Specific Discrimination Research Articles

Label-free fluorescence aptasensor for sensitive determination of bisphenol S by the salt-adjusted FRET between CQDs and MoS2

Although the salt-adjusted properties of nanomaterials have been extensively used for colorimetric assays of all kinds of analytes, their applications in the design of fluorescence sensor are very limited. Herein, a novel fluorescence aptasensor was developed for the sensitive determination of Bisphenol S (BPS) by the salt-adjusted fluorescence resonance energy transfer (FRET) between the zero-dimensional emitter (CQDs) and the two-dimensional absorber (MoS2 nanosheets) and the roles of specific discrimination and protective effect of anti-BPS aptamer to layered MoS2. It is shown that layered MoS2 can serve as a good fluorescent quencher towards carbon dots with decent quenching efficiency. Importantly, the established fluorescent method achieved satisfactory results for the determination of BPS with a good linear correlation from 0.05 μM to 2 μM and a detection limit of 2 nM. It is expected that this method may offer a new direction for the application of the phenomenon of salt-assisted aggregation of nanomaterials in designing high-performance fluorescent biosensors.

A Synchronous Fluorescence Spectrofluorometric Method for the Simultaneous Determination of Clonazepam and Paroxetine Hydrochloride in Combined Pharmaceutical Dose Form

First derivative synchronous spectrofluorimetry has been found to be superior because of its highly specific spectral discrimination and readily available solvent, it is economical, eco-friendly, and lacks an extraction procedure. In the present study, a new simple, sensitive, and time-saving first derivative synchronous spectrofluorimetry method has been developed for simultaneous estimation of clonazepam (CLO) and paroxetine hydrochloride (PH) in pharmaceutical dose forms. CLO was determined at the emission wavelength of 512.79 nm (zero-crossing wavelength point of PH). Similarly, PH was measured at 336.00 nm (zero-crossing wavelength point of CLO). The first derivative amplitude-concentration plots were rectilinear over the range of 1-5 μg/ mL for CLO and 5-25 μg/mL for PH. The method was validated statistically as per the ICH guidelines. The limits of detection were 0.055 and 0.033 μg/mL and quantification limits were 0.169 and 0.102 μg/mL for CLO and PH, respectively. The percentage recovery in commercial formulation was found to be in the range 100.45% and 99.38% for CLO and PH, respectively, by the proposed method, and percent relative standard deviation values for precision and accuracy studies were found to be less than 2. This spectrofluorimetry method has been found to have several advantages such as simple spectra, high selectivity, and low interference. By virtue of its high sensitivity, this method could be applied to the analysis of both CLO and PH in their co-formulated dose forms.

Toenail Manganese: A Sensitive and Specific Biomarker of Exposure to Manganese in Career Welders.

Manganese (Mn) is an essential trace metal. It is also a component of welding fume. Chronic inhalation of manganese from welding fume has been associated with decreased neurological function. Currently, there is not a universally recognized biomarker for Mn exposure; however, hair and toenails have shown promise. In a cohort of 45 male welders and 35 age-matched factory control subjects, we assessed the sensitivity and specificity of toenail Mn to distinguish occupationally exposed subjects from unexposed controls. Further we examined the exposure time window that best correlates with the proposed biomarker, and investigated if non-occupational exposure factors impacted toenail Mn concentrations. Toenail clippings were analyzed for Mn using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Exposure to respirable Mn-containing particles (<4 µm) was estimated using an exposure model that combines personal air monitoring, work history information, and dietary intake to estimate an individual's exposure to Mn from inhalation of welding fume. We assessed the group differences in toenail concentrations using a Student's t-test between welders and control subjects and performed a receiver operating characteristic (ROC) curve analysis to identify a threshold in toenail concentration that has the highest sensitivity and specificity in distinguishing welders from control subjects. Additionally, we performed mixed-model regressions to investigate the association between different exposure windows and toenail Mn concentrations. We observed that toenail Mn concentrations were significantly elevated among welders compared to control subjects (6.87 ± 2.56 versus 2.70 ± 1.70 µg g-1; P < 0.001). Our results show that using a toenail Mn concentration of 4.14 µg g-1 as cutoff allows for discriminating between controls and welders with 91% specificity and 94% sensitivity [area under curve (AUC) = 0.98]. Additionally, we found that a threshold of 4.66 µg g-1 toenail Mn concentration enables a 90% sensitive and 90% specific discrimination (AUC = 0.96) between subjects with average exposure above or below the American Conference of Governmental Industrial Hygienist (ACGIH) Threshold Limit Value (TLV) of 0.02 mg m-3 during the exposure window of 7-12 months prior to the nail being clipped. Investigating which exposure window was best reflected by toenail Mn reproduced the result from another study of toenail Mn being significantly (P < 0.001) associated with exposure 7-12 months prior to the nail being clipped. Lastly, we found that dietary intake, body mass index, age, smoking status, and ethnicity had no significant effect on toenail Mn concentrations. Our results suggest that toenail Mn is a sensitive, specific, and easy-to-acquire biomarker of Mn exposure, which is feasible to be used in an industrial welder population.

Polymeric Chemosensors: A Conventional Platform with New Click Chemistry

Abstract Polymers are a good platform for the production of various functional materials, since functional moieties can be introduced into both the main chain backbone and side chain pendants by elegant molecular design and utilizing efficient synthetic protocols. Highly colored and fluorescent π-systems have often been employed as ion sensing units especially when heteroaromatic rings are included. The heteroaromatic rings can form supramolecular complexes with metal ions or anions, resulting in the visual color changes of absorption and fluorescence. Conjugated polymers have been traditionally employed to this end, because they are highly emissive and very sensitive to various ions. However, most of such conjugated polymers are synthesized by costly cross-coupling polycondensations, which do not meet the green chemistry concepts of this century. Click chemistry is a new concept representing an efficient and atom-economic synthesis, and one of the most common reactions is the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) yielding 1,2,3-triazole rings. The 1,2,3-triazole derivatives are electronically almost inert, but they possess fluorescent chemosensor properties. Recent examples of polymeric chemosensors based on the 1,2,3-triazole derivatives are introduced. Furthermore, an emerging click chemistry reaction, i.e., the alkyne-acceptor click chemistry, is also introduced. This reaction produces highly colored donor-acceptor (D-A) chromophores on a polymer platform, enabling visual detection of the ion sensing behavior. The polymeric chemosensors with the D-A chromophores show a specific discrimination between hard and soft metal ions by different color changes. These polymers are also useful for anion sensing.

Psychometric properties of a short form of the Center for Epidemiologic Studies Depression (CES-D-10) scale for screening depressive symptoms in healthy community dwelling older adults.

The 10-item Center for the Epidemiological Studies of Depression Short Form (CES-D-10) is a widely used self-report measure of depression symptomatology. The aim of this study is to investigate the psychometric properties of the CES-D-10 in healthy community dwelling older adults. The sample consists of 19,114 community-based individuals residing in Australia and the United States who participated in the ASPREE trial baseline assessment. All individuals were free of any major illness at the time. We evaluated construct validity by performing confirmatory factor analysis, examined measurement invariance across country and gender followed by evaluating item discrimination bias in age, gender, race, ethnicity and education level, and assessing internal consistency. High item-total correlations and Cronbach's alpha indicated high internal consistency. The factor analyses suggested a unidimensional factor structure. Construct validity was supported in the overall sample, and by country and gender sub-groups. The CES-D-10 was invariant across countries, and although evidence of marginal gender non-invariance was observed there was no evidence of notable gender specific item discrimination bias. No notable differences in discrimination parameters or group membership measurement non-invariance were detected by gender, age, race, ethnicity, and education level. These findings suggest the CES-D-10 is a reliable and valid measure of depression in a volunteer sample. No noteworthy evidence of invariance and/or item discrimination bias is observed across gender, age, race, language and ethnic groups.

Balancing specificity, sensitivity, and speed of ligand discrimination by zero-order ultraspecificity.

Specific interactions between receptors and their target ligands in the presence of nontarget ligands are crucial for biological processes such as T cell ligand discrimination. To discriminate between the target and nontarget ligands, cells have to increase specificity to the target ligands by amplifying the small differences in affinity among ligands. In addition, sensitivity to the ligand concentration and quick discrimination are also important to detect low amounts of target ligands and facilitate fast cellular decision making after ligand recognition. In this work we propose a mechanism for nonlinear specificity amplification (ultraspecificity) based on zero-order saturating reactions, which was originally proposed to explain nonlinear sensitivity amplification (ultrasensitivity) to the ligand concentration. In contrast to the previously proposed proofreading mechanisms that amplify the specificity by a multistep reaction, our model can produce an optimal balance of specificity, sensitivity, and quick discrimination. Furthermore, we show that a model for insensitivity to a large number of nontarget ligands can be naturally derived from a model with the zero-order ultraspecificity. The zero-order ultraspecificity, therefore, may provide an alternative way to understand ligand discrimination from the viewpoint of nonlinear properties in biochemical reactions.

Abstract 2728: Frequency and prognostic value of PI3KCA mutations in early stage of colorectal cancer in Mexican patients

Abstract Background: There are molecular associations between mutated profiles and microsatelital instability, both related with tumor growth and oncogenic development by activating tyrosine receptors families in colorectal cancer (CRC). It is known that exon 9 and exon 20 (H1047R) mutations in PIK3CA increased PI3K activity. Moreover, PIK3CA mutations are significantly associated with tumor recurrence and poor overall survival. The frequency of PIK3CA mutations in CCR occurs in 15-20%, being the catalytic subunit more frequently affected. The aim of our study was to investigate the frequencies and clinical implications of these genetic alterations in advanced CRC. Methods: Retrospectively, we analyzed the initial paraffin embedded tissue block of 71 Mexican patients with CCR stage II. We evaluated mutations frequency of PIK3CA exon 9 (E542K, E545K) and exon 20 (H1047R) using qBiomarker Somatic Mutation PCR for real-time PCR-based. These methodology increases specificity, multiplex PCR and allelic discrimination. The data analysis was done using Ct values and Analysis Webportal. Results: We found in our population a frequency of PIK3CA mutations of 26%. Of those, double mutants were present in 7% with a higher frequency for E545K/H1047R. Clinical implication that we found is that any active mutation of PIK3CA is associated to an increase of recurrence risk (HR 1.86;CI 95% =0.46-7.5), but most important is for E545K mutation (HR 4.17; CI 95% 0.85-20.39), meanwhile comparing no mutated with H1074R mutated samples there were no differences in HR (0.53 vs. 0.60, respectively). Conclusions: We found a higher number of PI3KCA mutations that literature reports and that E545K mutation have a worst prognostic implication but we need to increase our sample looking for statistical significance results. Data from H1047R mutation raise de hypothesis that it could exist a compensatory mechanism related to structural interactions between both helicoidal and catalitic domains. Citation Format: Erika Ruiz-Garcia, Alette Ortega, Antonio Bahena, Edith Fernandez, German Calderillo, Cesar Lopez Camarillo, Laurence Marchat, Jorge Guadarrama, Abelardo Meneses-Garcia, Horacio Astudillo-de la Vega. Frequency and prognostic value of PI3KCA mutations in early stage of colorectal cancer in Mexican patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2728. doi:10.1158/1538-7445.AM2017-2728

Characteristic and intermingled neocortical circuits encode different visual object discriminations

Synaptic plasticity and neural network theories hypothesize that the essential information for advanced cognitive tasks is encoded in specific circuits and neurons within distributed neocortical networks. However, these circuits are incompletely characterized, and we do not know if a specific discrimination is encoded in characteristic circuits among multiple animals. Here, we determined the spatial distribution of active neurons for a circuit that encodes some of the essential information for a cognitive task. We genetically activated protein kinase C pathways in several hundred spatially-grouped glutamatergic and GABAergic neurons in rat postrhinal cortex, a multimodal associative area that is part of a distributed circuit that encodes visual object discriminations. We previously established that this intervention enhances accuracy for specific discriminations. Moreover, the genetically-modified, local circuit in POR cortex encodes some of the essential information, and this local circuit is preferentially activated during performance, as shown by activity-dependent gene imaging. Here, we mapped the positions of the active neurons, which revealed that two image sets are encoded in characteristic and different circuits. While characteristic circuits are known to process sensory information, in sensory areas, this is the first demonstration that characteristic circuits encode specific discriminations, in a multimodal associative area. Further, the circuits encoding the two image sets are intermingled, and likely overlapping, enabling efficient encoding. Consistent with reconsolidation theories, intermingled and overlapping encoding could facilitate formation of associations between related discriminations, including visually similar discriminations or discriminations learned at the same time or place.

Real-time fluorescence assay of alkaline phosphatase in living cells using boron-doped graphene quantum dots as fluorophores

This work reports a convenient and real-time assay of alkaline phosphatase (ALP) in living cells based on a fluorescence quench-recovery process at a physiological pH using the boron-doped graphene quantum dots (BGQDs) as fluorophore. The fluorescence of BGQDs is found to be effectively quenched by Ce3+ ions because of the coordination of Ce3+ ions with the carboxyl group of BGQDs. Upon addition of adenosine triphosphate (ATP) into the system, the quenched fluorescence can be recovered by the ALP-positive expressed cells (such as MCF-7 cells) due to the removal of Ce3+ ions from BGQDs surface by phosphate ions, which are generated from ATP under catalytic hydrolysis of ALP that expressed in cells. The extent of fluorescence signal recovery depends on the level of ALP in cells, which establishes the basis of ALP assay in living cells. This approach can also be used for specific discrimination of the ALP expression levels in different type of cells and thus sensitive detection of those ALP-positive expressed cells (for example MCF-7 cells) at a very low abundance (10±5 cells mL–1). The advantages of this approach are that it has high sensitivity because of the significant suppression of the background due to the Ce3+ ion quenching the fluorescence of BGQDs, and has the ability of avoiding false signals arising from the nonspecific adsorption of non-target proteins because it operates via a fluorescence quench-recovery process. In addition, it can be extended to other enzyme systems, such as ATP-related kinases.

Harnessing the DNA Dye-triggered Side Population Phenotype to Detect and Purify Cancer Stem Cells from Biological Samples.

Cancer is a stem cell-driven disease and eradication of these cells has become a major therapeutic goal. Deciphering vulnerabilities of Cancer Stem Cells (CSCs) and identifying suitable molecular targets relies on methods that allow their specific discrimination in heterogeneous samples such as cell lines and ex vivo tumor tissue. Flow cytometry/FACS is a powerful technology to multi-parametrically dissect biological samples at the single cell level and is to date the method of choice to recover live cells for downstream analyses. Surface markers such as CD44 and CD133 as well as detection of aldehyde dehydrogenase enzymatic activity have often been used to define and sort out CSCs from tumor samples by FACS. A complementary approach, depicted here in methodological detail, makes use of functional dye extrusion by ABC drug transporters, which identifies a distinct population of fluorescence-dim cells commonly referred to as side population (SP). SPcancer cells exhibit canonical stem cell characteristics and can be abrogated and functionally confirmed using agents that inhibit the dye-extruding drug transporter (most frequently ABCB1/P-glycoprotein/MDR1/CD243 and ABCG2/Bcrp1/CD338). Moreover, the SPassay is compatible with other flow cytometric evaluations such as staining of surface antigens, aldehyde dehydrogenase detection and dead cell discrimination (e.g., with 7-AAD or propidium iodide (PI)). Thus, we describe a valuable and broadly applicable method for CSC identification, isolation and sub-characterization mechanistically based on a functional, rather than a phenotypic parameter. Although originally performed with Hoechst 33342 as triggering dye, we here focus on the more recent Violet dye-based SP phenotype that is resolvable on any flow cytometer equipped with a violet laser source.

Selective visualization of DNA G-quadruplex structures in live cells with 1-methylquinolinium-based molecular probes: The importance of indolyl moiety position towards specificity

A class of small 1-methylquinolinium-based molecular fluorescent probes with high specificity in DNA G-quadruplex structures imaging in live cells was developed through the structural inclusion with an indolyl moiety. The study reveals that the scaffold of 1-methylquinolinium and indole ring is a distinctive combination for molecular design of new probes with effective and sensitive fluorescent signal switch-on functionality, particularly for identifying telomeric DNA, recognizing G-quadruplexes in promoters, and imaging or visualization of DNA G-quadruplex from other DNA structures. In addition, the experimental results demonstrate a rarely investigated factor on the importance of the indolyl moiety and its position when conjugating with a 1-methylquinolinium scaffold though a ethylene bridge in molecular probe design and synthesis; and these factors are determined as the crucial root leading to the excellent fluorescent signal switch-on property for the specific discrimination of DNA G-quadruplexes against other nucleic acids in live human prostate cancer cells (PC-3 cells) experiments. The characteristics of the new probes were comprehensively investigated with fluorescence titration, native PAGE experiments, and CD analysis to validate the selectivity, sensitivity, and stability while interacting with DNA G-quadruplex structures.

Assessing the dispersive and electrostatic components of the selenium-aromatic interaction energy by DFT.

Selenium has been increasingly recognized as an important element in biological systems, which participates in numerous biochemical processes in organisms, notably in enzyme reactions. Selenium can substitute sulfur of cysteine and methionine to form their selenium analogues, selenocysteine (Sec) and selenomethionine (SeM). The nature of amino acid pockets in proteins is dependent on their composition and thus different non-covalent forces determine the interactions between selenium of Sec or SeM and other functional groups, resulting in specific biophysical behavior. The discrimination of selenium toward sulfur has been reported. In order to elucidate the difference between the nature of S-π and Se-π interactions, we performed extensive DFT calculations of dispersive and electrostatic contributions of Se-π interactions in substituted benzenes/hydrogen selenide (H2Se) complexes. The results are compared with our earlier reported S-π calculations, as well as with available experimental data. Our results show a larger contribution of dispersive interactions in Se-π systems than in S-π ones, which mainly originate from the attraction between Se and substituent groups. We found that selenium exhibits a strong interaction with aromatic systems and may thus play a significant role in stabilizing protein folds and protein-inhibitor complexes. Our findings can also provide molecular insights for understanding enzymatic specificity discrimination between single selenium versus a sulfur atom, notwithstanding their very similar chemical properties.

A branch-migration based fluorescent probe for straightforward, sensitive and specific discrimination of DNA mutations

Genetic mutations are important biomarkers for cancer diagnostics and surveillance. Preferably, the methods for mutation detection should be straightforward, highly specific and sensitive to low-level mutations within various sequence contexts, fast and applicable at room-temperature. Though some of the currently available methods have shown very encouraging results, their discrimination efficiency is still very low. Herein, we demonstrate a branch-migration based fluorescent probe (BM probe) which is able to identify the presence of known or unknown single-base variations at abundances down to 0.3%-1% within 5 min, even in highly GC-rich sequence regions. The discrimination factors between the perfect-match target and single-base mismatched target are determined to be 89–311 by measurement of their respective branch-migration products via polymerase elongation reactions. The BM probe not only enabled sensitive detection of two types of EGFR-associated point mutations located in GC-rich regions, but also successfully identified the BRAF V600E mutation in the serum from a thyroid cancer patient which could not be detected by the conventional sequencing method. The new method would be an ideal choice for high-throughput in vitro diagnostics and precise clinical treatment.

Effects of Two Conventional Insecticides on Male-Specific Sex Pheromone Discrimination and Mate Choice in Trichogramma chilonis (Hymenoptera: Trichogrammatidae).

Trichogramma chilonis Ishii is an important natural enemy of many lepidopterous pests on vegetables and field crops. The effects of two conventional insecticides on male-specific sex pheromone discrimination and mate choice in T. chilonis was evaluated in the laboratory. Beta-cypermethrin LC20 exposure induced decreases in male conspecific sex pheromone discrimination and mating rate in T. chilonis, and these decreases were not due to the lower locomotor activity of the surviving T. chilonis males. Spinosad LC20 exposure caused a significant decrease in male locomotor activity of T. chilonis, but did not affect male-specific sex pheromone discrimination (conspecific sex pheromone discrimination or virgin sex pheromone discrimination) or mating rate. However, there was no significant difference in specific sex pheromone discrimination, mate choice, and locomotor activity between control males and males exposed to the low concentration (LC1) of insecticide (beta-cypermethrin or spinosad). In conclusion, beta-cypermethrin LC20 exposure was harmful to male-specific sex pheromone discrimination and mate choice in T. chilonis.

Empirical Investigation of a Model of Sexual Minority Specific and General Risk Factors for Intimate Partner Violence among Lesbian Women.

This study proposed and tested the first conceptual model of sexual minority specific (discrimination, internalized homophobia) and more general risk factors (perpetrator and partner alcohol use, anger, relationship satisfaction) for intimate partner violence among partnered lesbian women. Self-identified lesbian women (N=1048) were recruited from online market research panels. Participants completed an online survey that included measures of minority stress, anger, alcohol use and alcohol-related problems, relationship satisfaction, psychological aggression, and physical violence. The model demonstrated good fit and significant links from sexual minority discrimination to internalized homophobia and anger, from internalized homophobia to anger and alcohol problems, and from alcohol problems to intimate partner violence. Partner alcohol use predicted partner physical violence. Relationship dissatisfaction was associated with physical violence via psychological aggression. Physical violence was bidirectional. Minority stress, anger, alcohol use and alcohol-related problems play an important role in perpetration of psychological aggression and physical violence in lesbian women's intimate partner relationships. The results of this study provide evidence of potentially modifiable sexual minority specific and more general risk factors for lesbian women's partner violence.

A polymer-based probe for specific discrimination of cysteine.

A novel optically active methacrylic polymer with an amide-linked acrylate appendage as a chemosensor was synthesized by atom transfer radical polymerization (ATRP) followed by post-modification through a bottom-up design. The sensing behavior of the polymeric probe to various α-amino acids has been investigated through fluorescence, absorption, circular dichroism (CD), and visual color changes at physiological pH. It was found that the sensor exhibits specificity for the fluorescent recognition of cysteine against other amino acids and thiols in a turn-on mode, being significantly more effective than the corresponding small molecule counterpart. The detection limit was estimated to be in the micromolar range. In addition, the use of this chiral polymer allows the selective discrimination of cysteine enantiomers based on either fluorescence or CD spectral responses. Interestingly, the cysteine assay could also be visualized by the naked eye in the presence of small amounts of ferric ions.

A chiral BINOL-based Gemini amphiphilic gelator and its specific discrimination of native arginine by gelation in water.

A novel axially chiral cationic Gemini amphiphile gelator (S1) derived from (S)-BINOL has been synthesized and characterized by 1H NMR, 13C NMR, ESI-MS and FT-IR analyses. The critical micelle concentration (CMC) of S1 was determined to be 0.21 mM in water at room temperature. A transparent hydrogel with S1 at 43 mM was obtained at room temperature and characterized using various methods including SEM, CD, fluorescence, 1H NMR, FT-IR, and XRD. The results indicate that the hydrophobic effect of long alkyl chains, π-π stacking of naphthalene rings, and intermolecular hydrogen-bonding of the amide groups of S1 should be responsible for the hydrogel formation. Moreover, an 8.5 mM aqueous solution of S1 could gel by the addition of l-arginine, whereas it failed to gel in the presence of other 15 amino acids, respectively. It is suggested that S1 could discriminate native arginine by hydrogel formation, mainly due to the electrostatic interaction and hydrogen bonding effects between S1 and l-arginine molecules.

Ultra-specific discrimination of single-nucleotide mutations using sequestration-assisted molecular beacons.

Reliably distinguishing single-nucleotide mutations (SNMs) at low abundance is of great significance in clinical diagnosis. However, the specificity of most current SNM discrimination methods based on the Watson-Crick hybridization is seriously limited by the cross-reactivity of the probe with closely related unintended sequences. Herein, we propose a sequestration-assisted molecular beacon (MB) strategy for highly specific SNM discrimination. The new SNM discrimination system consists of a target-specific MB and a series of hairpin sequestering agents (SEQs). The rationally designed hairpin SEQs can effectively sequester the corresponding unintended sequences and thus dramatically improve the hybridization specificity of the MB in recognizing SNMs. The developed SNM discrimination method shows remarkably high specificity (discrimination factors ranging from 12 to 1144 with a median of 117) against 20 model SNMs, and can work rapidly and robustly over a wide range of conditions. Notably, our SNM discrimination method can be easily combined with PCR amplification for the detection of KRAS G12D (c.35G>A) and G12V (c.35G>T) mutations at abundance as low as 0.5%. This work expands the rule set of designing hybridization-based SNM discrimination strategies and shows promising potential application in clinical diagnosis.

Phenotypic spandrel: absolute discrimination and ligand antagonism

We consider the general problem of sensitive and specific discrimination between biochemical species. An important instance is immune discrimination between self and not-self, where it is also observed experimentally that ligands just below the discrimination threshold negatively impact response, a phenomenon called antagonism. We characterize mathematically the generic properties of such discrimination, first relating it to biochemical adaptation. Then, based on basic biochemical rules, we establish that, surprisingly, antagonism is a generic consequence of any strictly specific discrimination made independently from ligand concentration. Thus antagonism constitutes a ‘phenotypic spandrel’: a phenotype existing as a necessary by-product of another phenotype. We exhibit a simple analytic model of discrimination displaying antagonism, where antagonism strength is linear in distance from the detection threshold. This contrasts with traditional proofreading based models where antagonism vanishes far from threshold and thus displays an inverted hierarchy of antagonism compared to simpler models. The phenotypic spandrel studied here is expected to structure many decision pathways such as immune detection mediated by TCRs and FCϵRIs, as well as endocrine signalling/disruption.

Transfer in Rule-Based Category Learning Depends on the Training Task.

While learning is often highly specific to the exact stimuli and tasks used during training, there are cases where training results in learning that generalizes more broadly. It has been previously argued that the degree of specificity can be predicted based upon the learning solution(s) dictated by the particular demands of the training task. Here we applied this logic in the domain of rule-based categorization learning. Participants were presented with stimuli corresponding to four different categories and were asked to perform either a category discrimination task (which permits learning specific rule to discriminate two categories) or a category identification task (which does not permit learning a specific discrimination rule). In a subsequent transfer stage, all participants were asked to discriminate stimuli belonging to two of the categories which they had seen, but had never directly discriminated before (i.e., this particular discrimination was omitted from training). As predicted, learning in the category-discrimination tasks tended to be specific, while the category-identification task produced learning that transferred to the transfer discrimination task. These results suggest that the discrimination and identification tasks fostered the acquisition of different category representations which were more or less generalizable.