The GTPase KRAS acts as a switch in cellular signaling, transitioning between inactive GDP-bound and active GTP-bound states. In about 20% of human cancers, oncogenic RAS mutations disrupt this ...balance, favoring the active form and promoting proliferative signaling, thus rendering KRAS an appealing target for precision medicine in oncology. In 2013, Shokat and co-workers achieved a groundbreaking feat by covalently targeting a previously undiscovered allosteric pocket (switch II pocket (SWIIP)) of KRASG12C. This breakthrough led to the development and approval of sotorasib (AMG510) and adagrasib (MRTX849), revolutionizing the treatment of KRASG12C-dependent lung cancer. Recent achievements in targeting various KRASG12X mutants, using SWIIP as a key binding pocket, are discussed. Insights from successful KRASG12C targeting informed the design of molecules addressing other mutations, often in a covalent manner. These findings offer promise for innovative approaches in addressing commonly occurring KRAS mutations such as G12D, G12V, G12A, G12S, and G12R in various cancers.
•Stimulus-driven theories hold that all salient stimuli capture attention.•goal-driven theories posit that salient but irrelevant stimuli can be inhibited.•despite absent behavioral costs, pop-out ...distractors captured attention initially.•attention to distractors is withdrawn at a later stage, while it is sustained for targets.•marking stimulus positions speeds up neural processing and improves performance.
There is much debate about the neural mechanisms that achieve suppression of salient distracting stimuli during visual search. The proactive suppression hypothesis asserts that if exposed to the same distractors repeatedly, these stimuli are actively inhibited before attention can be shifted to them. A contrasting proposal holds that attention is initially captured by salient distractors but is subsequently withdrawn. By concurrently measuring stimulus-driven and intrinsic brain potentials in 36 healthy human participants, we obtained converging evidence against early proactive suppression of distracting input. Salient distractors triggered negative event-related potentials (N1pc/N2pc), enhanced the steady-state visual evoked potential (SSVEP) relative to non-salient (filler) stimuli, and suppressed contralateral relative to ipsilateral alpha-band amplitudes—three electrophysiological measure associated with the allocation of attention—even though these distractors did not interfere with behavioral responses to the search targets. Furthermore, these measures indicated that both stimulus-driven and goal-driven allocations of attention occurred in conjunction with one another, with the goal-driven effect enhancing and prolonging the stimulus-driven effect. These results provide a new perspective on the traditional dichotomy between bottom-up and top-down attentional allocation. Control experiments revealed that continuous marking of the locations at which the search display items were presented resulted in a dramatic and unexpected conversion of the target-elicited N2pc into a shorter-latency N1pc in association with faster reaction times to the targets.
In this paper, the concepts of input/output-to-state stability (IOSS) and state-norm estimators are considered for switched nonlinear systems under average dwell-time switching signals. We show that ...when the average dwell-time is large enough, a switched system is IOSS if all of its constituent subsystems are IOSS. Moreover, under the same conditions, a non-switched state-norm estimator exists for the switched system. Furthermore, if some of the constituent subsystems are not IOSS, we show that still IOSS can be established for the switched system, if the activation time of the non-IOSS subsystems is not too big. Again, under the same conditions, a state-norm estimator exists for the switched system. However, in this case, the state-norm estimator is a switched system itself, consisting of two subsystems. We show that this state-norm estimator can be constructed such that its switching times are independent of the switching times of the switched system it is designed for.
This paper introduces and analyzes an improved Q-learning algorithm for discrete-time linear time-invariant systems. The proposed method does not require any knowledge of the system dynamics, and it ...enjoys significant efficiency advantages over other data-based optimal control methods in the literature. This algorithm can be fully executed off-line, as it does not require to apply the current estimate of the optimal input to the system as in on-policy algorithms. It is shown that a persistently exciting input, defined from an easily tested matrix rank condition, guarantees the convergence of the algorithm. A data-based method is proposed to design the initial stabilizing feedback gain that the algorithm requires. Robustness of the algorithm in the presence of noisy measurements is analyzed. We compare the proposed algorithm in simulation to different direct and indirect data-based control design methods.
PyblioNet is a software tool for the creation, visualization and analysis of bibliometric networks. It combines a Python-based data collection tool that accesses the Scopus database with a ...browser-based visualization and analysis tool. It allows users to create networks of publication data based on joint authorship, citations, co-citations, bibliographic coupling, and shared keywords. The overall goal of PyblioNet is to provide valuable insight and context when conducting research, to help users identify areas for further investigation, and to support the development of a robust research framework.
Rab proteins are the major regulators of vesicular trafficking in eukaryotic cells. Their activity can be tightly controlled within cells: Regulated by guanine nucleotide exchange factors (GEFs) and ...GTPase activating proteins (GAPs), they switch between an active GTP-bound state and an inactive GDP-bound state, interacting with downstream effector proteins only in the active state. Additionally, they can bind to membranes via C-terminal prenylated cysteine residues and they can be solubilized and shuttled between membranes by chaperone-like molecules called GDP dissociation inhibitors (GDIs). In this review we give an overview of Rab proteins with a focus on the current understanding of their regulation by GEFs, GAPs and GDI.
This study used a typical four-item search display to investigate top-down control over attentional capture in an additional singleton paradigm. By manipulating target and distractor color and shape, ...stimulus saliency relative to the remaining items was systematically varied. One group of participants discriminated the side of a dot within a salient orange target (ST group) presented with green circles (fillers) and a green diamond distractor. A second group discriminated the side of the dot within a green diamond target presented with green circle fillers and a salient orange square distractor (SD group). Results showed faster reaction times and a shorter latency of the N2pc component in the event-related potential (ERP) to the more salient targets in the ST group. Both salient and less salient distractors elicited Pd components of equal amplitude. Behaviorally, no task interference was observed with the less salient distractor, indicating the prevention of attentional capture. However, reaction times were slower in the presence of the salient distractor, which conflicts with the hypothesis that the Pd reflects proactive distractor suppression. Contrary to recent proposals that elicitation of the Pd requires competitive interactions with a target, we found a greater Pd amplitude when the distractor was presented alone. Alpha-band amplitudes decreased during target processing (event-related desynchronization), but no significant amplitude enhancement was observed at electrodes contralateral to distractors regardless of their saliency. The results demonstrate independent neural mechanisms for target and distractor processing and support the view that top-down guidance of attention can be offset (counteracted) by relative stimulus saliency.
Our visual system extracts the emotional meaning of human facial expressions rapidly and automatically. Novel paradigms using fast periodic stimulations have provided insights into the ...electrophysiological processes underlying emotional content extraction: the regular occurrence of specific identities and/or emotional expressions alone can drive diagnostic brain responses. Consistent with a processing advantage for social cues of threat, we expected angry facial expressions to drive larger responses than neutral expressions. In a series of four EEG experiments, we studied the potential boundary conditions of such an effect: (i) we piloted emotional cue extraction using 9 facial identities and a fast presentation rate of 15 Hz (N = 16); (ii) we reduced the facial identities from 9 to 2, to assess whether (low or high) variability across emotional expressions would modulate brain responses (N = 16); (iii) we slowed the presentation rate from 15 Hz to 6 Hz (N = 31), the optimal presentation rate for facial feature extraction; (iv) we tested whether passive viewing instead of a concurrent task at fixation would play a role (N = 30). We consistently observed neural responses reflecting the rate of regularly presented emotional expressions (5 Hz and 2 Hz at presentation rates of 15 Hz and 6 Hz, respectively). Intriguingly, neutral expressions consistently produced stronger responses than angry expressions, contrary to the predicted processing advantage for threat-related stimuli. Our findings highlight the influence of physical differences across facial identities and emotional expressions.
We present an extension of Willems' Fundamental Lemma to the class of multi-input multi-output discrete-time feedback linearizable nonlinear systems, thus providing a data-based representation of ...their input-output trajectories. Two sources of uncertainty are considered. First, the unknown linearizing input is inexactly approximated by a set of basis functions. Second, the measured output data is contaminated by additive noise. Further, we propose an approach to approximate the solution of the data-based simulation and output matching problems, and show that the difference from the true solution is bounded. Finally, the results are illustrated on an example of a fully-actuated double inverted pendulum.
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