A Combined Approach Reveals a Regulatory Mechanism Coupling Src's Kinase Activity, Localization, and Phosphotransferase-Independent Functions.

Multiple layers of regulation modulate the activity and localization of protein kinases. However, many details of kinase regulation remain incompletely understood. Here, we apply saturation mutagenesis and a chemical genetic method for allosterically modulating kinase global conformation to Src kinase, providing insight into known regulatory mechanisms and revealing a previously undiscovered interaction between Src's SH4 and catalytic domains. Abrogation of this interaction increased phosphotransferase activity, promoted membrane association, and provoked phosphotransferase-independent alterations in cell morphology. Thus, Src's SH4 domain serves as an intramolecular regulator coupling catalytic activity, global conformation, and localization, as well as mediating a phosphotransferase-independent function. Sequence conservation suggests that the SH4 domain regulatory interaction exists in other Src-family kinases. Our combined approach's ability to reveal a regulatory mechanism in one of the best-studied kinases suggests that it could be applied broadly to provide insight into kinase structure, regulation, and function.

Bioassay Development for Bispecific Antibodies-Challenges and Opportunities.

Antibody therapeutics are expanding with promising clinical outcomes, and diverse formats of antibodies are further developed and available for patients of the most challenging disease areas. Bispecific antibodies (BsAbs) have several significant advantages over monospecific antibodies by engaging two antigen targets. Due to the complicated mechanism of action, diverse structural variations, and dual-target binding, developing bioassays and other types of assays to characterize BsAbs is challenging. Developing bioassays for BsAbs requires a good understanding of the mechanism of action of the molecule, principles and applications of different bioanalytical methods, and phase-appropriate considerations per regulatory guidelines. Here, we review recent advances and case studies to provide strategies and insights for bioassay development for different types of bispecific molecules.

Characteristics of deformity surgery in patients with severe and rigid cervical kyphosis (CK): results of the CSRS-Europe multi-centre study project.

INTRODUCTION AND PURPOSE: Little information exists on surgical characteristics, complications and outcomes with corrective surgery for rigid cervical kyphosis (CK). To collate the experience of international experts, the CSRS-Europe initiated an international multi-centre retrospective study. METHODS: Included were patients at all ages with rigid CK. Surgical and patient specific characteristics, complications and outcomes were studied. Radiographic assessment included global and regional sagittal parameters. Cervical sagittal balance was stratified according to the CSRS-Europe classification of sagittal cervical balance (types A-D). RESULTS: Eighty-eight patients with average age of 58 years were included. CK etiology was ankylosing spondlitis (n = 34), iatrogenic (n = 25), degenerative (n = 9), syndromatic (n = 6), neuromuscular (n = 4), traumatic (n = 5), and RA (n = 5). Blood loss averaged 957 ml and the osteotomy grade 4.CK-correction and blood loss increased with osteotomy grade (r = 0.4/0.6, p < .01). Patients with different preop sagittal balance types had different approaches, preop deformity parameters and postop alignment changes (e.g. C7-slope, C2-7 SVA, translation). Correction of the regional kyphosis angle (RKA) was average 34° (p < .01). CK-correction was increased in patients with osteoporosis and osteoporotic vertebrae (POV, p = .006). 22% of patients experienced a major long-term complication and 14% needed revision surgery. Patients with complications had larger preop RKA (p = .01), RKA-change (p = .005), and postop increase in distal junctional kyphosis angle (p = .02). The POV-Group more often experienced postop complications (p < .0001) and revision surgery (p = .02). Patients with revision surgery had a larger RKA-change (p = .003) and postop translation (p = .04). 21% of patients had a postop segmental motor deficit and the risk was elevated in the POV-Group (p = .001). CONCLUSIONS: Preop patient specific, radiographic and surgical variables had a significant bearing on alignment changes, outcomes and complication occurrence in the treatment of rigid CK.

Interplay of Chiral and Helical States in a Quantum Spin Hall Insulator Lateral Junction.

We study the electronic transport across an electrostatically gated lateral junction in a HgTe quantum well, a canonical 2D topological insulator, with and without an applied magnetic field. We control the carrier density inside and outside a junction region independently and hence tune the number and nature of 1D edge modes propagating in each of those regions. Outside the bulk gap, the magnetic field drives the system to the quantum Hall regime, and chiral states propagate at the edge. In this regime, we observe fractional plateaus that reflect the equilibration between 1D chiral modes across the junction. As the carrier density approaches zero in the central region and at moderate fields, we observe oscillations in the resistance that we attribute to Fabry-Perot interference in the helical states, enabled by the broken time reversal symmetry. At higher fields, those oscillations disappear, in agreement with the expected absence of helical states when band inversion is lifted.

Imaging currents in HgTe quantum wells in the quantum spin Hall regime.

The quantum spin Hall (QSH) state is a state of matter characterized by a non-trivial topology of its band structure, and associated conducting edge channels. The QSH state was predicted and experimentally demonstrated to be realized in HgTe quantum wells. The existence of the edge channels has been inferred from local and non-local transport measurements in sufficiently small devices. Here we directly confirm the existence of the edge channels by imaging the magnetic fields produced by current flowing in large Hall bars made from HgTe quantum wells. These images distinguish between current that passes through each edge and the bulk. On tuning the bulk conductivity by gating or raising the temperature, we observe a regime in which the edge channels clearly coexist with the conducting bulk, providing input to the question of how ballistic transport may be limited in the edge channels. Our results represent a versatile method for characterization of new QSH materials systems.

Development and inter-laboratory evaluation of the VISAGE Enhanced Tool for Appearance and Ancestry inference from DNA.

Responding to the growing scientific and practical interest in forensic DNA phenotyping, the VISible Attributes through GEnomics (VISAGE) Consortium was founded in 2017 with the main goal of developing and validating new and reliable molecular and statistical tools to predict appearance, ancestry and age from DNA. Here, we describe the development and inter-laboratory evaluation and validation of the VISAGE Enhanced Tool for Appearance and Ancestry inference from DNA. The VISAGE Enhanced Tool for Appearance and Ancestry is the first forensic-driven genetic laboratory tool that comprises well-established markers for eye, hair and skin color with more recently discovered DNA markers for eyebrow color, freckling, hair shape and male pattern baldness and bio-geographic ancestry informative DNA markers. The bio-geographic ancestry markers include autosomal SNPs (bi- and tri-allelic SNPs), X-SNPs, Y-SNPs and autosomal Microhaplotypes. In total, primers targeting 524 SNPs (representing a 97.6% assay conversion rate) were successfully designed using AmpliSeq into a single primer pool (i.e., one multiplex assay) and sequenced with the Ion S5. In a collaborative framework, five VISAGE laboratories tested the VISAGE Enhanced Tool for Appearance and Ancestry on reproducibility, sensitivity, genotyping concordance, mixtures, species specificity and performance in relevant forensic conditions, including inhibitor-spiked, mock casework and artificially degraded samples. Based on our results, the VISAGE Enhanced Tool for Appearance and Ancestry is a robust, reproducible, and - for the large SNP number - fairly sensitive MPS assay with high concordance rates. With the VISAGE Enhanced Tool for Appearance and Ancestry introduced here, the VISAGE Consortium delivers the first single DNA-test for combined appearance prediction based on seven traits together with bio-geographic ancestry inference based on major continental regions for separated bi-parental and paternal ancestry, which represents the most comprehensive validated laboratory tool currently available for Forensic DNA Phenotyping.

The fatigue life of contoured cobalt chrome posterior spinal fusion rods.

Intraoperative contouring of posterior rods in lumbar arthrodesis constructs introduces stress concentrations that can substantially reduce fatigue life. The sensitivity of titanium (Ti) and stainless steel (SS) to intraoperative contouring has been established in the literature; however, notch sensitivity has yet to be quantified for cobalt chrome (CoCr), which is now being advocated for use in posterior arthrodesis constructs. The goal of this study is to evaluate the sensitivity of CoCr rods to intraoperative contouring for posterior lumbar screwrod arthrodesis constructs. In this paper lumbar bilateral vertebrectomy models are constructed based on ASTM F1717-01 with curved rods (26-30 degrees total curvature) and poly-axial pedicle screws. Three types of constructs are assembled: first, 5.5 mm SS rods with SS screws (6.5 x 35 mm), second, 6.0 mm Ti rods with Ti screws (7.5 x 35 mm), and third, 6.0 mm CoCr rods with Ti screws (7.5 x 35 mm). All specimens are tested at 4 Hz in dynamic axial compression-bending with a load ratio of ten and maximum load levels of 250, 400, and 700 N until run-out at 2 000 000 cycles. Results are presented that show that the fatigue life of CoCr constructs tend to be greater than Ti constructs at all levels. At the 400 N maximum loading, CoCr lasts an average of 350 000 cycles longer than the Ti constructs. The CoCr constructs are able to sustain the 250 N load until run-out at 2 000 000 cycles but they fail at high load levels (maximum 700 N). The CoCr constructs fail at the neck of the Ti screw at high loads whereas Ti screws fail at the notch induced by contouring. Since CoCr is compatible with magnetic resonance imaging and has high static strength characteristics, the results of this study suggest that it may be an appropriate substitute for Ti.

How ATP-Competitive Inhibitors Allosterically Modulate Tyrosine Kinases That Contain a Src-like Regulatory Architecture.

Small molecule kinase inhibitors that stabilize distinct ATP binding site conformations can differentially modulate the global conformation of Src-family kinases (SFKs). However, it is unclear which specific ATP binding site contacts are responsible for modulating the global conformation of SFKs and whether these inhibitor-mediated allosteric effects generalize to other tyrosine kinases. Here, we describe the development of chemical probes that allow us to deconvolute which features in the ATP binding site are responsible for the allosteric modulation of the global conformation of Src. We find that the ability of an inhibitor to modulate the global conformation of Src's regulatory domain-catalytic domain module relies mainly on the influence it has on the conformation of a structural element called helix αC. Furthermore, by developing a set of orthogonal probes that target a drug-sensitized Src variant, we show that stabilizing Src's helix αC in an active conformation is sufficient to promote a Src-mediated, phosphotransferase-independent alteration in cell morphology. Finally, we report that ATP-competitive, conformation-selective inhibitors can influence the global conformation of tyrosine kinases beyond the SFKs, suggesting that the allosteric networks we observe in Src are conserved in kinases that have a similar regulatory architecture. Our study highlights that an ATP-competitive inhibitor's interactions with helix αC can have a major influence on the global conformation of some tyrosine kinases.

An improved metric for quantifying the stiffnesses of intact human vertebrae.

Accurately quantifying the compressive stiffnesses of whole human vertebrae is important in the development of new treatment regimes for fractures due to osteoporosis or metastatic involvement. Two methods are commonly used to quantify compressive stiffnesses of whole vertebrae: first, the maximum slope of the force-deformation curve over a 0.2 per cent strain window; second, the slope of the best-fit line to the load-deflection curve over a specified loading range. Because the whole bone load-displacement response is non-linear, these two measurement systems yield different stiffness values for the same set of experimental data. Thus, the goal of this study was to develop and validate a standard method for deriving the whole bone stiffnesses of human vertebrae. Data from uniaxial compression tests on isolated human thoracic vertebrae (N=30 from 24 donors; T7-T10; age, 84 +/- 10, seven male, and 17 female) were analysed using the two aforementioned stiffness measurement techniques. A sensitivity analysis was also conducted whereby stiffness values were calculated for strain windows ranging from 0.05 per cent to 10 per cent. The results showed that the whole vertebra stiffness was sensitive to the calculation method. Using strain window approaches, the calculated stiffness was erratic at small strain ranges (less than 0.75 per cent), but it began to stabilize at 1 per cent strain. Comparing the historical measurement techniques versus the new standard, it was found that the 1 per cent and 0.2 per cent strain window techniques were well correlated (R2 = 0.91; p < 0.01); however, compared with the 1 per cent strain window method, the 0.2 per cent technique consistently overestimated stiffness and had five times the sensitivity to small changes in strain window magnitude. In conclusion, it is recommended that the 1 per cent strain window technique is adopted as a new standard for measuring the whole bone compressive stiffnesses of human vertebrae based on this method's superior level of accuracy and repeatability when compared with current techniques. The adoption of such a standard in the biomechanics field is important because it allows for inter-study comparisons of new orthopaedic treatments, such as vertebroplasty products.

Development of a bioassay to detect T-cell-activating impurities for T-cell-dependent bispecific antibodies.

T-cell-dependent bispecific antibodies (TDBs) are promising cancer immunotherapies that recruit a patient's T cells to kill cancer cells. There are increasing numbers of TBDs in clinical trials, demonstrating their widely recognized therapeutic potential. Due to the fact that TDBs engage and activate T cells via an anti-CD3 (aCD3) arm, aCD3 homodimer (aCD3 HD) and high-molecular-weight species (HMWS) are product-related impurities that pose a potential safety risk by triggering off-target T-cell activation through bivalent engagement and dimerization of T-cell receptors (TCRs). To monitor and control the level of unspecific T-cell activation, we developed a sensitive and quantitative T-cell-activation assay, which can detect aCD3 HD in TDB drug product by exploiting its ability to activate T cells in the absence of target cells. This assay provides in-vivo-relevant off-target T-cell-activation readout. Furthermore, we have demonstrated that this assay can serve as a platform assay for detecting T-cell-activating impurities across a broad spectrum of aCD3 bispecific molecules. It therefore has the potential to significantly benefit many T-cell-recruiting bispecific programs.

Image-guided robotic stereotactic body radiotherapy for benign spinal tumors: theUniversity of California San Francisco preliminary experience.

We evaluate our preliminary experience using the Cyberknife Radiosurgery System in treating benign spinal tumors. A retrospective review of 16 consecutively treated patients, comprising 19 benign spinal tumors, was performed. Histologic types included neurofibroma [11], chordoma [4], hemangioma [2], and meningioma [2]. Three patients had Neurofibromatosis Type 1 (NF1). Only one tumor, recurrent chordoma, had been previously irradiated, and as such not considered in the local failure analysis. Local failure, for the remaining 18 tumors, was based clinically on symptom progression and/or tumor enlargement based on imaging. Indications for spine stereotactic body radiotherapy (SBRT) consisted of either adjuvant to subtotal resection (5/19), primary treatment alone (12/19), boost following external beam radiotherapy (1/19), and salvage following previous radiation (1/19). Median tumor follow-up is 25 months (2-37), and one patient (with NF1) died at 12 months from a stroke. The median total dose, number of fractions, and prescription isodose was 21 Gy (10-30 Gy), 3 fx (1-5 fx), 80% (42-87%). The median tumor volume was 7.6 cc (0.2-274.1 cc). The median V100 (volume V receiving 100% of the prescribed dose) and maximum tumor dose was 95% (77-100%) and 26.7 Gy (15.4-59.7 Gy), respectively. Three tumors progressed at 2, 4, and 36 months post-SR (n=18). Two tumors were neurofibromas (both in NF1 patients), and the third was an intramedullary hemangioblastoma. Based on imaging, two tumors had MRI documented progression, three had regressed, and 13 were unchanged (n=18). With short follow-up, local control following Cyberknife spine SBRT for benign spinal tumors appear acceptable.

Allosteric Modulation of Src Family Kinases with ATP-Competitive Inhibitors.

The Src family kinases (SFKs) are an important family of tyrosine kinases that are allosterically regulated by their SH2 and SH3 domains. Engagement of SFK SH2 and SH3 domains with their intramolecular ligands leads to reduced kinase activity by stabilizing an inactive ATP-binding site conformation. Disruption of these intramolecular interactions stabilizes a more active ATP-binding site conformation and restores SFK activity. Interestingly, this allosteric relationship is bidirectional in that ATP-competitive ligands that stabilize distinct active site conformations can divergently modulate the abilities of the regulatory SH2 and SH3 domains to participate in intermolecular interactions. Here, we describe a series of assays that profile the bidirectional relationship between the ATP-binding sites and regulatory domains of SFKs. These methods can be used to discover ATP-competitive inhibitors that are selective for distinct ATP-binding site conformations of SFKs and for characterizing the effects that ATP-competitive inhibitors of SFKs have on domains that are distal to their site of interaction.

Observation of the universal magnetoelectric effect in a 3D topological insulator.

The electrodynamics of topological insulators (TIs) is described by modified Maxwell's equations, which contain additional terms that couple an electric field to a magnetization and a magnetic field to a polarization of the medium, such that the coupling coefficient is quantized in odd multiples of α/4π per surface. Here we report on the observation of this so-called topological magnetoelectric effect. We use monochromatic terahertz (THz) spectroscopy of TI structures equipped with a semitransparent gate to selectively address surface states. In high external magnetic fields, we observe a universal Faraday rotation angle equal to the fine structure constant α=e2/2hc (in SI units) when a linearly polarized THz radiation of a certain frequency passes through the two surfaces of a strained HgTe 3D TI. These experiments give insight into axion electrodynamics of TIs and may potentially be used for a metrological definition of the three basic physical constants.

Targeting ABL-IRE1α Signaling Spares ER-Stressed Pancreatic ß Cells to Reverse Autoimmune Diabetes.

In cells experiencing unrelieved endoplasmic reticulum (ER) stress, the ER transmembrane kinase/endoribonuclease (RNase)-IRE1α-endonucleolytically degrades ER-localized mRNAs to promote apoptosis. Here we find that the ABL family of tyrosine kinases rheostatically enhances IRE1α's enzymatic activities, thereby potentiating ER stress-induced apoptosis. During ER stress, cytosolic ABL kinases localize to the ER membrane, where they bind, scaffold, and hyperactivate IRE1α's RNase. Imatinib-an anti-cancer tyrosine kinase inhibitor-antagonizes the ABL-IRE1α interaction, blunts IRE1α RNase hyperactivity, reduces pancreatic ß cell apoptosis, and reverses type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse model. A mono-selective kinase inhibitor that allosterically attenuates IRE1α's RNase-KIRA8-also efficaciously reverses established diabetes in NOD mice by sparing ß cells and preserving their physiological function. Our data support a model wherein ER-stressed ß cells contribute to their own demise during T1D pathogenesis and implicate the ABL-IRE1α axis as a drug target for the treatment of an autoimmune disease.

4π-periodic Josephson supercurrent in HgTe-based topological Josephson junctions.

The Josephson effect describes the generic appearance of a supercurrent in a weak link between two superconductors. Its exact physical nature deeply influences the properties of the supercurrent. In recent years, considerable efforts have focused on the coupling of superconductors to the surface states of a three-dimensional topological insulator. In such a material, an unconventional induced p-wave superconductivity should occur, with a doublet of topologically protected gapless Andreev bound states, whose energies vary 4π-periodically with the superconducting phase difference across the junction. In this article, we report the observation of an anomalous response to rf irradiation in a Josephson junction made of a HgTe weak link. The response is understood as due to a 4π-periodic contribution to the supercurrent, and its amplitude is compatible with the expected contribution of a gapless Andreev doublet. Our work opens the way to more elaborate experiments to investigate the induced superconductivity in a three-dimensional insulator.

Evaluation of surgical performance with standard rigid and flexible-tip laparoscopes.

BACKGROUND: Flexible-tip laparoscopes have recently been introduced into clinical practice, with the goal of improving surgeon performance during complex laparoscopic procedures. We used objective and subjective performance parameters to compare standard rigid 0 degrees and 30 degrees lens laparoscopes two flexible-tip laparoscopes in an in vitro model. METHODS: Twenty-nine subjects with varied levels of surgical experience performed complex laparoscopic tasks in three different models simulating (a) prostate dissection from the rectum, (b) cystic duct clipping, and (c) distal posterior rectum dissection. Each task was performed using two Storz rigid laparoscopes (0 degrees and 30 degrees) and two flexible-tip laparoscopes, the Olympus LTF-V3 and the Fujinon EL2-TF310. The sequence of application of the two flexible-tip laparoscopes was randomized. In each case, an experienced laparoscopic camera driver controlled the field of vision. Time to complete each task, operative precision, and subjective surgeon rating scores were compared. Statistical analysis was performed with analysis of variance (ANOVA) and a two-sided fisher's exact test. RESULTS: In all three models, the flexible laparoscopes offered no advantage in terms of procedure time, surgical precision, or subjective surgeon rating score when compared with the 30 degrees lens rigid laparoscope. The 30 degrees rigid lens laparoscope and the two flexible-tip laparoscopes were superior to the 0 degrees lens rigid laparoscope for all parameters evaluated, with the exception of subjective rating in the cystic duct model and procedure time in the colorectal model. CONCLUSION: In this in vitro experimental model, the flexible-tip laparoscopes found to have no advantage over the standard rigid 30 degrees lens laparoscope. These models were validated, as the 0 degrees lens rigid laparoscope was surpassed by the 30 degrees lens rigid laparoscope and the flexible-tip laparoscopes. Both flexible-tip laparoscopes produced similar results and excellent image quality, but some experience is required before their smooth application can be achieved.

A preliminary investigation of schematic beliefs and unusual experiences in children.

BACKGROUND: In cognitive models of adult psychosis, schematic beliefs about the self and others are important vulnerability and maintaining factors, and are therefore targets for psychological interventions. Schematic beliefs have not previously been investigated in children with distressing unusual, or psychotic-like, experiences (UEDs). The aim of this study was firstly to investigate whether a measure of schematic beliefs, originally designed for adults with psychosis, was suitable for children; and secondly, to examine the association of childhood schematic beliefs with internalising and externalising problems and with UEDs. METHOD: Sixty-seven children aged 8-14 years, with emotional and behavioural difficulties, completed measures of UEDs, internalising (depression and anxiety), and externalising (conduct and hyperactivity-inattention) problems, together with the Brief Core Schema Scales (BCSS). RESULTS: The BCSS was readily completed by participants, and scale psychometric properties were good. Children tended to view themselves and others positively. Internalising and externalising problems and UEDs were all associated with negative schematic beliefs; effect sizes were small to medium. CONCLUSIONS: Schematic beliefs in young people can be measured using the BCSS, and negative schematic beliefs are associated with childhood psychopathology and with UEDs. Schematic beliefs may therefore form a useful target in psychological interventions for young people with UEDs.

Linkage analysis of fifty-seven microsatellite loci to bipolar disorder.

The authors' goal was to screen for genetic linkage with highly informative deoxyribonucleic acid (DNA) microsatellite markers on a series of moderately sized North American bipolar disorder (BP) pedigrees. These BP pedigrees were genotyped with 57 short tandem-repeat polymorphic systems (microsatellites) that were enzymatically amplified from genomic DNA. We did not find significant evidence for genetic linkage. We found isolated LOD scores greater than 2 on chromosome 1 at two loci in individual pedigrees. Simulation studies for multiple analyses under the assumptions of linkage and nonlinkage were performed. The simulations show that LOD scores greater than 2 could be expected even when linkage is absent. Significance levels need to be considered carefully in systematic linkage studies.

Anorexic action of a new potential neuropeptide Y antagonist [D-Tyr27,36, D-Thr32]-NPY (27-36) infused into the hypothalamus of the rat.

Neuropeptide Y (NPY) produces a vigorous feeding response in several species when it is injected into hypothalamic structures involved in eating behavior. The purpose of this study was to determine whether a unique carboxy terminal fragment of NPY would alter the pattern of eating induced in the rat either by NPY injected into the hypothalamus or by a 24-h period of food deprivation. In this case, two L-tyrosine residues and one L-threonine residue of the NPY27-36 fragment were transformed to their D-conformation to produce [D-Tyr27,36,D-Thr32]-NPY (27-36), i.e., D-NPY27-36. Guide cannulae for microinjection were implanted stereotaxically just dorsal to the paraventricular nucleus (PVN) or ventromedial hypothalamus (VMH) of 24 adult male Sprague-Dawley rats. Following postoperative recovery, a microinjection of artificial CSF or 1.1 microgram or 3.3 micrograms of a peptide was made directly into the PVN or VMH as follows: native NPY; D-NPY27-36; or [L-Tyr27,36, L-Thr32]-NPY (27-36), i.e., L-NPY27-36. Food intakes were measured at intervals of 0.25, 0.5, 1.1, 2.0, 4.0, and 24 h. When D-NPY27-36 was microinjected at NPY reactive sites in the PVN or VMH of the rat 15 min before a similar microinjection of NPY, the intense eating response induced by the peptide was reduced significantly. Not only was the effect dose dependent, but D-NPY27-36 also augmented the latency to feed. A mixture of the two doses of NPY and D-NPY27-36 injected at the same hypothalamic loci did not attenuate the intake of food but tended to enhance the feeding response in the rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Measuring the effect of attention on simple visual search.

Set-size in visual search may be due to 1 or more of 3 factors: sensory processes such as lateral masking between stimuli, attentional processes limiting the perception of individual stimuli, or attentional processes affecting the decision rules for combining information from multiple stimuli. These possibilities were evaluated in tasks such as searching for a longer line among shorter lines. To evaluate sensory contributions, display set-size effects were compared with cuing conditions that held sensory phenomena constant. Similar effects for the display and cue manipulations suggested that sensory processes contributed little under the conditions of this experiment. To evaluate the contribution of decision processes, the set-size effects were modeled with signal detection theory. In these models, a decision effect alone was sufficient to predict the set-size effects without any attentional limitation due to perception.