Unrelated Targets Research Articles

Saccade trajectories reveal dynamic interactions of semantic and spatial information during the processing of implicitly spatial words.

Implicit up/down words, such as bird and foot, systematically influence performance on visual tasks involving immediately following targets in compatible versus incompatible locations. Recent studies have observed that the semantic relation between prime words and target pictures can strongly influence the size and even the direction of the effect: Semantically related targets are processed faster in congruent versus incongruent locations (location-specific priming), whereas unrelated targets are processed slower in congruent locations. Here, we used eye-tracking to investigate the moment-to-moment processes underlying this pattern. Our reaction time (RT) results for related targets replicated the location-specific priming effect and showed a trend toward interference for unrelated targets. We then used growth curve analysis to test how up/down words and their match versus mismatch with immediately following targets in terms of semantics and vertical location influence concurrent saccadic eye movements. There was a strong main effect of spatial association on linear growth, with up words biasing changes in y-coordinates over time upward relative to down words (and vice versa). Similar to the case with the RT data, this effect was strongest for semantically related targets and reversed for unrelated targets. It is intriguing that all conditions showed a bias in the congruent direction in the initial stage of the saccade. Then, at around halfway into the saccade the effect kept increasing in the semantically related condition and reversed in the unrelated condition. These results suggest that online processing of up/down words triggers direction-specific oculomotor processes that are dynamically modulated by the semantic relation between prime words and targets. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

The impact of variety of episodic contexts on the integration of novel words into semantic network

ABSTRACTThe current study examined whether and how the variety of episodic contexts influences the integration of novel words into semantic network via thematic and taxonomic relations in a semantic priming task with event-related potential (ERP) technique. The novel words were acquired from discourses containing either single or multiple episodes. We found that corresponding concepts, targets thematic-related to learning episodes (Experiment 1) and taxonomic-related targets (Experiment 2) elicited semantic-priming N400s/LPCs effects compared to the unrelated targets in both conditions, whereas the targets thematic-related to unlearned episodes (Experiment 1) and feature-related targets (Experiment 2) elicited semantic-priming N400s/LPCs effects only in the multiple episodic condition. These results indicated that only the novel words learned from variable episodes could successfully prime thematically related words in unlearned episodes and feature-related words. Our findings suggest that the variety of episodic contexts contributes to establishing more stable and richer semantic representations of the novel words.

Artificial Intelligence/Machine Learning Challenges and Evolution

For 2018, one of the big challenges is the construction of security systems based on AI. However, it should take time and considerable resources to verify the effect of technologies involving machine learning and driving patterns. We can say that these structures are, conceptually, a computerized replica of their developers. While the trend is interesting, it does not provide any real guarantee as long as the same steps can be performed by criminals. The two armies faced in the virtual environment are in a continuous arms race, as faithful copies of their creators. Even if efforts seem to be hampered by the dynamics of the criminal spectrum, they are necessary precisely because of their mobility. Malware and ransomware attacks have targeted disparate and seemingly unrelated targets, globally. Condensing huge amounts of data at certain points or in mega-cloud spaces offers management advantages, but it can also be the premise of future offensive, not at all desirable. The confrontation engages the brightest minds on the planet, from both camps.

Development of bidirectional phono-semantic activation in toddlers.

A mediated priming effect refers to the activation of a target via a mediator previously activated by a prime. This effect has been found at 24 months of age for phono-semantic links: a prime ( cup) activates a target ( dog) via a mediator ( cat), providing evidence of activation in a forward direction (phonological to semantic). Interactive models, however, propose that activation propagates in both forward and backward directions between processing levels. This study investigated the development of bidirectional co-activation of phonological and semantic levels of processing in Spanish-speaking toddlers. In a primed preferential looking task, participants were exposed to an unlabelled prime image, followed by the presentation of two images, a target and a distractor. In Experiment 1, when images with a semantic-phonological relationship were presented, both 24- and 30-month-olds preferred to look at the named target with a relationship to the prime image ( dog- cat- cup). However, when an unrelated target image was named, 24-month-olds preferred to look at the target, but 30-month-olds did not. In Experiment 2, both 24- and 30-month-olds preferred to look at a target with a phono-semantic relationship to the prime ( cup- cat- dog) over an unrelated target. These results provide strong evidence of differences in the development of forward and backward interactions between semantic and phonological processing levels.

Sequence effects of the involuntary and the voluntary components of symbolic cueing.

The orienting of attention has been found to be influenced by the previous cueing status in a spatial-cueing paradigm. The explanation for this sequence effect remains uncertain. This study separated the involuntary and the voluntary components of arrow cueing by manipulating the predicted target locations. For example, a left arrow cue may have indicated that the target was more likely to appear at the up location. Therefore, three trial types were repeated or switched between trials: cued (targets appeared along the direction of the arrows), predicted (targets appeared at the locations predicted by the arrows), and unrelated (targets appeared at the other two locations, neither cued nor predicted). RTs of cued trials were found to be significantly facilitated after a previous cued trial; however, the same effect was not observed for predicted trials. The results suggest that significant sequence effects are induced only in the involuntary component of arrow cueing. The findings support the feature-integration hypothesis for the sequence effect of symbolic cueing.

Priming production: Neural evidence for enhanced automatic semantic activity preceding language production in schizophrenia.

IntroductionLexico-semantic disturbances are considered central to schizophrenia. Clinically, their clearest manifestation is in language production. However, most studies probing their underlying mechanisms have used comprehension or categorization tasks. Here, we probed automatic semantic activity prior to language production in schizophrenia using event-related potentials (ERPs).Methods19 people with schizophrenia and 16 demographically-matched healthy controls named target pictures that were very quickly preceded by masked prime words. To probe automatic semantic activity prior to production, we measured the N400 ERP component evoked by these targets. To determine the origin of any automatic semantic abnormalities, we manipulated the type of relationship between prime and target such that they overlapped in (a) their semantic features (semantically related, e.g. “cake” preceding a < picture of a pie >, (b) their initial phonemes (phonemically related, e.g. “stomach” preceding a < picture of a starfish >), or (c) both their semantic features and their orthographic/phonological word form (identity related, e.g. “socks” preceding a < picture of socks >). For each of these three types of relationship, the same targets were paired with unrelated prime words (counterbalanced across lists). We contrasted ERPs and naming times to each type of related target with its corresponding unrelated target.ResultsPeople with schizophrenia showed abnormal N400 modulation prior to naming identity related (versus unrelated) targets: whereas healthy control participants produced a smaller amplitude N400 to identity related than unrelated targets, patients showed the opposite pattern, producing a larger N400 to identity related than unrelated targets. This abnormality was specific to the identity related targets. Just like healthy control participants, people with schizophrenia produced a smaller N400 to semantically related than to unrelated targets, and showed no difference in the N400 evoked by phonemically related and unrelated targets. There were no differences between the two groups in the pattern of naming times across conditions.ConclusionPeople with schizophrenia can show abnormal neural activity associated with automatic semantic processing prior to language production. The specificity of this abnormality to the identity related targets suggests that that, rather than arising from abnormalities of either semantic features or lexical form alone, it may stem from disruptions of mappings (connections) between the meaning of words and their form.

The Influence of Concreteness of Concepts on the Integration of Novel Words into the Semantic Network.

On the basis of previous studies revealing a processing advantage of concrete words over abstract words, the current study aimed to further explore the influence of concreteness on the integration of novel words into semantic memory with the event related potential (ERP) technique. In the experiment during the learning phase participants read two-sentence contexts and inferred the meaning of novel words. The novel words were two-character non-words in Chinese language. Their meaning was either a concrete or abstract known concept which could be inferred from the contexts. During the testing phase participants performed a lexical decision task in which the learned novel words served as primes for either their corresponding concepts, semantically related or unrelated targets. For the concrete novel words, the semantically related words belonged to the same semantic categories with their corresponding concepts. For the abstract novel words, the semantically related words were synonyms of their corresponding concepts. The unrelated targets were real words which were concrete or abstract for the concrete or abstract novel words respectively. The ERP results showed that the corresponding concepts and the semantically related words elicited smaller N400s than the unrelated words. The N400 effect was not modulated by the concreteness of the concepts. In addition, the concrete corresponding concepts elicited a smaller late positive component (LPC) than the concrete unrelated words. This LPC effect was absent for the abstract words. The results indicate that although both concrete and abstract novel words can be acquired and linked to their related words in the semantic network after a short learning phase, the concrete novel words are learned better. Our findings support the (extended) dual coding theory and broaden our understanding of adult word learning and changes in concept organization.

Assay interference and off-target liabilities of reported histone acetyltransferase inhibitors

Many compounds with potentially reactive chemical motifs and poor physicochemical properties are published as selective modulators of biomolecules without sufficient validation and then propagated in the scientific literature as useful chemical probes. Several histone acetyltransferase (HAT) inhibitors with these liabilities are now routinely used to probe epigenetic pathways. We profile the most commonly used HAT inhibitors and confirm that the majority of them are nonselective interference compounds. Most (15 out of 23, 65%) of the inhibitors are flagged by ALARM NMR, an industry-developed counter-screen for promiscuous compounds. Biochemical counter-screens confirm that most of these compounds are either thiol-reactive or aggregators. Selectivity panels show many of these compounds modulate unrelated targets in vitro, while several also demonstrate nonspecific effects in cell assays. These data demonstrate the usefulness of performing counter-screens for bioassay promiscuity and assay interference, and raise caution about the utility of many widely used, but insufficiently validated, compounds employed in chemical biology.

Repetition priming reveals hemispheric differences in compound word processing

ABSTRACTThe left (LH) and right (RH) hemispheres are thought to implement different mechanisms for visual word recognition; the LH’s parallel encoding strategy is more efficient than the RH’s serial, letter-by-letter analysis. Here we examine differences in hemispheric language processing strategy by investigating repetition priming of compound words (e.g. buttercup) and their constituents (e.g. butter, cup). Eighty-eight right-handed participants (29 M, 59 F) completed a lexical decision experiment in which centrally-presented compounds primed related (whole compound, first constituent, second constituent) and unrelated targets presented laterally to the left or right visual field; participants made button-press word/nonword decisions. Consistent with the LH parallel/RH serial distinction, repetition priming prompted an RH advantage for first constituents, whereas the LH performed equally efficiently in response to both first and second constituents. These data thus highlight differences in the hemispheres’ language processing strategies, offering new evidence supporting a relative parallel/serial distinction in LH/RH visual word recognition.

Abstract 2640: Small-molecule inhibitors of CD73, CD39 and A2aR: Three anti-cancer targets in the ATP/adenosine signaling pathway

Abstract INTRODUCTION: In the tumor micro-environment (TME) Adenosine (ADO) dampens the immune response towards cancer cells by inhibiting the cytotoxic activity of effector cells and promoting the proliferation of immunosuppressive cells. Extracellular ADO is generated by the two ecto-nucleotidases CD39 (ATP→AMP) and CD73 (AMP→ADO). In immune cells ADO signals primarily through the G-protein coupled receptor A2aR. Inhibition of ADO generation and signaling have been shown to be promising therapeutic approaches for the treatment of cancer. METHODS: Potent and highly selective small molecule inhibitors for A2aR, CD73 and CD39 have been designed and synthesized by the Medicinal Chemistry Department at Arcus Biosciences. Enzymatic assays: CD39 and CD73 activity was assayed by quantitating hydrolysis of ATP or AMP, respectively. Inorganic phosphate was detected using a colorimetric (malachite green) protocol. ADO receptor assays: The potency of A2aR antagonists and selectivity towards related receptors was determined by measuring cAMP elevation in stably-expressing CHO cells following NECA (ADO mimic) stimulation. CD8+ T cell assays: Activation, proliferation and effector function of CD8+ T cells were quantified following compound treatment in the presence and absence of ATP. Mixed Lymphocyte Reaction (MLR): Cytokine levels were determined in an MLR assay after compound treatment in the presence and absence of ATP. Tumor models: CT26 and B16F10 syngeneic tumor models were used to assess the therapeutic effect of the inhibitors. RESULTS: Potent and highly selective small molecules have been generated to block either ADO generation or ADO signaling. The therapeutic potential of these molecules was assessed in CD8+ T cell assays, MLR assays and in various tumor models. CD73 inhibition blocked the conversion of AMP to ADO. CD39 inhibition blocked the conversion of ATP to AMP and A2aR inhibition abolished the increases in intracellular cAMP following ADO stimulation. The compounds are highly selective relative to related enzymes/receptors, as well as a large panel of unrelated targets. Inhibition of any one of the three targets robustly reversed adenosine-mediated inhibition of proliferation, CD25 expression, and IFN-γ and granzyme B production by human CD8+ T-cells. Robust inhibition of tumor growth in combination with anti-PD1 antibody was observed for several of these compounds. CONCLUSIONS: Highly potent and selective inhibitors of each of the 3 molecular targets involved in the ATP/adenosine pathway have been identified. Their ability to interfere with the extracellular generation of ADO and the immune-suppressive effects of ADO, as well as their effects on experimental tumor biology, have been demonstrated in various in vitro and in vivo models. Citation Format: Ulrike Schindler, Joanne B. Tan, Matt Walters, Annette Becker, Fangfang Yin, Ada Chen, Yu Chen, Wan Hsin Lim, Steve Young, Manmohan Leleti, Jay Powers, Juan C. Jaen. Small-molecule inhibitors of CD73, CD39 and A2aR: Three anti-cancer targets in the ATP/adenosine signaling pathway [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 2640. doi:10.1158/1538-7445.AM2017-2640

Identifying relationships between unrelated pharmaceutical target proteins on the basis of shared active compounds.

Aim:Computational exploration of small-molecule-based relationships between target proteins from different families.Materials & methods:Target annotations of drugs and other bioactive compounds were systematically analyzed on the basis of high-confidence activity data.Results:A total of 286 novel chemical links were established between distantly related or unrelated target proteins. These relationships involved a total of 1859 bioactive compounds including 147 drugs and 141 targets.Conclusion:Computational analysis of large amounts of compounds and activity data has revealed unexpected relationships between diverse target proteins on the basis of compounds they share. These relationships are relevant for drug discovery efforts. Target pairs that we have identified and associated compound information are made freely available.

On thwarted goals and displaced aggression: A compensatory competence model

Thwarted goals and motivational obstacles are antecedents of aggression, but it is not entirely clear what motivates the aggressive response or why it is often displaced onto unrelated targets. The present work applies Goal Systems Theory (Kruglanski et al., 2002) to consider how displaced aggression can sometimes operate like any other means to an end. Specifically, in five studies, we find that thwarted goals motivate displaced aggression to compensate for a threatened sense of competence. First, when an achievement goal is experimentally thwarted, it both threatens self-efficacy beliefs and increases displaced aggression (Studies 1–2). Second, when goal-thwarted individuals have the means to engage in displaced aggression, it reestablishes self-efficacy in the thwarted goal domain (Study 3). However, we find that the superordinate goal being served is competence and not to be aggressive per se: In Study 4, goal thwarted individuals choose to help someone rather than remain idle, even if idleness is the more aggressive alternative. In Study 5, displaced aggression is attenuated among individuals who expect a second performance opportunity in the thwarted goal domain. Together, the results suggest goal-thwarted individuals mainly resort to displaced aggression when they lack other means to interact effectively with the environment.

Explaining negative kin discrimination in a cooperative mammal society

Kin selection theory predicts that, where kin discrimination is possible, animals should typically act more favorably toward closer genetic relatives and direct aggression toward less closely related individuals. Contrary to this prediction, we present data from an 18-y study of wild banded mongooses, Mungos mungo, showing that females that are more closely related to dominant individuals are specifically targeted for forcible eviction from the group, often suffering severe injury, and sometimes death, as a result. This pattern cannot be explained by inbreeding avoidance or as a response to more intense local competition among kin. Instead, we use game theory to show that such negative kin discrimination can be explained by selection for unrelated targets to invest more effort in resisting eviction. Consistent with our model, negative kin discrimination is restricted to eviction attempts of older females capable of resistance; dominants exhibit no kin discrimination when attempting to evict younger females, nor do they discriminate between more closely or less closely related young when carrying out infanticidal attacks on vulnerable infants who cannot defend themselves. We suggest that in contexts where recipients of selfish acts are capable of resistance, the usual prediction of positive kin discrimination can be reversed. Kin selection theory, as an explanation for social behavior, can benefit from much greater exploration of sequential social interactions.

Returns to acquirers of listed and unlisted targets: an empirical study of Australian bidders

PurposeThis paper aims to evaluate the robustness of the listing effect in Australia, that is whether acquisitions of private firms create more value to the bidding firm’s shareholders than acquisitions of publicly listed firms.Design/methodology/approachThe authors analyze the market reaction to the announcement of takeover bids initiated by Australian public firms on private and public targets over the period 1990-2011. The analysis controls for a wide range of bidder, deal and target country characteristics that are likely to correlate with the target’s listing status and acquirer abnormal returns. The authors also use a selection model to address the endogenous choice of the target’s listing status.FindingsThe results indicate that bidders experience significantly higher abnormal returns of about 1.7 per cent in the 11-day event window when the target is a private firm. The authors show that this result is broad-based and persistent. It does not appear to depend on whether the target is small or large; whether it is related or unrelated to the bidder’s industry; whether it is in the resources sector; and whether the transaction is domestic or cross-border. They find some evidence that bidder returns might be stronger for larger acquisitions, for unrelated targets, and in poor market conditions such as in the wake of the recent global financial crisis.Research limitations/implicationsThe research would benefit from the inclusion of the bidding firm’s ownership and governance characteristics.Practical implicationsThe results support the view that market frictions contribute to make private firms attractive targets.Originality/valueThe analysis confirms the pervasiveness of the listing effect in a market characterized by a lesser degree of competition, higher search costs and the significance of the natural resources sector.

Influence of family ownership on the industry-diversifying nature of a firm’s M&A strategy: Empirical evidence from Continental Europe

We investigate how family ownership influences the industry-diversifying nature of M&As by listed companies in Continental Europe and the corresponding shareholder value effects at deal announcement. For a large sample of 3485 M&As during 2005–2013, we observe that acquirers having a family as the largest shareholder are less inclined to take over an unrelated target firm than lone-founder and other types of non-family firms. However, as the size of the family ownership stake increases, family firms become more eager to follow an industry-diversifying M&A strategy. While industry-diversifying M&As are associated with lower abnormal returns for acquirer shareholders on average, we also observe that family ownership fully reverses this negative effect. We therefore conclude that those unrelated M&As, although still representing a conflict of interest with the family firm’s minority investors, do not destroy shareholder value on average.

Abstract B090: Evaluation of a novel impedance-based assay for label free and dynamic assessment of CAR-T constructs efficacy against B-cell leukemia and lymphoma

Abstract Immunotherapy is emerging as a promising approach in cancer treatment, allowing specific targeting of cancer cells based on surface marker expression. In vitro characterization of the effectiveness of the treatment is a necessary step before moving into clinical trials, but currently technologies rely on endpoint assays that are unable to capture the complexity and dynamics of the in vivo immune response. Here we present the adaptation of an impedance-based technology to measure immune-mediated cell killing of B lymphoid and lymphoma tumor cells. Impedance technology is able to detect alterations in cell adhesion, morphology and cell number of adherent cells by measuring changes in conductance of microelectrodes embedded in 96 and 384-wells cell culture plates. The variation is reported through an impedance-related parameter termed Cell Index (CI). The platform enables label-free and continuous monitoring of cell viability, leaving the same cells still available for secondary end point assays. To adapt such adhesion-based technology to monitor non-adherent B cells, we developed a strategy where the bottom of the wells is coated with an anti-CD40 antibody. The coating allows specific adhesion and retention of B cells and measurement of changes in impedance that are proportional to cell number. Using primary T lymphocytes expressing Chimeric Antigen Receptors (CAR) against CD19 or unrelated targets, we were able to demonstrate specific killing of tumor B cell lines and primary cells also at very low effector:target ratios. The results were also confirmed by flow cytometry. Taken together our results demonstrate the high sensitivity of this high throughput approach when compared to end point assays like 51Cr release or flow cytometry, improving the workflow for therapy validation and optimization in the context of personalized medicine. Citation Format: Chelsea Xue, Fabio Cerignoli, Vladimir Senyukov, Piotr Pierog, Thomas Miller, Amy Shaw, Biao Xi, Lincoln Muir, Yama Abassi, Sadik Kassim. Evaluation of a novel impedance-based assay for label free and dynamic assessment of CAR-T constructs efficacy against B-cell leukemia and lymphoma [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B090.

Word-pair priming with biased homonyms: N400 and LPC effects

Abstract In an ERP investigation of biased homonym processing in minimal context, isolated homonym primes (e.g., ruler) preceded targets that were associated with either the dominant (e.g., inch) or subordinate (e.g., king) meaning of the homonym, were unrelated words (e.g., claw), or were nonwords (e.g., smole), presented 250 ms later in a lexical decision paradigm. Both dominant and subordinate associates elicited smaller amplitude N400s and LPCs than unrelated word targets. The N400 priming effect was greater for dominant than subordinate associates, reflecting sensitivity to meaning frequency and lexical competition between the two homonym meanings. The LPC priming effect was similar for dominant and subordinate associates, reflecting post-lexical relational processing between prime and target. In this paradigm, priming effects of meaning frequency due to automatic spreading activation extended only to the N400 time window; shortly thereafter, effects of lexical dominance disappeared and reprocessing of the binary relatedness of the homonym prime and subsequent word target took precedence.

Bilingual and Monolingual Idiom Processing Is Cut from the Same Cloth: The Role of the L1 in Literal and Figurative Meaning Activation.

The present study examines non-native (L2) and native (L1) listeners' access to figurative idiomatic meaning and literal constituent meaning in two cross-modal priming experiments. Proficient German learners of English (L2) and native speakers of American English (L1) responded to English target words preceded by English idioms embedded in non-biasing prime sentences in a lexical decision task. English idioms differed in levels of translatability: Lexical level idioms had word-for-word translation equivalents in German, while post-lexical level idioms had matching idiomatic concepts in German but could not be translated word for word. Target words either related to the figurative meaning of the idiom or related to the literal meaning of the final constituent word of the idiom (e.g., to pull someone's leg, literal target: walk, figurative target: joke). Both L1 and L2 listeners showed facilitatory priming for literally- and figuratively-related target words compared to unrelated control target words, with only marginal differences between the listener groups. No effect of translatability was found; that is, the existence of word-for-word translation equivalents in German neither facilitated nor hindered meaning activation for German L2 listeners. The results are interpreted in the context of L1 and L2 models of idiom processing as well as further relevant translation studies.

Conservation and Divergence in Nucleotide Excision Repair Lesion Recognition

Nucleotide excision repair is an important and highly conserved DNA repair mechanism with an exceptionally large range of chemically and structurally unrelated targets. Lesion verification is believed to be achieved by the helicases UvrB and XPD in the prokaryotic and eukaryotic processes, respectively. Using single molecule atomic force microscopy analyses, we demonstrate that UvrB and XPD are able to load onto DNA and pursue lesion verification in the absence of the initial lesion detection proteins. Interestingly, our studies show different lesion recognition strategies for the two functionally homologous helicases, as apparent from their distinct DNA strand preferences, which can be rationalized from the different structural features and interactions with other nucleotide excision repair protein factors of the two enzymes.

Individual Differences in Working Memory Capacity Modulates Semantic Negative Priming from Single Prime Words.

The present study investigated whether semantic negative priming from single prime words depends on the availability of cognitive control resources. Participants with high vs. low working memory capacity (as assessed by their performance in complex span and attentional control tasks) were instructed to either attend to or ignore a briefly presented single prime word that was followed by either a semantically related or unrelated target word on which participants made a lexical decision. Individual differences in working memory capacity (WMC) mainly affected the processing of the ignored primes, but not the processing of the attended primes: While the latter produced reliable positive semantic priming for both high- and low-WMC participants, the former gave rise to reliable semantic negative priming only for high WMC participants, with low WMC participants showing the opposite positive priming effect. The present results extend previous findings in demonstrating that (a) single negative priming can reliably generalize to semantic associates of the prime words, and (b) a differential availability of cognitive control resources can reliably modulate the negative priming effect at a semantic level of representation.