In vivo selection of carbapenem resistance during persistent Klebsiella pneumoniae sequence type 395 bloodstream infection due to OmpK36 deletion.

Non-carbapenemase-producing carbapenem-resistant Enterobacterales (non-CP CRE) may be associated with a grave outcome. The common underlying mechanism is beta-lactamases and mutations in outer membrane porins. We report a case of a deep-seated infection caused by Klebsiella pneumoniae ST395 not amenable to source control, involving recurrent bloodstream infection, resulting in in vivo selection of carbapenem resistance under therapy. Three consecutive K. pneumoniae blood isolates were studied using short- and long-read sequencing. The genomes were subject to resistome and virulome, phylogenetic, and plasmid analyses. ompK36 porins were analyzed at the nucleotide and amino acid levels. Genomes were compared to 297 public ST395 K. pneumoniae genomes using cgMLST, resistome, and porin analyses and the EuSCAPE project. Relevant ompK36 and micF sequences were extracted and analyzed as above. The three sequential K. pneumoniae blood isolates belonged to the same clone. Subsequent CR isolates revealed a new large deletion of the ompK36 gene also involving the upstream region (deletion of micF). Comparison with public ST395 genomes revealed the study isolates belonged to clade B, representing a separate clone. N-terminal large ompK36 truncations were uncommon in both public data sets. In vivo selection of non-CP CRE K. pneumoniae could have substantial clinical implications. Such selection should be scrutinized through repeated cultures and frequent susceptibility testing during antimicrobial treatment, especially in the context of persistent or recurrent bloodstream infections and when adequate source control cannot be achieved. The occurrence of an unusually large deletion involving the ompK36 locus and upstream micF should be further studied.

A shared novelty-seeking basis for creativity and curiosity: Response to the commentators.

In our target article, we proposed that curiosity and creativity are both manifestations of the same novelty-seeking process. We received 29 commentaries from diverse disciplines that add insights to our initial proposal. These commentaries ultimately expanded and supplemented our model. Here we draw attention to five central practical and theoretical issues that were raised by the commentators: (1) The complex construct of novelty and associated concepts; (2) the underlying subsystems and possible mechanisms; (3) the different pathways and subtypes of curiosity and creativity; (4) creativity and curiosity "in the wild"; (5) the possible link(s) between creativity and curiosity.

A shared novelty-seeking basis for creativity and curiosity.

Curiosity and creativity are central pillars of human growth and invention. While they have been studied extensively in isolation, the relationship between them has not yet been established. We propose that curiosity and creativity both emanate from the same mechanism of novelty-seeking. We first present a synthesis showing that curiosity and creativity are affected similarly by a number of key cognitive faculties such as memory, cognitive control, attention, and reward. We then review empirical evidence from neuroscience research, indicating that the same brain regions are involved in both curiosity and creativity, focusing on the interplay between three major brain networks: the default-mode network, the salience network, and the executive control network. After substantiating the link between curiosity and creativity, we propose a novelty-seeking model (NSM) that underlies them both and suggest that the manifestation of the NSM is governed by one's state of mind (SoM).

Price reductions in hearing aids and access to audiologists, Israel.

Problem: Hearing rehabilitation with hearing aids is a complex process which requires professional expertise and the involvement of audiologists or hearing-care specialists. Professional care, however, requires extra resources, making it tempting to rely solely on technology and reduce the role of professional counselling. Approach: To reduce the out-of-pocket share for adults needing hearing rehabilitation, in 2011 the Israeli government tripled the subsidy for adult hearing aids by converting 3 years of subsidies into a triennial, enlarged fund. Regulations for providing hearing rehabilitation and a set of rules for tenders for the supply of hearing aids were issued. Local setting: Auditory diagnosis and rehabilitation are included in the Israeli national health insurance system. Before 2011, the annual government-funded subsidy for hearing aids was negligible; hearing aids were expensive and bought mostly with patients' own resources. Relevant changes: A series of tenders for companies to supply hearing aids, aiming to control public and individual expenses, resulted in a large reduction in prices, which in turn raised the demand for hearing aids and increased public expenditure. As the price of hearing aids fell markedly, hearing rehabilitation is approaching a point of becoming limited to supplying hearing devices, while reducing the importance placed on professional elements of the rehabilitation course. Lessons learnt: Lowering out-of-pocket costs for patients should not be the only consideration in hearing rehabilitation. Our goal should be to control public expenditure but also provide affordable hearing aids with sufficient intervention of hearing-care specialists, to ensure access to advanced technologies and proper professional care.

How associative thinking influences scene perception.

Perception of our external environment is not isolated from the influence of our internal thoughts, and past evidence points to a possible common associative mechanism underlying both the perception of scenes and our internal thought. Here, we investigated the nature of the interaction between an associative mindset and scene perception, hypothesizing a functional advantage to an associative thought pattern in the perception of scenes. Experiments 1 and 2 showed that associative thinking facilitates scene perception, which evolved over the course of the experiments. In contrast to scene perception, Experiment 3 showed that associative thinking hinders the perception of mundane objects, in which associative information is minimized. Nevertheless, object perception was facilitated when associative thinking was reduced. This double dissociation suggests that an associative mind is more receptive of externally perceived associative information, and that a match between the orientation of internal and external processing may be key for perception.

Natural genetic variation for expression of a SWEET transporter among wild species of Solanum lycopersicum (tomato) determines the hexose composition of ripening tomato fruit.

The sugar content of Solanum lycopersicum (tomato) fruit is a primary determinant of taste and quality. Cultivated tomato fruit are characterized by near-equimolar levels of the hexoses glucose and fructose, derived from the hydrolysis of translocated sucrose. As fructose is perceived as approximately twice as sweet as glucose, increasing its concentration at the expense of glucose can improve tomato fruit taste. Introgressions of the FgrH allele from the wild species Solanum habrochaites (LA1777) into cultivated tomato increased the fructose-to-glucose ratio of the ripe fruit by reducing glucose levels and concomitantly increasing fructose levels. In order to identify the function of the Fgr gene, we combined a fine-mapping strategy with RNAseq differential expression analysis of near-isogenic tomato lines. The results indicated that a SWEET protein was strongly upregulated in the lines with a high fructose-to-glucose ratio. Overexpressing the SWEET protein in transgenic tomato plants dramatically reduced the glucose levels and increased the fructose : glucose ratio in the developing fruit, thereby proving the function of the protein. The SWEET protein was localized to the plasma membrane and expression of the SlFgr gene in a yeast line lacking native hexose transporters complemented growth with glucose, but not with fructose. These results indicate that the SlFgr gene encodes a plasma membrane-localized glucose efflux transporter of the SWEET family, the overexpression of which reduces glucose levels and may allow for increased fructose levels. This article identifies the function of the tomato Fgr gene as a SWEET transporter, the upregulation of which leads to a modified sugar accumulation pattern in the fleshy fruit. The results point to the potential of the inedible wild species to improve fruit sugar accumulation via sugar transport mechanisms.

Increasing propensity to mind-wander with transcranial direct current stimulation.

Humans mind-wander quite intensely. Mind wandering is markedly different from other cognitive behaviors because it is spontaneous, self-generated, and inwardly directed (inner thoughts). However, can such an internal and intimate mental function also be modulated externally by means of brain stimulation? Addressing this question could also help identify the neural correlates of mind wandering in a causal manner, in contrast to the correlational methods used previously (primarily functional MRI). In our study, participants performed a monotonous task while we periodically sampled their thoughts to assess mind wandering. Concurrently, we applied transcranial direct current stimulation (tDCS). We found that stimulation of the frontal lobes [anode electrode at the left dorsolateral prefrontal cortex (DLPFC), cathode electrode at the right supraorbital area], but not of the occipital cortex or sham stimulation, increased the propensity to mind-wander. These results demonstrate for the first time, to our knowledge, that mind wandering can be enhanced externally using brain stimulation, and that the frontal lobes play a causal role in mind-wandering behavior. These results also suggest that the executive control network associated with the DLPFC might be an integral part of mind-wandering neural machinery.

Predictions penetrate perception: Converging insights from brain, behaviour and disorder.

It is argued that during ongoing visual perception, the brain is generating top-down predictions to facilitate, guide and constrain the processing of incoming sensory input. Here we demonstrate that these predictions are drawn from a diverse range of cognitive processes, in order to generate the richest and most informative prediction signals. This is consistent with a central role for cognitive penetrability in visual perception. We review behavioural and mechanistic evidence that indicate a wide spectrum of domains-including object recognition, contextual associations, cognitive biases and affective state-that can directly influence visual perception. We combine these insights from the healthy brain with novel observations from neuropsychiatric disorders involving visual hallucinations, which highlight the consequences of imbalance between top-down signals and incoming sensory information. Together, these lines of evidence converge to indicate that predictive penetration, be it cognitive, social or emotional, should be considered a fundamental framework that supports visual perception.

Associated Information Increases Subjective Perception of Duration.

Our sense of time is prone to various biases. For instance, one factor that can dilate an event's perceived duration is the violation of predictions; when a series of repeated stimuli is interrupted by an unpredictable oddball. On the other hand, when the probability of a repetition itself is manipulated, predictable conditions can also increase estimated duration. This suggests that manipulations of expectations have different or even opposing effects on time perception. In previous studies, expectations were generated because stimuli were repeated or because the likelihood of a sequence or a repetition was varied. In the natural environment, however, expectations are often built via associative processes, for example, the context of a kitchen promotes the expectation of plates, appliances, and other associated objects. Here, we manipulated such association-based expectations by using oddballs that were either contextually associated or nonassociated with the standard items. We find that duration was more strongly overestimated for contextually associated oddballs. We reason that top-down attention is biased toward associated information, and thereby dilates subjective duration for associated oddballs. Based on this finding, we propose an interplay between top-down attention and predictive processing in the perception of time.

Cortical Integration of Contextual Information across Objects.

Recognizing objects in the environment and understanding our surroundings often depends on context: the presence of other objects and knowledge about their relations with each other. Such contextual information activates a set of medial lobe brain regions, the parahippocampal cortex and the retrosplenial complex. Both regions are more activated by single objects with a unique contextual association than by objects not associated with any specific context. Similarly they are more activated by spatially coherent arrangements of objects when those are consistent with their known spatial relations. The current study tested how context in multiple-object displays is represented in these regions in the absence of relevant spatial information. Using an fMRI slow-event-related design, we show that the precuneus (a subpart of the retrosplenial complex) is more activated by simultaneously presented contextually related objects than by unrelated objects. This suggests that the representation of context in this region is cumulative, representing integrated information across objects in the display. We discuss these findings in relation to processing of visual information and relate them to previous findings of contextual effects in perception.

Linking major depression and the neural substrates of associative processing.

It has been proposed that mood correlates with the breadth of associative thinking. Here we set this hypothesis to the test in healthy and depressed individuals. Generating contextual associations engages a network of cortical regions including the parahippocampal cortex (PHC), retrosplenial complex, and medial prefrontal cortex. The link between mood, associative processing, and its underlying cortical infrastructure provides a promising avenue for elucidating the mechanisms underlying the cognitive impairments in major depressive disorder (MDD). The participants included 15 nonmedicated individuals with acute major depressive episodes and 15 healthy matched controls. In an fMRI experiment, participants viewed images of objects that were either strongly or weakly associated with a specific context (e.g., a beach chair vs. a water bottle) while rating the commonality of each object. Analyses were performed to examine the brain activation and structural differences between the groups. Consistent with our hypothesis, controls showed greater activation of the contextual associations network than did depressed participants. In addition, PHC structural volume was correlated with ruminative tendencies, and the volumes of the hippocampal subfields were significantly smaller in depressed participants. Surprisingly, depressed participants showed increased activity in the entorhinal cortex (ERC), as compared with controls. We integrated these findings within a mechanistic account linking mood and associative thinking and suggest directions for the future.

Prior probability modulates anticipatory activity in category-specific areas.

Bayesian models are currently a dominant framework for describing human information processing. However, it is not clear yet how major tenets of this framework can be translated to brain processes. In this study, we addressed the neural underpinning of prior probability and its effect on anticipatory activity in category-specific areas. Before fMRI scanning, participants were trained in two behavioral sessions to learn the prior probability and correct order of visual events within a sequence. The events of each sequence included two different presentations of a geometric shape and one picture of either a house or a face, which appeared with either a high or a low likelihood. Each sequence was preceded by a cue that gave participants probabilistic information about which items to expect next. This allowed examining cue-related anticipatory modulation of activity as a function of prior probability in category-specific areas (fusiform face area and parahippocampal place area). Our findings show that activity in the fusiform face area was higher when faces had a higher prior probability. The finding of a difference between levels of expectations is consistent with graded, probabilistically modulated activity, but the data do not rule out the alternative explanation of a categorical neural response. Importantly, these differences were only visible during anticipation, and vanished at the time of stimulus presentation, calling for a functional distinction when considering the effects of prior probability. Finally, there were no anticipatory effects for houses in the parahippocampal place area, suggesting sensitivity to stimulus material when looking at effects of prediction.

Associative Activation and Its Relation to Exploration and Exploitation in the Brain.

Associative activation is commonly assumed to rely on associative strength, such that if A is strongly associated with B, B is activated whenever A is activated. We challenged this assumption by examining whether the activation of associations is state dependent. In three experiments, subjects performed a free-association task while the level of a simultaneous load was manipulated in various ways. In all three experiments subjects in the low-load conditions provided significantly more diverse and original associations compared with subjects in the high-load conditions, who exhibited high consensus. In an additional experiment, we found increased semantic priming of immediate associations under high load and of remote associations under low load. Taken together, these findings imply that activation of associations is an exploratory process by default, but is narrowed to exploiting the more immediate associations under conditions of high load. We propose a potential mechanism for processing associations in exploration and in exploitation modes, and suggest clinical implications.

Neural Correlates of Subliminal Language Processing.

Language is a high-level cognitive function, so exploring the neural correlates of unconscious language processing is essential for understanding the limits of unconscious processing in general. The results of several functional magnetic resonance imaging studies have suggested that unconscious lexical and semantic processing is confined to the posterior temporal lobe, without involvement of the frontal lobe-the regions that are indispensable for conscious language processing. However, previous studies employed a similarly designed masked priming paradigm with briefly presented single and contextually unrelated words. It is thus possible, that the stimulation level was insufficiently strong to be detected in the high-level frontal regions. Here, in a high-resolution fMRI and multivariate pattern analysis study we explored the neural correlates of subliminal language processing using a novel paradigm, where written meaningful sentences were suppressed from awareness for extended duration using continuous flash suppression. We found that subjectively and objectively invisible meaningful sentences and unpronounceable nonwords could be discriminated not only in the left posterior superior temporal sulcus (STS), but critically, also in the left middle frontal gyrus. We conclude that frontal lobes play a role in unconscious language processing and that activation of the frontal lobes per se might not be sufficient for achieving conscious awareness.

Convergent evidence for top-down effects from the "predictive brain".

Modern conceptions of brain function consider the brain as a "predictive organ," where learned regularities about the world are utilised to facilitate perception of incoming sensory input. Critically, this process hinges on a role for cognitive penetrability. We review a mechanism to explain this process and expand our previous proposals of cognitive penetrability in visual recognition to social vision and visual hallucinations.

Visual predictions in the orbitofrontal cortex rely on associative content.

Predicting upcoming events from incomplete information is an essential brain function. The orbitofrontal cortex (OFC) plays a critical role in this process by facilitating recognition of sensory inputs via predictive feedback to sensory cortices. In the visual domain, the OFC is engaged by low spatial frequency (LSF) and magnocellular-biased inputs, but beyond this, we know little about the information content required to activate it. Is the OFC automatically engaged to analyze any LSF information for meaning? Or is it engaged only when LSF information matches preexisting memory associations? We tested these hypotheses and show that only LSF information that could be linked to memory associations engages the OFC. Specifically, LSF stimuli activated the OFC in 2 distinct medial and lateral regions only if they resembled known visual objects. More identifiable objects increased activity in the medial OFC, known for its function in affective responses. Furthermore, these objects also increased the connectivity of the lateral OFC with the ventral visual cortex, a crucial region for object identification. At the interface between sensory, memory, and affective processing, the OFC thus appears to be attuned to the associative content of visual information and to play a central role in visuo-affective prediction.

Human preferences are biased towards associative information.

There is ample evidence that the brain generates predictions that help interpret sensory input. To build such predictions the brain capitalizes upon learned statistical regularities and associations (e.g., "A" is followed by "B"; "C" appears together with "D"). The centrality of predictions to mental activities gave rise to the hypothesis that associative information with predictive value is perceived as intrinsically valuable. Such value would ensure that this information is proactively searched for, thereby promoting certainty and stability in our environment. We therefore tested here whether, all else being equal, participants would prefer stimuli that contained more rather than less associative information. In Experiments 1 and 2 we used novel, meaningless visual shapes and showed that participants preferred associative shapes over shapes that had not been associated with other shapes during training. In Experiment 3 we used pictures of real-world objects and again demonstrated a preference for stimuli that elicit stronger associations. These results support our proposal that predictive information is affectively tagged, and enhance our understanding of the formation of everyday preferences.

Contributions of low and high spatial frequency processing to impaired object recognition circuitry in schizophrenia.

Patients with schizophrenia exhibit cognitive and sensory impairment, and object recognition deficits have been linked to sensory deficits. The "frame and fill" model of object recognition posits that low spatial frequency (LSF) information rapidly reaches the prefrontal cortex (PFC) and creates a general shape of an object that feeds back to the ventral temporal cortex to assist object recognition. Visual dysfunction findings in schizophrenia suggest a preferential loss of LSF information. This study used functional magnetic resonance imaging (fMRI) and resting state functional connectivity (RSFC) to investigate the contribution of visual deficits to impaired object "framing" circuitry in schizophrenia. Participants were shown object stimuli that were intact or contained only LSF or high spatial frequency (HSF) information. For controls, fMRI revealed preferential activation to LSF information in precuneus, superior temporal, and medial and dorsolateral PFC areas, whereas patients showed a preference for HSF information or no preference. RSFC revealed a lack of connectivity between early visual areas and PFC for patients. These results demonstrate impaired processing of LSF information during object recognition in schizophrenia, with patients instead displaying increased processing of HSF information. This is consistent with findings of a preference for local over global visual information in schizophrenia.

Early onset of neural synchronization in the contextual associations network.

Objects are more easily recognized in their typical context. However, is contextual information activated early enough to facilitate the perception of individual objects, or is contextual facilitation caused by postperceptual mechanisms? To elucidate this issue, we first need to study the temporal dynamics and neural interactions associated with contextual processing. Studies have shown that the contextual network consists of the parahippocampal, retrosplenial, and medial prefrontal cortices. We used functional MRI, magnetoencephalography, and phase synchrony analyses to compare the neural response to stimuli with strong or weak contextual associations. The context network was activated in functional MRI and preferentially synchronized in magnetoencephalography (MEG) for stimuli with strong contextual associations. Phase synchrony increased early (150-250 ms) only when it involved the parahippocampal cortex, whereas retrosplenial-medial prefrontal cortices synchrony was enhanced later (300-400 ms). These results describe the neural dynamics of context processing and suggest that context is activated early during object perception.