A Proteogenomic Pipeline for the Analysis of Protein Biosynthesis Errors in the Human Pathogen Candida albicans.

Candida albicans is a diploid pathogen known for its ability to live as a commensal fungus in healthy individuals but causing both superficial infections and disseminated candidiasis in immunocompromised patients where it is associated with high morbidity and mortality. Its success in colonizing the human host is attributed to a wide range of virulence traits that modulate interactions between the host and the pathogen, such as optimal growth rate at 37 °C, the ability to switch between yeast and hyphal forms, and a remarkable genomic and phenotypic plasticity. A fascinating aspect of its biology is a prominent heterogeneous proteome that arises from frequent genomic rearrangements, high allelic variation, and high levels of amino acid misincorporations in proteins. This leads to increased morphological and physiological phenotypic diversity of high adaptive potential, but the scope of such protein mistranslation is poorly understood due to technical difficulties in detecting and quantifying amino acid misincorporation events in complex protein samples. We have developed and optimized mass spectrometry and bioinformatics pipelines capable of identifying rare amino acid misincorporation events at the proteome level. We have also analyzed the proteomic profile of an engineered C. albicans strain that exhibits high level of leucine misincorporation at protein CUG sites and employed an in vivo quantitative gain-of-function fluorescence reporter system to validate our LC-MS/MS data. C. albicans misincorporates amino acids above the background level at protein sites of diverse codons, particularly at CUG, confirming our previous data on the quantification of leucine incorporation at single CUG sites of recombinant reporter proteins, but increasing misincorporation of Leucine at these sites does not alter the translational fidelity of the other codons. These findings indicate that the C. albicans statistical proteome exceeds prior estimates, suggesting that its highly plastic phenome may also be modulated by environmental factors due to translational ambiguity.

Epidemic responses under uncertainty.

We examine how policymakers react to a pandemic with uncertainty around key epidemiological and economic policy parameters by embedding a macroeconomic SIR model in a robust control framework. Uncertainty about disease virulence and severity leads to stricter and more persistent quarantines, while uncertainty about the economic costs of mitigation leads to less stringent quarantines. On net, an uncertainty-averse planner adopts stronger mitigation measures. Intuitively, the cost of underestimating the pandemic is out-of-control growth and permanent loss of life, while the cost of underestimating the economic consequences of quarantine is more transitory.

Distinct neural dynamics of the observed ostracism effect in decision-making under risk and ambiguity.

Observational ostracism, as a form of social exclusion, can significantly affect human behavior. However, the effects of observed ostracism on risky and ambiguous decision-making and the underlying neural mechanisms remain unclear. This event-related potential study investigated these issues by involving participants in a wheel-of- fortune task, considering observed ostracism and inclusion contexts. The results showed that the cue-P3 component was more enhanced during the choice phase for risky decisions than for ambiguous decisions in the observed inclusion contexts but not in the observed ostracism contexts. During the outcome evaluation phase, feedback-related negativity amplitudes following both risky and ambiguous decisions were higher in the no-gain condition than in the gain condition in the observed inclusion context. In contrast, this effect was only observed following risky decisions in the observed ostracism context. The feedback-P3 component did not exhibit an observed ostracism effect in risky and ambiguous decision-making tasks. Risk levels further modulated the cue-P3 and feedback-related negativity components, while ambiguity levels further modulated the feedback-P3 components. These findings demonstrate a neural dissociation between risk and ambiguity decision-making during observed ostracism that unfolds from the choice phase to the outcome evaluation phase.

Fractionating difficulty during sentence comprehension using functional neuroimaging.

Sentence comprehension is highly practiced and largely automatic, but this belies the complexity of the underlying processes. We used functional neuroimaging to investigate garden-path sentences that cause difficulty during comprehension, in order to unpack the different processes used to support sentence interpretation. By investigating garden-path and other types of sentences within the same individuals, we functionally profiled different regions within the temporal and frontal cortices in the left hemisphere. The results revealed that different aspects of comprehension difficulty are handled by left posterior temporal, left anterior temporal, ventral left frontal, and dorsal left frontal cortices. The functional profiles of these regions likely lie along a spectrum of specificity to generality, including language-specific processing of linguistic representations, more general conflict resolution processes operating over linguistic representations, and processes for handling difficulty in general. These findings suggest that difficulty is not unitary and that there is a role for a variety of linguistic and non-linguistic processes in supporting comprehension.

In the face of ambiguity: intrinsic brain organization in development predicts one's bias toward positivity or negativity.

Exacerbated negativity bias, including in responses to ambiguity, represents a common phenotype of internalizing disorders. Individuals differ in their propensity toward positive or negative appraisals of ambiguity. This variability constitutes one's valence bias, a stable construct linked to mental health. Evidence suggests an initial negativity in response to ambiguity that updates via regulatory processes to support a more positive bias. Previous work implicates the amygdala and prefrontal cortex, and regions of the cingulo-opercular system, in this regulatory process. Nonetheless, the neurodevelopmental origins of valence bias remain unclear. The current study tests whether intrinsic brain organization predicts valence bias among 119 children and adolescents (6 to 17 years). Using whole-brain resting-state functional connectivity, a machine-learning model predicted valence bias (r = 0.20, P = 0.03), as did a model restricted to amygdala and cingulo-opercular system features (r = 0.19, P = 0.04). Disrupting connectivity revealed additional intra-system (e.g. fronto-parietal) and inter-system (e.g. amygdala to cingulo-opercular) connectivity important for prediction. The results highlight top-down control systems and bottom-up perceptual processes that influence valence bias in development. Thus, intrinsic brain organization informs the neurodevelopmental origins of valence bias, and directs future work aimed at explicating related internalizing symptomology.

RNA or DNA? Revisiting the Chemical Nature of the Cenancestral Genome.

One of the central issues in the understanding of early cellular evolution is the characterisation of the cenancestor. This includes the description of the chemical nature of its genome. The disagreements on this question comprise several proposals, including the possibility that AlkB-mediated methylation repair of alkylated RNA molecules may be interpreted as evidence of a cenancestral RNA genome. We present here an evolutionary analysis of the cupin-like protein superfamily based on tertiary structure-based phylogenies that includes the oxygen-dependent AlkB and its homologs. Our results suggest that the repair of methylated RNA molecules is the outcome of the enzyme substrate ambiguity, and doesn´t necessarily indicates that the last common ancestor was endowed with an RNA genome.

Suppressing contextually irrelevant meanings of homophonic versus heterophonic homographs: A tDCS study targeting LIFG.

Readers frequently encounter homographs (e.g., bank) whose resolution requires selection-suppression processes: selecting the contextually relevant meaning, while suppressing the irrelevant one. In two experiments, we investigated how these processes are modulated by the phonological status of the homograph (homographs with one vs. two possible pronunciations); and what is the involvement of the left inferior frontal gyrus (LIFG, including Broca's area) in these processes. To these ends, Experiment 1 utilized the context verification task with two types of Hebrew homographs: homophonic (e.g., bank) and heterophonic (e.g., tear). In the task, participants read sentences ending either with a homograph (e.g., bank) or an unambiguous word (e.g., shore). The sentences were biased towards the homograph's subordinate meaning (e.g., The fisherman sat on the bank/shore), and were followed by a target word related to the homograph's dominant meaning (e.g., MONEY). The participants were asked to judge whether the target was related to the overall meaning of the sentence. An ambiguity effect was observed for both types of homographs, reflecting interference from the irrelevant dominant meaning. However, this ambiguity effect was larger for heterophonic than for homophonic homographs, indicating that dominant meanings of heterophonic homographs are more difficult to suppress. Experiment 2 was identical, except that the procedure was coupled with transcranial direct current stimulation (tDCS) over the LIFG (including Broca's area). We found that stimulating the LIFG abolished the ambiguity effect, but only in the case of heterophonic homographs. Together, these findings highlight the distinction between phonological and semantic levels of selection-suppression processes, and the involvement of the LIFG in the phonological level of these processes.

Attenuated neural activity in processing decision-making feedback in uncertain conditions in patients with mild cognitive impairment.

The present study aimed to explore the potential neural correlates during feedback evaluation during decision-making under risk and ambiguity in MCI. Nineteen individuals with MCI and twenty age-matched HCs were enrolled. Decision-making performance under risk and ambiguity was examined with the modified game of dice task (GDT) and an Iowa gambling task (IGT). Using task-related EEG data, reward positivity (RewP) and feedback P3 (fb-P3) were used to characterize participants' motivation and allocation of cognitive resources. Also, response time and event-related oscillation (ERO) were used to evaluate information processing speed, and the potent of post-feedback information integration and behavioral modulation. MCI patients had lower RewP (p = 0.022) and fb-P3 (p = 0.045) amplitudes in the GDT than HCs. Moreover, the amount and valence of feedback modulated the RewP (p = 0.008; p = 0.017) and fb-P3 (p < 0.001; p < 0.001). In the IGT, in addition to the significantly reduced fb-P3 observed in MCI patients (p = 0.010), the amount and valence of feedback modulated the RewP (p = 0.002; p = 0.020). Furthermore, MCI patients took longer to make decisions (t = 2.15, p = 0.041). The ERO analysis revealed that delta power was reduced in MCI (GDT: p = 0.045; p = 0.011). The findings suggest that, during feedback evaluation when making risky and ambiguous decisions, motivation, allocation of cognitive resources, information processing and neuronal excitability were attenuated in MCI. It implies that neural activity related to decision making was compromised in MCI.

Early life adversity is associated with greater similarity in neural representations of ambiguous and threatening stimuli.

Exposure to early life adversity (ELA) is hypothesized to sensitize threat-responsive neural circuitry. This may lead individuals to overestimate threat in the face of ambiguity, a cognitive-behavioral phenotype linked to poor mental health. The tendency to process ambiguity as threatening may stem from difficulty distinguishing between ambiguous and threatening stimuli. However, it is unknown how exposure to ELA relates to neural representations of ambiguous and threatening stimuli, or how processing of ambiguity following ELA relates to psychosocial functioning. The current fMRI study examined multivariate representations of threatening and ambiguous social cues in 41 emerging adults (aged 18 to 19 years). Using representational similarity analysis, we assessed neural representations of ambiguous and threatening images within affective neural circuitry and tested whether similarity in these representations varied by ELA exposure. Greater exposure to ELA was associated with greater similarity in neural representations of ambiguous and threatening images. Moreover, individual differences in processing ambiguity related to global functioning, an association that varied as a function of ELA. By evidencing reduced neural differentiation between ambiguous and threatening cues in ELA-exposed emerging adults and linking behavioral responses to ambiguity to psychosocial wellbeing, these findings have important implications for future intervention work in at-risk, ELA-exposed populations.

The effect of the attitude towards risk/ambiguity on examination grades: cross-sectional study in a Portuguese medical school.

Given the high prevalence of multiple-choice examinations with formula scoring in medical training, several studies have tried to identify other factors in addition to the degree of knowledge of students which influence their response patterns. This study aims to measure the effect of students' attitude towards risk and ambiguity on their number of correct, wrong, and blank answers. In October 2018, 233 3rd year medical students from the Faculty of Medicine of the University of Porto, in Porto, Portugal, completed a questionnaire which assessed the student's attitudes towards risk and ambiguity, and aversion to ambiguity in medicine. Simple and multiple regression models and the respective regression coefficients were used to measure the association between the students' attitudes, and their answers in two examinations that they had taken in June 2018. Having an intermediate level of ambiguity aversion in medicine (as opposed to a very high or low level) was associated with a significant increase in the number of correct answers and decrease in the number of blank answers in the first examination. In the second examination, high levels of ambiguity aversion in medicine were associated with a decrease in the number of wrong answers. Attitude towards risk, tolerance for ambiguity, and gender did not show significant association with the number of correct, wrong, and blank answers for either examination. Students' ambiguity aversion in medicine is correlated with their performance in multiple-choice examinations with negative marking. Therefore, it is suggested the planning and implementation of counselling sessions with medical students regarding the possible impact of ambiguity aversion on their performance in multiple-choice questions with negative marking.

The cost of doubt: assessing the association between attributional ambiguity and mental health.

OBJECTIVE: To quantify the association between attributional ambiguity-the uncertainty of whether an experience is discrimination-and mental health. METHODS: Using a nationally representative sample of U.S. adults recruited through an online survey by Ipsos (April 23 and May 3, 2021), attributional ambiguity was quantified by asking participants if they experienced anything in the past 6 months that they were unsure was discrimination. The survey also assessed the degree to which these experiences caused participants to feel bothered and to ruminate on them. Multiple linear regression models were used to analyze associations between attributional ambiguity and depressive symptoms and mental health status. RESULTS: Black and Hispanic participants reported higher rates of attributional ambiguity than White participants. Experiencing attributional ambiguity was associated with higher levels of depressive symptoms and poorer self-reported mental health status. Among those who reported attributional ambiguity, increases in bother and rumination scores were positively associated with depressive symptoms. CONCLUSION: Attributional ambiguity is an important yet overlooked social determinant of mental health. More research is needed to fully understand the impact of this stressor on population health, particularly among minoritized populations.

Online revision process in clause-boundary garden-path sentences.

A long-standing question in sentence processing research concerns the online parsing process in clause-boundary garden-path sentences, such as After Mary dressed John bathed. In this sentence, "John" must be parsed as the matrix subject DP but can be locally analysed as the object of the embedded verb. There is considerable evidence that the parser misanalyses these garden-path sentences. However, the controversy lies in whether the parser revises them during the online parsing process. The present study investigated this revision process through two self-paced reading experiments utilising grammatical constraints on reflexives and subject or object relative clauses embedded within the locally ambiguous DP. The results provided evidence of revision when a subject relative clause was embedded but not when an object relative clause was embedded. These findings suggest that the parser assigns grammatical structures that correspond to input strings during the revision of clause-boundary ambiguities but that object relative clauses affect the online revision process.

Effects of emotional ambiguity and emotional intensity on true and false memory.

Whereas the effects of emotional intensity (the perceived strength of an item's valence or arousal) have long been studied in true- and false-memory research, emotional ambiguity (the uncertainty that attaches to perceived emotional intensity) has only been studied recently. Available evidence suggests that emotional ambiguity has reliable effects on true memory that are distinct from those of emotional intensity. However, those findings are mostly restricted to recall, and the effects of emotional ambiguity on false memory remain unexplored. The current study addressed both limitations by measuring the effects of emotional ambiguity and emotional intensity on true and false recognition. In two experiments, we manipulated valence ambiguity and valence intensity (Experiment 1) and arousal ambiguity and arousal intensity (Experiment 2) of Deese/Roediger/McDermott lists. Multiple linear regression analyses were conducted for Experiment 1, Experiment 2, and the combined data of the experiments to separate the effects of emotional ambiguity and emotional intensity. Our results showed that both valence ambiguity and arousal ambiguity improved true recognition, and the effects of valence ambiguity remained robust even when controlling for valence intensity, arousal intensity, and arousal ambiguity. More importantly, for both valence and arousal, there was an interaction between ambiguity and intensity in false memory. Specifically, we found that valence ambiguity increased false recognition with positive valence, while arousal ambiguity amplified the effect of arousal intensity on false recognition. Our results are discussed in the context of the emotional ambiguity hypothesis and fuzzy-trace theory.

Rational policymaking during a pandemic.

Policymaking during a pandemic can be extremely challenging. As COVID-19 is a new disease and its global impacts are unprecedented, decisions are taken in a highly uncertain, complex, and rapidly changing environment. In such a context, in which human lives and the economy are at stake, we argue that using ideas and constructs from modern decision theory, even informally, will make policymaking a more responsible and transparent process.

An implicit representation of stimulus ambiguity in pupil size.

To guide behavior, perceptual systems must operate on intrinsically ambiguous sensory input. Observers are usually able to acknowledge the uncertainty of their perception, but in some cases, they critically fail to do so. Here, we show that a physiological correlate of ambiguity can be found in pupil dilation even when the observer is not aware of such ambiguity. We used a well-known auditory ambiguous stimulus, known as the tritone paradox, which can induce the perception of an upward or downward pitch shift within the same individual. In two experiments, behavioral responses showed that listeners could not explicitly access the ambiguity in this stimulus, even though their responses varied from trial to trial. However, pupil dilation was larger for the more ambiguous cases. The ambiguity of the stimulus for each listener was indexed by the entropy of behavioral responses, and this entropy was also a significant predictor of pupil size. In particular, entropy explained additional variation in pupil size independent of the explicit judgment of confidence in the specific situation that we investigated, in which the two measures were decoupled. Our data thus suggest that stimulus ambiguity is implicitly represented in the brain even without explicit awareness of this ambiguity.

Twelve tips for developing healthcare learners' uncertainty tolerance.

BACKGROUND: Uncertainty is pervasive throughout healthcare practice. Uncertainty tolerance (i.e. adaptively responding to perceived uncertainty) is considered to benefit practitioner wellbeing, encourage person-centred care, and support judicious healthcare resource utilisation. Accordingly, uncertainty tolerance development is increasingly referenced within training frameworks. Practical approaches to support healthcare learners' uncertainty tolerance development, however, are lacking. AIMS: Drawing on findings across the literature, and the authors' educational experiences, twelve tips for promoting healthcare learners' uncertainty tolerance were developed. RESULTS: Tips are divided into 1. Tips for Learners, 2. Tips for Educators and Supervisors, and 3. Tips for Healthcare Education Institutions and Systems. Each tip summarises relevant research findings, alongside applications to educational practice. CONCLUSIONS: Approaches to developing uncertainty tolerance balance factors supporting learners through uncertain experiences, with introducing challenges for learners to further develop uncertainty tolerance. These tips can reassure healthcare education stakeholders that developing learner uncertainty tolerance, alongside core knowledge, is achievable.

Ambiguity potentiates effects of loneliness on feelings of rejection.

For social species, having strong and high-quality social relationships is an important safety cue. Loneliness occurs when an individual perceives they have insufficient relationships resulting in feelings of lack of safety. States of perceived unsafety are linked to an increased tendency to construe ambiguous information - information lacking a unique clear interpretation - as threatening. Here, we explore whether the ambiguity of social cues of interpersonal rejection moderates effects of loneliness on feelings of rejection while undergoing social exclusion. Data were collected in 2021; 144 adults completed a progressive social exclusion paradigm where they were randomly assigned to be equally included, excluded, or over-included. Social exclusion/inclusion cues became more pronounced over the course of multiple rounds of a ball-tossing game (Cyberball) resulting in a scenario where ambiguity was highest in earlier rounds and decreased over time. Participants reported feelings of loneliness prior to the task and feelings of rejection throughout the task. Results demonstrated that higher loneliness predicted increased feelings of rejection regardless of exclusion condition. Notably, this positive relationship was strongest during earlier rounds when social cues were most ambiguous. These findings contribute to our understanding of how loneliness modulates social perception to enable organisms to adequately adapt to changing circumstances.

Associations of clinical context-specific ambiguity tolerance with burnout and work engagement among Japanese physicians: a nationwide cross-sectional study.

PURPOSE: Ambiguity tolerance specific to the clinical context - in contrast to ambiguity tolerance as a personality trait - may vary with experience and has received considerable attention. Although this tolerance appears to be related to burnout and work engagement, few studies have examined this association among physicians. Thus, we aimed to examine the relationships between clinical context-specific ambiguity tolerance, burnout, and work engagement among physicians in Japan. METHODS: We conducted a nationwide cross-sectional study in Japan. We invited family physicians from 14 family medicine residency programs and physicians with specialties other than family medicine from monitors of an Internet survey company to participate in the study. We measured ambiguity tolerance in the clinical context using the Japanese version of the Tolerance of Ambiguity in Medical Students and Doctors (J-TAMSAD) scale, burnout using the Japanese version of the Burnout Assessment Scale (BAT-J), and work engagement using the Utrecht Work Engagement Scale (UWES). We performed a multivariable linear regression analysis to determine whether the J-TAMSAD scale score was associated with the BAT-J and UWES scores. RESULTS: 383 respondents were included in the analysis. After adjustment for possible confounders, clinical context-specific ambiguity tolerance showed a dose-dependent negative association with burnout (adjusted mean difference -0.39, 95% confidence interval (CI) -0.56 to -0.22 for the highest J-TAMSAD score quartile compared with the lowest). Ambiguity tolerance in the clinical context also showed a dose-dependent positive association with work engagement (adjusted mean difference 0.83, 95% CI 0.49 to 1.16 for the highest J-TAMSAD score quartile compared with the lowest). CONCLUSIONS: Our study showed that tolerance for ambiguity in the clinical context was negatively associated with burnout, and positively associated with work engagement. These findings will be useful in developing interventions aimed at preventing burnout and promoting work engagement among physicians.

Investigation into the Co-Phase Detection Methodology for Segmented Plane Mirrors Utilizing Grazing Incidence Interferometry.

Segmented plane mirrors constitute a crucial component in the self-aligned detection process for large-aperture space optical imaging systems. Surface shape errors inherent in segmented plane mirrors primarily manifest as tilt errors and piston errors between sub-mirrors. While the detection and adjustment techniques for tilt errors are well-established, addressing piston errors poses a more formidable challenge. This study introduces a novel approach to achieve long-range, high-precision, and efficient co-phase detection of segmented plane mirrors by proposing a segmented plane mirror shape detection method based on grazing incidence interferometry. This method serves to broaden the detection range of piston errors, mitigate the issue of the 2π ambiguity resulting from piston errors in co-phase detection, and extend the detection capabilities of the interferometer. By manipulating the incident angle of the interferometer, both rough and precise adjustments of the segmented plane mirrors can be effectively executed.

Research and Verification of a Novel Interferometry Method by Joint Processing of Downlink Pseudo-Noise Ranging and DOR Signals for Deep Space Exploration.

The remarkably long distances covered by deep space probes result in extremely weak downlink signals, which poses great challenges for ground measurement systems. In the current climate, improving the comprehensive utilization of downlink signal power to increase the detection distance or enhance the measurement accuracy is of great significance in deep space exploration. Facing this problem, we analyze the delta Differential One-way Range (ΔDOR) error budget of the X-band of the China Deep Space Network (CDSN). Then, we propose a novel interferometry method that detunes one group of DOR beacons and reuses the clock components of regenerative pseudo-code ranging signals for interferometry delay estimation. The primary advantage of this method is its ability to enhance the power utilization efficiency of downlink signals, thereby facilitating more efficient tracking and measurement without necessitating additional design requirements for deep space transponders. Finally, we analyze and verify the correctness and effectiveness of our proposed method using measured data from CDSN. Our results indicate that the proposed method can save approximately 13% of the downlink signal power and increase the detection distance by about 6.25% using typical modulation parameters. Furthermore, if the relative power of other signal components remains unchanged, the power of the DOR tone can be directly increased by more than 100%, improving the deep space exploration ability more significantly.