Phosphocatalytic Kinome Activity Profiling of Apoptotic and Ferroptotic Agents in Multiple Myeloma Cells

Through phosphorylation of their substrate proteins, protein kinases are crucial for transducing cellular signals and orchestrating biological processes, including cell death and survival. Recent studies have revealed that kinases are involved in ferroptosis, an iron-dependent mode of cell death associated with toxic lipid peroxidation. Given that ferroptosis is being explored as an alternative strategy to eliminate apoptosis-resistant tumor cells, further characterization of ferroptosis-dependent kinase changes might aid in identifying novel druggable targets for protein kinase inhibitors in the context of cancer treatment. To this end, we performed a phosphopeptidome based kinase activity profiling of glucocorticoid-resistant multiple myeloma cells treated with either the apoptosis inducer staurosporine (STS) or ferroptosis inducer RSL3 and compared their kinome activity signatures. Our data demonstrate that both cell death mechanisms inhibit the activity of kinases classified into the CMGC and AGC families, with STS showing a broader spectrum of serine/threonine kinase inhibition. In contrast, RSL3 targets a significant number of tyrosine kinases, including key players of the B-cell receptor signaling pathway. Remarkably, additional kinase profiling of the anti-cancer agent withaferin A revealed considerable overlap with ferroptosis and apoptosis kinome activity, explaining why withaferin A can induce mixed ferroptotic and apoptotic cell death features. Altogether, we show that apoptotic and ferroptotic cell death induce different kinase signaling changes and that kinome profiling might become a valid approach to identify cell death chemosensitization modalities of novel anti-cancer agents.     

Timed excitatory conditioning under zero and negative contingencies.

Rats (rattus norvegicus) anticipated the arrival of a food pellet unconditioned stimulus (US) even when the conditioned stimulus (CS) signaled no overall change or a substantial decrease in the overall rate of US occurrence. Pellet USs were scheduled probabilistically in the intertrial interval at either an equivalent rate (Experiment 1) or a four times higher rate (Experiments 2 and 3) than in the CS, which included one fixed-time target US. Conditioning has been said to involve learning "whether" (contingency) the CS signals a change in the US, and if so, "when" (contiguity) the US is scheduled to arrive. Our results suggest that "when" trumps "whether," challenging the received view that a positive CS-US contingency is necessary for successful conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Employing subgroup evolution for irregular-shape nesting

This paper introduces a new method to solve the irregular-shape, full-rotation nesting problem by a genetic algorithm. Layout patterns are evolved in hierarchical subgroups to facilitate the search for an optimal solution in such a complex solution space. The genotype used in the genetic algorithm contains both the sequence and rotation for each shape, requiring new genetic operators to manipulate a multi-type genetic representation. A lower-left placement heuristic coupled with matrix encoding of the shapes and plate prevents overlap and constrains the solution space to valid solutions. This new method is able to efficiently search the solution space for large problems involving complex shapes with 360 degrees of freedom. The algorithm generates better solutions than previously published evolutionary methods.     

Intravital imaging of human prostate cancer using viral nanoparticles targeted to gastrin-releasing Peptide receptors

Multivalent nanoparticles have several key advantages in terms of solubility, binding avidity, and uptake, making them particularly well suited to molecular imaging applications. Herein is reported the stepwise synthesis and characterization of NIR viral nanoparticles targeted to gastrin-releasing peptide receptors that are over-expressed in human prostate cancers. The pan-bombesin analogue, [β-Ala11, Phe13, Nle14]bombesin-(7-14), is conjugated to cowpea mosaic virus particles functionalized with an NIR dye (Alexa Fluor 647) and polyethylene glycol (PEG) using the copper(I)-catalyzed azide-alkyne cycloaddition reaction. Targeting and uptake in human PC-3 prostate cells is demonstrated in vitro. Tumor homing is observed using human prostate tumor xenografts on the chicken chorioallantoic membrane model using intravital imaging. Further development of this viral nanoparticle platform may open the door to potential clinical noninvasive molecular imaging strategies.     

The Solomon effect in learning disabilities diagnosis: Can we learn from history?

The Individuals with Disabilities Act (Individuals with Disabilities Education Improvement Act; IDEIA, 2004) has been reauthorized, and new parameters for defining learning disabilities (LD) have been established that provide more flexibility for corresponding state and local regulations. The field now has a unique opportunity to shape the practice of LD diagnosis and should consider important conceptual, theoretical, empirical, economic, legal, and practical issues related to LD diagnosis. This article highlights five key recommendations for the diagnostic definition of learning disabilities: (1) the definition needs to be unambiguous; (2) it must be universally accepted across professions, researchers, and governmental entities; (3) it must incorporate clearly defined subtypes of learning disabilities; (4) it must be empirically supported; and (5) it must point to valid, reliable, and cost-effective procedures for the identification of children with and without learning disabilities. Consideration of these points may help the field to avoid repeating past mistakes and returning to the folly of poor LD diagnostic practice. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The influence of improper sets of information on judgment: How irrelevant information can bias judged probability.

This article introduces 2 new sources of bias in probability judgment, discrimination failure and inhibition failure, which are conceptualized as arising from an interaction between error prone memory processes and a support theory like comparison process. Both sources of bias stem from the influence of irrelevant information on participants' probability judgments, but they postulate different mechanisms for how irrelevant information affects judgment. The authors used an adaptation of the proactive interference (PI) and release from PI paradigm to test the effect of irrelevant information on judgment. The results of 2 experiments support the discrimination failure account of the effect of PI on probability judgment. In addition, the authors show that 2 commonly used measures of judgment accuracy, absolute and relative accuracy, can be dissociated. The results have broad implications for theories of judgment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The Content of Reality Dating Shows and Viewer Perceptions of Dating

This research utilized a content analysis of 64 hours of reality dating shows and a survey of 197 young adults to determine the extent to which the content on these shows was related to actual dating attitudes, preferred date characteristics, and dating behaviors of viewers of that genre. Results show that male viewers, those who perceived higher realism in the shows, and those with higher average viewing scores were more likely to endorse attitudes found within the programming. Dating characteristics were portrayed infrequently, and no relationship between viewing and endorsement of those characteristics was found. Viewing reality dating shows was related to self-reports of drinking alcohol and using hot tubs early in the dating relationship.     

Development and Characterization of Degradable Thiol-Allyl Ether Photopolymers

Degradable thiol-ene photopolymer networks were formed through radically mediated step-growth reactions. Variations in the network structure were used to alter the initial and temporal moduli, mass loss profiles, and equilibrium swelling ratios. Mass loss rates varied with changes in the solvent concentration, monomer molecular weight, average monomer functionality, and concentration of degradable linkages. The time required for the networks to degrade completely ranged from 1.20 ± 0.01 to 24.5 ± 0.1 days, which corresponded to hydrolysis rates of 0.18 ± 0.01 and 0.021 ± 0.0003 day⁻¹. Initial moduli also varied considerably as a function of network structure, ranging from 150 ± 35 to nearly 5000 ± 100 kPa, and initial equilibrium swelling ratios ranged from 2.5 ± 0.01 to 18.7 ± 2. Collectively, these results demonstrate how the material properties and the mass loss behavior of thiol-ene networks can be independently tuned for specific applications.     

Improved Efficiency in Blue Phosphorescent Organic Light‐Emitting Devices Using Host Materials of Lower Triplet Energy than the Phosphorescent Blue Emitter

Data from a series of phosphorescent blue organic light‐emitting devices with emissive layers consisting of either 4,4′‐bis(N‐carbazolyl)‐2,2′‐biphenyl (CBP):6% bis[(4,6‐difluorophenyl)pyridinato‐N,C²](picolinato)iridium(III) (FIrpic) or bis(9‐carbazolyl)benzene (mCP):6% FIrpic show that the triplet energy of the hole and electron transport layers can have a larger influence on the external quantum efficiency of an operating device than the triplet energy of the host material. A maximum external quantum efficiency of 14% was obtained for CBP:6% FIrpic devices which is nearly double all other published CBP:6% FIrpic results. A new host material, 4‐(diphenylphosphoryl)‐N,N‐di‐p‐tolylaniline (DHM‐A2), which has a triplet energy lower than that of FIrpic is also reported. Devices fabricated using DHM‐A2 show improved performance (lower drive voltage and higher external quantum efficiency) over devices using 4‐(diphenylphosphoryl)‐N,N‐diphenylaniline (HM‐A1), a high performance ambipolar DHM‐A2 analogue with a triplet energy greater than FIrpic. Nearly 18% external quantum efficiency was obtained for the DHM‐A2:5% FIrpic devices. The results suggest modified design rules for the development of high performance host materials: more focus can be placed on molecular structures that provide good charge transport (ambipolarity for charge balance) and good molecular stability (for long lifetimes) rather than first focusing on the triplet energy of the host material.