simple main effects of lighting condition using paired-samples t tests; simple main effects of time of day were evaluated using Tukey’s honestly significant difference test. Masking behavior during the ultradian LD cycle (3. 5 h light/3. 5 h dark) was assessed by comparing the total amount of activity that occurred during the light period with the total activity that occurred during the dark period. For the ultradian LD cycle, a 2-way mixed ANOVA was used to assess within-subjects effects of lighting condition (light vs. dark) and the between-subjects effects of surgical condition (sham vs. bilateral lesion). Significant interactions were followed by the evaluation of simple main effects of lighting condition and surgical condition using paired-samples t tests and independent-samples t tests, respectively. Masking behavior during DD and LL was assessed by comparing the total amount of activity that occurred in DD with the total activity that occurred in LL and dividing by the total amount of days in each condition.

Output: pass


Input: Claim: Quantum computing could revolutionize data encryption and processing. [SEP] Text: AbstractWe propose a homomorphic search protocol based on quantum homomorphic encryption, in which a client Alice with limited quantum ability can give her encrypted data to a powerful but untrusted quantum server and let the server search for her without decryption. By outsourcing the interactive key-update process to a trusted key center, Alice only needs to prepare and encrypt her original data and to decrypt the ciphered search result in linear time. Besides, we also present a compact and perfectly secure quantum homomorphic evaluation protocol for Clifford circuits, where the decryption key can be calculated by Alice with polynomial overhead with respect to the key length. Similar content being viewed by others Experimental quantum homomorphic encryption 1. In the quantum context, Sun proposed a quantum symmetric searchable encryption scheme for classical inputs2, in which encryption and decryption are rotations along a coordinate axis, and the secret key composes of random rotation angles. The search procedure of this scheme is to linearly check and compare the encrypted items, which is inefficient for a large search space. Intuitively, linear search on encrypted data could be accelerated by Grover’s algorithm3, provided that there exists an encryption method allowing quantum operations without the encryption key. Fortunately, quantum homomorphic encryption (QHE) satisfies this requirement, which intrigued us to take advantage of its merits and to construct a quantum homomorphic search protocol. The notion of QHE was first introduced by Liang4 in 2013, who observed the commutation rules between the encryption operators of quantum one-time pad (QOTP)5 and a universal set of quantum gates (containing rotation operators and CNOT gate) and demonstrated a symmetric one-party QHE scheme where homomorphic evaluations require the secret key. Later, he presented an interactive two-party scheme6 based on commutation rules for another universal gate set (consisting of and T gates). Aside from QHE, there are many other closely related constructions based on the combination of QOTP and commutation rules, such as secure assisted quantum computation7, quantum computing on encrypted data8, and delegating private quantum computations9, which could be considered as early forms of QHE. In 2014, Yu et al. 10 came up with a no-go result on QHE, which concludes that “quantum mechanics does not allow for efficient information-theoretically-secure fully homomorphic encryption scheme”.

Output: corroborate


Input: Claim: Gene editing is completely risk-free with no side effects. [SEP] Text: The mutant APPSW allele can be selectively disrupted usingCas9 both ex vivo and in vivo and thereby decrease pathogenic amyloid-β (Aβ) [39]. 2. 3. 3. 4Cas9 were tried to inhibit hepatocellular carcinoma (HCC). miR-125b can suppress the expression of SIRT6 by directly targeting the seed-matching region of its 3′UTR. After the expression of SIRT6 knocked out throughCas9, HCC cells showed the decreased viability and invasiveness, which had the similar function upon the overexpression of the miR-125b [40]. /Cas9 was also tried to inhibit breast cancer. Cyclin-dependent kinases (CDKs) are established anti-cancer drug targets, and a new generation of CDK inhibitors provides clinical benefits to the patients. Breast cancer cells were genetically manipulated using a deactivatedCas9 (d) approach to strengthen the endogenous CDK18 promoter to express highly to exhibit an increased sensitivity [41]. Advertisement 3. ConclusionThe gene editing technologies, especiallyCas9, have been extensively used as tools in basic research for genome encoding, silencing, enhancing, and modification. Currently, they are further applied in manufacturing nonhuman therapeutic products and medicinal products. Particularly, the discovery of medicinal products using gene editing technologies will open a new era for human therapeutics and expect to bring a hope for patient recovery from being seriously sick. Many biotechnology companies and pharmaceutical plants have successfully produced products using gene editing technologies. For example, has become an industry which is prosperously developing recently. Nonhuman therapeutic products are usually manufactured nonexclusively, while human therapeutic products are manufactured exclusively because they are highly technical, ethically concerned, and more profitable. Gene editing technologies are very promising in applications, though there are still many technical (e. g. , off target effects, option of delivery tools, localization of function) and ethical challenges (e. g. , evaluation of benefits and risks, compatibility of private interests and the public good, random manipulation of genes, commercialization of human therapy) unsolved. More and more products based on these technologies are approved for marketing. We also expect the challenges of safety concerns (e. g. , genetically modified organism, tumorigenesis, etc. ) and ethical issues will be overcome in the near future. 1. . Applications ofCas9 for gene editing in hereditary movement disorders.

Output: contrast


Input: Claim: The suprachiasmatic nucleus is the master regulator of circadian rhythms. [SEP] Text: A 2-way mixed ANOVA was used to assess within-subjects effects of lighting condition (DD vs. LL) and between-subjects effects of surgical condition (sham vs. bilateral lesion). Significant interactions were followed by the evaluation of simple main effects of lighting condition and surgical condition using dependent- and independent-samples t tests, respectively. For the 1 animal that free ran through all lighting conditions, a paired-samples t test was used to assess the effect of lighting condition (light vs. dark). In addition, activity counts from 12-h light periods and 12-h dark periods for this animal were averaged across the 21-day interval before surgery and the 21-day interval that began 2 weeks after surgery. The activity counts after surgery began 2 weeks after surgery, to allow time for the animal to recover from surgery. Daily mean activity counts were calculated during the light phase and compared to the dark phase. To analyze circadian rhythmicity, actograms were first viewed using ClockLab software (). We determined the daily onsets and offsets of activity and the period of the rhythm using ClockLab, but when visual inspection indicated that ClockLab detected these improperly, these measures were manually corrected (Schrader et al. , 2009; Gall et al. , 2013). We also calculated alpha (i. e. , the duration of the active period). was used to assess the between-subjects effects of surgical condition (sham vs. bilateral lesion) on alpha and period. Finally, to analyze total activity in LD conditions, we examined day-night activity by averaging the total activity during the day and night for 21 days for each animal prior to surgery and comparing it to the average activity during the day and night, also for 21 days, at 14 days after surgery. A 3-way ANOVA was used to analyze the data with a 2 × 2 × 2 factorial design (surgical condition [sham vs. bilateral lesion] × lighting condition [dark vs. light] × surgical time [surgical time]; surgical condition as the between-group factor and both lighting condition and surgical time as the within-group factors). Significant interactions were followed by the evaluation of simple main effects of lighting condition and surgical condition using paired-samples t tests and independent-samples t tests, respectively. For all comparisons, differences were considered significant when p < 0. 05 (2-tailed for all t tests).

Output: pass