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Experts in traditional pricing literature often assume that consumers are rational in their purchasing decisions, and tend to ignore the effect of psychological behavior. One of the fundamental irrational psychological behaviors is overconfidence, which refers to overestimation. The benefits of three-part tariffs under demand uncertainty caused by overconfident consumers have been demonstrated in various forms. In the present study, we investigate the design of a three-part tariff pricing plan when consumers are overconfident in the sense of overestimating their amount of service usage or consumption. An analytical model and a numerical analysis are carried out using a genetic algorithm approach to determine the optimal three-part tariff and to compare other tariff structures (e.g., two-part tariff and menu of three-part tariff) to investigate the critical factors influencing their performance. With overconfidence in consumers, service providers need clear direction on how to optimally implement a three-part pricing strategy. Specifically, we observe the effect of overconfidence on the profitability of service providers, and their other performance in general. Thus, service providers are given clear guidance on when to offer three-part tariffs and alternative structures to overconfident consumers and push marketing plans to increase their profits and market share., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Merdikawati et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This study presents a thermo-economic assessment of three low-global-warming-potential (GWP) substitutes, R1233zd(E), R1234ze(Z) and R1234ze(E), for R245fa used in organic Rankine cycle (ORC) systems, considering two models with different heat sources. The exhaust heat from a diesel generator is served as heat source of Model I, while the waste heat of exhaust and jacket cooling water are used as heat source of Model II. It is noted that the working pressure of R1234ze(E) is much higher than that of R1233zd(E), R1234ze(Z) and R245fa in a fixed evaporation-temperature range. Furthermore, the system using R1234ze(E) has the minimum net power output for Model I, while it turns into the maximum net power output for Model II. In addition, both R1234ze(Z) and R1233zd(E) can be used as good alternative working fluids for R245fa because R1234ze(Z), R1233zd(E) and R245fa have close working pressures, maximum net power outputs, and minimum levelized energy costs. Compared to Model I, LEC min of R1233ed(E) and R1234ze(Z) are reduced by 10.8 % and 9.9 % and PB min of R1233ed(E) and R1234ze(Z) are reduced by 11.5 % and 10.1 %, respectively, in Model II. However, R1233zd(E) has the highest minimum payback period for both Model I and Model II among the four working fluids investigated., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Fetal loss (FL) from the 45th day of gestation until calving can impose a significant economic burden on dairy farmers, resulting in lost profits and increased production costs. Pregnancy-associated glycoprotein (PAG) is commonly used for detecting pregnancy in cows. PAG is secreted by binucleated trophoblast cells of the placenta and regulated by more than 24 genes. The purpose of this study was to determine the PAG threshold for FL and a probability of pregnancy maintenance until calving based on milk PAG levels. Our results reveal that primiparous and multiparous cows that maintained pregnancy until the 40th week exhibited higher PAG sample-negative (SN) values in their milk in the 6th week of gestation than did those that experienced FL later in gestation. Pregnant cows with higher PAG SN values in the 6th week of gestation were more likely to maintain their pregnancies. The area under the receiver operating characteristic curve for predicting the probability of pregnancy maintenance was 0.722 for our prediction model. On the other hand, a milk PAG SN value of <0.192 indicated 95 % confidence that FL would occur between the 7th and 40th weeks of gestation. Milk PAG testing is a noninvasive sampling technique that does not induce additional stress in lactating cows. The study reveals that PAG SN values increase significantly in Holstein cows during the 6th week of gestation. The predictive model developed was effective in forecasting pregnancy outcomes up to the 40th week of gestation or calving. The model's performance is moderately good for field application and could be a useful tool for dairy producers., Competing Interests: Declarations of competing interest The authors declare no competing interest., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: The progression patterns, dispositions, and outcomes of patients with advanced hepatocellular carcinoma (HCC) who achieved durable responses with immunotherapy remain poorly characterized., Methods: Patients with advanced HCC who received immune checkpoint inhibitor (ICI)-based immunotherapy and achieved durable responses were retrospectively included. A durable response was defined as partial response (PR) or stable disease (SD) per RECIST 1.1 for more than 8 months after initiation of immunotherapy. Oligoprogression and polyprogression were defined as progression at ≤3 and >3 lesions, respectively., Results: A total of 91 durable responders (63 PR and 28 SD) were identified. The majority had chronic viral hepatitis ( n = 69, 75.8%). Forty-seven (51.6%) and 44 (48.4%) patients received the index immunotherapy as first-line and second- or beyond-line therapy, respectively. Fifty-four (59.3%) patients subsequently developed progression, with a predominant pattern of oligoprogression (66.7%). The median overall survival (OS) was 46.2 months (95% CI: 34.1-58.3). For patients with subsequent progression, employment of locoregional therapy (LRT) for progression was associated with prolonged OS (univariate analysis: hazard ratio [HR] 0.397, p = 0.009; multivariate analysis: HR 0.363, p = 0.050). Patients with oligoprogression who received LRT showed longer median OS than those who did not (48.4 vs. 20.5 months, p < 0.001). In contrast, the median OS of patients with polyprogression who received LRT was not different from those without LRT (27.7 vs. 25.5 months, p = 0.794)., Conclusion: Approximately 60% of the post-immunotherapy durable responders of HCC subsequently develop progression. Proactive LRT may further rescue patients who develop subsequent oligoprogression. Prospective studies are mandatory to clarify the proper management of durable responders with subsequent progression., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

This article addresses the practically predefined-time adaptive fuzzy tracking control problem of strict-feedback nonlinear stochastic systems, where the system under consideration includes stochastic disturbances and uncertain parameters. First, in this study, practically predefined-time stochastic stabilization (PPSS) in the p th moment sense is introduced, and a Lyapunov-type criterion for PPSS is proposed to assure the stabilization of the system considered. With these ideas, based on the backstepping design method, a semiglobally practically predefined-time adaptive fuzzy tracking control algorithm is proposed with a fuzzy system used to approximate the unknown part of the system. Moreover, the settling time of the system response can be arbitrarily adjusted in a mean-value sense, and such freedom can be used to improve the stochastic finite-/fixed-time control results. Finally, a practical example and a numerical example of a comparison are provided to validate the effectiveness of the proposed control strategy.

The event-triggered sliding-mode control (SMC) for discrete-time networked Markov jumping systems (MJSs) with channel fading is investigated by means of a genetic algorithm. In order to reduce resource consumption in the transmission process, an event-triggered protocol is adopted for networked MJSs. A key feature is that the signal transmission is inevitably affected by fading phenomenon due to delay, random noise, and amplitude attenuation in a networked environment. With the aid of a common sliding surface, an event-triggered SMC law is designed by adjusting the system network mode. Under the framework of stochastic Lyapunov stability, sufficient conditions are constructed to ensure the mean-square stability of the closed-loop networked MJSs, and the sliding region is reached around the specified sliding surface. Moreover, based on the iteration optimizing accessibility of objective function, an effective SMC approach under genetic algorithm is proposed to minimize the convergence region around the sliding surface. Finally, the effectiveness of the proposed method is proved by the F-404 aircraft model.

This study is aimed to select optimum keratin degradation ability from Bacillus strains for feather meal-soybean meal fermentation, and favorably water content for the strain during fermentation of feather meal-soybean meal, and finally investigate the effects of the fermented feather meal-soybean meal product (FFSMP) on growth performance, carcass trait, clinical blood biochemistry, and intestinal morphology of broilers. Thirty-six bacteria strains from soil, sewage pool, and feather waste were screened and selected Bacillus subtilis var. natto N21 (N21), B. subtilis CU14 (CU14), and B. amyloliquefaciens CU33 (CU33) with better keratinase activity and feather-degrading rate. The result of trial 1 showed that the FFSMP produced by CU33 had the optimum physiochemical characterizations, amino acid composition and feeding performance for broilers. Hence the effects of water content (45, 50, 55, and 60%) on FFMSP fermentation of CU33 were investigated in trial 2. Result showed that pH value, counts of Bacillus-like bacteria, γ-PGA, viscosity, surfactin yield and odor all significantly increased according to the water content (P < 0.05). The protease activity reached significantly highest in the 55% and 60% water content groups (P < 0.01). The broilers performance of 55% and 60% water content group were significantly higher than control group (P < 0.05) in weight gain (WG), feed intake (b) at 0 to 21-d-old and the WG, feed conversion ratio (FCR), and production efficiency factor at 0 to 35-d-old, and could reach the similar growth performance as fish meal group (P > 0.05). The fermentation groups significantly decreased urea nitrogen (P < 0.05) and increased creatinine (P < 0.05) in the blood. The fermentation groups also significantly decreased the crypt depth in the duodenum (P < 0.05) and increased villus height to crypt depth ratio of the duodenum (P < 0.05). In conclusion, CU33 shows the best degradation rate for feather and keratinase activity, and the FFSMP with a water content of 50% to 60% during fermentation is suggested. Diets supplemented with 5% FFSMP can promote the growth of broilers by improving the morphology of the duodenum and achieve the feeding effect of high-quality fish meal., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: We conducted a population-based cohort study enrolling patients with Stage II and III colon cancer receiving postoperative adjuvant chemotherapy with uracil and tegafur (UFT) or fluorouracil (5-FU) from the Taiwan National Health Insurance Research Database from 2000 to 2015. The outcomes of the current study were disease-free survival (DFS) and overall survival (OS). Hazard ratios (HRs) were calculated by multivariate Cox proportional hazard regression models. We compared our effectiveness results from the literature by meta-analysis, which provided the best evidence. Severe adverse events were compared in meta-analysis of reported clinical trials. In the nationwide cohort study, UFT (14,486 patients) showed DFS similar to postoperative adjuvant chemotherapy (adjusted HR 1.037; 95% confidence interval [CI] 0.954-1.126; P = .397) and OS (adjusted HR 0.964; 95% CI 0.891-1.041; P = .349) compared with the 5-FU (866 patients). Our meta-analysis confirmed the similarity of effectiveness and found the incidence of leucopaenia was statistically significantly reduced in UFT (risk ratio 0.12; 95% CI 0.02-0.67; I2 = 0%). Through our analysis, we have confirmed that UFT is a well-tolerated adjuvant therapy choice, and has similar treatment efficacy as 5-FU in terms of DFS and OS in patients with Stage II and III colon cancer., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Bacillus subtilis var. natto N21 (BS) and different lactic acid bacteria were applied to produce two-stage fermented feeds. Broilers were fed these feeds to select the best fermented feed. The selected fermented feed was pelleted and investigated for its effects on growth performance, carcass traits, intestinal microflora, serum biochemical constituents, and apparent ileal nutrient digestibility. Trial 1 involved three hundred thirty-six 1-d-old broilers with equal numbers of each sex, randomly assigned into control, BS + Bacillus coagulans L12 (BBC), BS + Lactobacillus casei (BLC), BS + Lactobacillus acidophilus (BLA), BS + Lactobacillus acidophilus L15 (BLA15), BS + Lactobacillus delbruekckii (BLD), and BS + Lactobacillus reuteri P24 (BLR24) groups with 3 replicates per group. Trial 2 involved two hundred forty 1-d-old broilers with equal numbers of each sex, randomly assigned into control, BBC, and pelleted BS + Bacillus coagulans L12 fermented feed (PBBC) groups with 4 replicates per group. Trial 3 involved sixteen 21-d-old male broilers randomly assigned into control and PBBC groups with 4 replicates per group for a nutrient digestibility trial. The feed conversion ratio (FCR) in the BBC group was better than the control (P < 0.05), and the production efficiency factor (PEF) was the best. However, weight gain (WG), feed intake (FI), and PEF were the lowest in the BLD group (P < 0.05). The WG during 0 to 21 d and 0 to 35 d in the PBBC groups were higher than the control (P < 0.05). The relative weight of the proventriculus + gizzard in the BBC and PBBC groups were higher than the control (P < 0.05). The digestible amino acid content in the PBBC group increased significantly (P < 0.05). Bacillus coagulans L12 is the best lactic acid bacteria for second stage fermentation. PBBC improved broiler growth performance, which may be due to the higher digestible amino acid content, it has the potential to become a commercial feed., (© The Author 2017. Published by Oxford University Press on behalf of Poultry Science Association.)

Resveratrol (Re), a stilbenoid, is associated with a potential benefit in controlling certain biomarkers in type II diabetes. Genistein (Ge), a phytoestrogen, may act as an antioxidant and thus may diminish damaging effects of free radicals in tissues. In the present study, a potential synergistic antioxidant effect of an Re/Ge combination on high-glucose (HG) incubation in Madin-Darby canine kidney (MDCK) epithelial cells was evaluated. Compared with the treatment of Re or Ge alone, the Re/Ge combination synergistically decreased intracellular reactive oxygen species (ROS) and hydroxyl radicals in MDCK cells. This synergistic antioxidant effect correlated with the inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression and an increase in γ-glutamylcysteine synthetase expression. In addition, mitochondrial complex I, NADPH oxidase, xanthine oxidase and lipoxygenase contributed towards ROS overproduction when the MDCK cells were incubated with HG. In conclusion, the Re/Ge combination synergistically enhanced the antioxidant effect in HG-incubated kidney cells, possibly through an enhanced antioxidant regulation mechanism. The Re/Ge combination may be a potential benefit against oxidative stress in diabetes mellitus.

Despite a plethora of literature has documented that osteoarthritis (OA) is veritably associated with oxidative stress-mediated chondrocyte death and matrix degradation, yet the possible involvement of synoviocyte abnormality as causative factor of OA has not been thoroughly investigated. For this reason, we conduct the current studies to insight into how synoviocytes could respond to an episode of folate-deprived (FD) condition. First, when HIG-82 synoviocytes were cultivated under FD condition, a time-dependent growth impediment was observed and the demise of these cells was demonstrated to be apoptotic in nature mediated through FD-evoked overproduction of reactive oxygen species (ROS) and drastically released of cytosolic calcium (Ca2+) concentrations. Next, we uncovered that FD-evoked ROS overproduction could only be strongly suppressed by either mitochondrial complex II inhibitors (TTFA and carboxin) or NADPH oxidase (NOX) inhibitors (AEBSF and apocynin), but not by mitochondrial complex I inhibitor (rotenone) and mitochondrial complex III inhibitor (antimycin A). Interestingly, this selective inhibition of FD-evoked ROS by mitochondrial complex II and NOX inhibitors was found to correlate excellently with the suppression of cytosolic Ca2+ release and reduced the magnitude of the apoptotic TUNEL-positive cells. Taken together, we present the first evidence here that FD-triggered ROS overproduction in synoviocytes is originated from mitochondrial complex II and NOX. Both elevated ROS in tandem with cytosolic Ca2+ overload serve as final arbitrators for apoptotic lethality of synoviocytes cultivated under FD condition. Thus, folate supplementation may be beneficial to patients with OA.

Infiltrating neutrophils, lymphocytes, macrophages, and cytokines constitute a state of chronic inflammation within the tumor microenvironment. Tartrate-resistant acid phosphatase 5a (TRACP5a) protein, a novel product of activated macrophage, is postulated to be a biomarker for systemic inflammatory burden in states of chronic inflammation. We aimed to investigate the clinical significance of TRACP5a expression in tumor-infiltrating macrophages and serum TRACP5a in patients with metastatic breast cancer (BC). We retrospectively analyzed the clinical data from 34 BC patients with confirmed skeletal/visceral metastasis upon or during first-line palliative treatment. Patients were stratified into 3 groups based on the therapeutic responses and follow-up disease course. The association of TRACP5a protein with other inflammatory and cancer biomarkers was assessed among the clinically distinct group of patients. Higher TRACP5a protein was significantly correlated with earlier disease progression and survival (P = 0.0045) in comparison to other inflammatory markers, CRP or IL-6. Patients with higher serum TRACP5a level and shorter survival and treatment refractoriness also had more TRACP+ tumor-infiltrating macrophages. Our data support a hypothesis that serum TRACP5a protein can potentially be a predictive and prognostic marker to evaluate disease progression and therapeutic response in BC patients with bone/visceral metastasis. The associations between overall survival and TRACP expression by macrophages require further prospective investigation.

Background: Patients with triple-negative breast cancer (TNBC) are at increased risk of brain metastases (BMs). In this retrospective single-institutional study, we assessed the radiographic features from a cohort of breast cancer (BC) patients with confirmed BM., Methods: Women diagnosed with BC with BM from January 1, 1996 to May 31, 2012 were identified through institutional databases. Relevant medical records were reviewed to assess patterns of recurrence, treatment, magnetic resonance imaging (MRI) features of BM, and survival after BM. The MRI finding of BM was classified as solid, necrotic, leptomeningeal spread, or mixed type. We assigned the patient into three groups according to histologic subtype of primary BC., Results: In total, 62 patients, median age 53 years (range 20-78), were identified and specific treatment for BM consisted of radiotherapy, surgical resection, and systemic chemotherapy. The initial stage, post-BM survival and overall survival were not significantly different. However, cystic necrotic BMs appeared on MR images were significantly more associated with the TNBC group., Conclusion: Patients with BMs from TNBC have distinct MRI features helping the assessment of newly developed BM. A large confirmatory study with correlated histology in this unique patient population will be required., (Copyright © 2014 by the American Society of Neuroimaging.)

Germination is a unique developmental transition from metabolically quiescent seed to actively growing seedling that requires an ensemble of hydrolases for coordinated nutrient mobilization to support heterotrophic growth until autotrophic photosynthesis is established. This study reveals two crucial transcription factors, MYBS1 and MYBGA, present in rice (Oryza sativa) and barley (Hordeum vulgare), that function to integrate diverse nutrient starvation and gibberellin (GA) signaling pathways during germination of cereal grains. Sugar represses but sugar starvation induces MYBS1 synthesis and its nuclear translocation. GA antagonizes sugar repression by enhancing conuclear transport of the GA-inducible MYBGA with MYBS1 and the formation of a stable bipartite MYB-DNA complex to activate the α-amylase gene. We further discovered that not only sugar but also nitrogen and phosphate starvation signals converge and interconnect with GA to promote the conuclear import of MYBS1 and MYBGA, resulting in the expression of a large set of GA-inducible but functionally distinct hydrolases, transporters, and regulators associated with mobilization of the full complement of nutrients to support active seedling growth in cereals.

Bacillus subtilis var. natto N21 (Bac; for greater proteolytic capacity) and Saccharomyces cerevisiae Y10 (Sac; for greater acidic capacity) were applied to produce a 2-stage combined fermentation feed. This study investigated whether the enhancement of Bac+Sac fermented feed on broiler growth performance was due to the probiotics per se or due to the fermentation process. Trial 1 included 1-d-old broiler chicks (n=144) randomly assigned to control, water added (same as in the fermentation feed, 23%), and Bac+Sac fermented feed (FBac+Sac) treatments with 4 replicates. Trial 2 included 21-d-old broiler chickens (n=12) assigned into control and FBac+Sac groups for a metabolic trial for nutrient availability. Trial 3 included 1-d-old male broiler chicks (n=216) randomly assigned into 6 treatments with 3 replicates. Treatments included a control, Sac fermented feed (FSac), FBac+Sac, Bac powder (PBac), Sac powder (PSac), and Bac+Sac powder (PBac+Sac). The results from trial 1 showed that FBac+Sac increased BW and feed intake (P<0.05) in 21- and 39-d-old chickens. The water-added group showed decreased BW, weight gain, and feed intake (P<0.05). Trial 2 showed that FBac+ Sac increased gross energy availability (P<0.05). Trial 3 showed that FBac+Sac increased 21- and 39-d-old BW and weight gain (P<0.05). Diets supplemented with probiotic powder or fermented with Sac did not improve broiler growth performance (P>0.05). The growth performance improvement of the FBac+Sac treatment was probably not due to the added water, probiotic powder inclusion, or through single-strain fermentation, but due to the 2-stage fermentation process using Bac and Sac strains.

Protein kinases, and the signal transduction pathways in which they participate, are now recognized to be medicinally attractive targets of opportunity. Inhibitors of the protein kinase family not only hold great promise as therapeutic agents, but are also of profound utility in the characterization of signaling pathways. The direct visualization of protein kinase activity in living cells provides a genuine assessment of the efficacy and selectivity of these inhibitors in a physiological setting. In addition, the ability to visualize the activity of a protein kinase in real time furnishes a direct measurement of the activation of specific signaling pathways in response to extracellular stimuli. We have developed two series of fluorescent substrates for protein kinase C (PKC) using a strategy that positions the reporter-group directly on the residue undergoing phosphorylation. The first series of PKC substrates is based, in part, on the Ca(+2) indicators developed by Tsien and his collaborators during the 1980s. In this case, phosphorylation of the substrate creates a divalent metal ion binding site. Upon metal ion coordination, a fluorescence change transpires via a mechanism analogous to that described for the Ca(+2) indicators. The second series of PKC sensors was identified via the preparation and subsequent screen of a library of fluorescently-labeled PKC peptide substrates. The lead derivative displays a phosphorylation-induced fluorescence change that allows the visualization of real-time PKC activity in both cell lysates and living cells. Furthermore, immunodepletion experiments demonstrate that the fluorescently-tagged peptide is selectively, if not exclusively, phosphorylated by the conventional PKCs. Both of the protein kinase biosensor strategies take advantage of the ease with which peptides can be modified to create libraries of structurally altered analogs. However, the inherent synthetic mutability of peptides is not just limited to library construction. For example, it may ultimately be possible to simultaneously monitor multiple protein kinases by affixing fluorophores with distinct photophysical properties to appropriately designed active site-directed peptides.

There is widespread interest in developing fluorescent reporters of protein kinase activity, species that can furnish a visual readout of both when and where intracellular kinases are activated in response to a stimulus. We have constructed and identified, via a combination of rational design, library synthesis, and screening, a difluorofluorescein-appended peptide-based species that responds to protein kinase C phosphorylation in a fluorescently sensitive fashion. The phosphorylation-induced divalent metal ion-mediated 265% enhancement in fluorescence proceeds with a V(max) of 8.5 micromol/min.mg and a K(m) of 20.5 microM.

A library of fluorescently labeled protein kinase C (PKC) peptide substrates was prepared to identify a phosphorylation-induced reporter of protein kinase activity. The lead PKC substrate displays a 2.5-fold change in fluorescence intensity upon phosphorylation. PKC activity is readily sampled in cell lysates containing the activated PKCs. Immunodepletion of conventional PKCs from the cell lysate eliminates the fluorescence response, suggesting that this peptide substrate is selectively phosphorylated by PKCalpha, beta, and gamma. Finally, living cells microinjected with the peptide substrate exhibit a 2-fold increase in fluorescence intensity upon exposure to a PKC activator. These results suggest that peptide-based protein kinase biosensors may be useful in monitoring the temporal and spatial dynamics of PKC activity in living cells.

Protein kinases recognize and bind to specific amino acid sequences on their protein substrates. These sequences can be readily identified using combinatorial peptide libraries. Unfortunately, conventional peptide libraries are not designed to identify subtle structural factors that can dramatically enhance enzyme affinity since the "local" diversity associated with these libraries is limited to the 20 standard amino acids. A parallel synthesis strategy was developed that possesses 2 key attributes: moderate size ( approximately 1000 members each), yet high structural diversity (50-fold greater than that of conventional peptide libraries). Due to their small size, these libraries can be synthesized in parallel, which allows each library member to be individually evaluated, and eliminates the requirement for subsequent structural deconvolution. Furthermore, since these libraries possess a high structural diversity focused within narrow spatial windows on the target protein, small regions of the protein can be challenged with a multitude of functionality containing structural differences that vary from subtle to gross.

A wide variety of proteins have been shown to recognize and bind to specific amino acid sequences on other proteins. These sequences can be readily identified using combinatorial peptide libraries. However, peptides containing these preferred sequences ("consensus sequence peptides") typically display only modest affinities for the consensus sequence-binding site on the intact protein. In this report, we describe a parallel synthesis strategy that transforms consensus sequence peptides into high affinity ligands. The work described herein has focused on the Lck SH2 domain, which binds the consensus peptide acetyl-Tyr(P)-Glu-Glu-Ile-amide with a K(D) of 1.3 micrometer. We employed a strategy that creates a series of spatially focused libraries that challenge specific subsites on the target protein with a diverse array of functionality. The final lead compound identified in this study displayed a 3300-fold higher affinity for the Lck SH2 domain than the starting consensus sequence peptide.