IκB kinase-α coordinates BRD4 and JAK/STAT signaling to subvert DNA damage-based anticancer therapy.

Activation of the IκB kinase (IKK) complex has recurrently been linked to colorectal cancer (CRC) initiation and progression. However, identification of downstream effectors other than NF-κB has remained elusive. Here, analysis of IKK-dependent substrates in CRC cells after UV treatment revealed that phosphorylation of BRD4 by IKK-α is required for its chromatin-binding at target genes upon DNA damage. Moreover, IKK-α induces the NF-κB-dependent transcription of the cytokine LIF, leading to STAT3 activation, association with BRD4 and recruitment to specific target genes. IKK-α abrogation results in defective BRD4 and STAT3 functions and consequently irreparable DNA damage and apoptotic cell death upon different stimuli. Simultaneous inhibition of BRAF-dependent IKK-α activity, BRD4, and the JAK/STAT pathway enhanced the therapeutic potential of 5-fluorouracil combined with irinotecan in CRC cells and is curative in a chemotherapy-resistant xenograft model. Finally, coordinated expression of LIF and IKK-α is a poor prognosis marker for CRC patients. Our data uncover a functional link between IKK-α, BRD4, and JAK/STAT signaling with clinical relevance.

Neurodesk: an accessible, flexible and portable data analysis environment for reproducible neuroimaging.

Neuroimaging research requires purpose-built analysis software, which is challenging to install and may produce different results across computing environments. The community-oriented, open-source Neurodesk platform ( https://www.neurodesk.org/ ) harnesses a comprehensive and growing suite of neuroimaging software containers. Neurodesk includes a browser-accessible virtual desktop, command-line interface and computational notebook compatibility, allowing for accessible, flexible, portable and fully reproducible neuroimaging analysis on personal workstations, high-performance computers and the cloud.

The influence of subcortical shortcuts on disordered sensory and cognitive processing.

The very earliest stages of sensory processing have the potential to alter how we perceive and respond to our environment. These initial processing circuits can incorporate subcortical regions, such as the thalamus and brainstem nuclei, which mediate complex interactions with the brain's cortical processing hierarchy. These subcortical pathways, many of which we share with other animals, are not merely vestigial but appear to function as 'shortcuts' that ensure processing efficiency and preservation of vital life-preserving functions, such as harm avoidance, adaptive social interactions and efficient decision-making. Here, we propose that functional interactions between these higher-order and lower-order brain areas contribute to atypical sensory and cognitive processing that characterizes numerous neuropsychiatric disorders.

The noncoding RNA CcnA modulates the master cell cycle regulators CtrA and GcrA in Caulobacter crescentus.

Bacteria are powerful models for understanding how cells divide and accomplish global regulatory programs. In Caulobacter crescentus, a cascade of essential master regulators supervises the correct and sequential activation of DNA replication, cell division, and development of different cell types. Among them, the response regulator CtrA plays a crucial role coordinating all those functions. Here, for the first time, we describe the role of a novel factor named CcnA (cell cycle noncoding RNA A), a cell cycle-regulated noncoding RNA (ncRNA) located at the origin of replication, presumably activated by CtrA, and responsible for the accumulation of CtrA itself. In addition, CcnA may be also involved in the inhibition of translation of the S-phase regulator, GcrA, by interacting with its 5' untranslated region (5' UTR). Performing in vitro experiments and mutagenesis, we propose a mechanism of action of CcnA based on liberation (ctrA) or sequestration (gcrA) of their ribosome-binding site (RBS). Finally, its role may be conserved in other alphaproteobacterial species, such as Sinorhizobium meliloti, representing indeed a potentially conserved process modulating cell cycle in Caulobacterales and Rhizobiales.

Are we really Bayesian? Probabilistic inference shows sub-optimal knowledge transfer.

Numerous studies have found that the Bayesian framework, which formulates the optimal integration of the knowledge of the world (i.e. prior) and current sensory evidence (i.e. likelihood), captures human behaviours sufficiently well. However, there are debates regarding whether humans use precise but cognitively demanding Bayesian computations for behaviours. Across two studies, we trained participants to estimate hidden locations of a target drawn from priors with different levels of uncertainty. In each trial, scattered dots provided noisy likelihood information about the target location. Participants showed that they learned the priors and combined prior and likelihood information to infer target locations in a Bayes fashion. We then introduced a transfer condition presenting a trained prior and a likelihood that has never been put together during training. How well participants integrate this novel likelihood with their learned prior is an indicator of whether participants perform Bayesian computations. In one study, participants experienced the newly introduced likelihood, which was paired with a different prior, during training. Participants changed likelihood weighting following expected directions although the degrees of change were significantly lower than Bayes-optimal predictions. In another group, the novel likelihoods were never used during training. We found people integrated a new likelihood within (interpolation) better than the one outside (extrapolation) the range of their previous learning experience and they were quantitatively Bayes-suboptimal in both. We replicated the findings of both studies in a validation dataset. Our results showed that Bayesian behaviours may not always be achieved by a full Bayesian computation. Future studies can apply our approach to different tasks to enhance the understanding of decision-making mechanisms.

Bayesian accounts of perceptual decisions in the nonclinical continuum of psychosis: Greater imprecision in both top-down and bottom-up processes.

Neurocomputational accounts of psychosis propose mechanisms for how information is integrated into a predictive model of the world, in attempts to understand the occurrence of altered perceptual experiences. Conflicting Bayesian theories postulate aberrations in either top-down or bottom-up processing. The top-down theory predicts an overreliance on prior beliefs or expectations resulting in aberrant perceptual experiences, whereas the bottom-up theory predicts an overreliance on current sensory information, as aberrant salience is directed towards objectively uninformative stimuli. This study empirically adjudicates between these models. We use a perceptual decision-making task in a neurotypical population with varying degrees of psychotic-like experiences. Bayesian modelling was used to compute individuals' reliance on prior relative to sensory information. Across two datasets (discovery dataset n = 363; independent replication in validation dataset n = 782) we showed that psychotic-like experiences were associated with an overweighting of sensory information relative to prior expectations, which seem to be driven by decreased precision afforded to prior information. However, when prior information was more uncertain, participants with greater psychotic-like experiences encoded sensory information with greater noise. Greater psychotic-like experiences were associated with aberrant precision in the encoding both prior and likelihood information, which we suggest may be related to generally heightened perceptions of task instability. Our study lends empirical support to notions of both weaker bottom-up and weaker (rather than stronger) top-down perceptual processes, as well as aberrancies in belief updating that extend into the non-clinical continuum of psychosis.

Assessing the influence of dopamine and mindfulness on the formation of routines in visual search.

Given experience in cluttered but stable visual environments, our eye-movements form stereotyped routines that sample task-relevant locations, while not mixing-up routines between similar task-settings. Both dopamine signaling and mindfulness have been posited as factors that influence the formation of such routines, yet quantification of their impact remains to be tested in healthy humans. Over two sessions, participants searched through grids of doors to find hidden targets, using a gaze-contingent display. Within each session, door scenes appeared in either one of two colors, with each color signaling a differing set of likely target locations. We derived measures for how well target locations were learned (target-accuracy), how routine were sets of eye-movements (stereotypy), and the extent of interference between the two scenes (setting-accuracy). Participants completed two sessions, where they were administered either levodopa (dopamine precursor) or placebo (vitamin C), under double-blind counterbalanced conditions. Dopamine and trait mindfulness (assessed by questionnaire) interacted to influence both target-accuracy and stereotypy. Increasing dopamine improved accuracy and reduced stereotypy for high mindfulness scorers, but induced the opposite pattern for low mindfulness scorers. Dopamine also disrupted setting-accuracy invariant to mindfulness. Our findings show that mindfulness modulates the impact of dopamine on the target-accuracy and stereotypy of eye-movement routines, whereas increasing dopamine promotes interference between task-settings, regardless of mindfulness. These findings provide a link between non-human and human models regarding the influence of dopamine on the formation of task-relevant eye-movement routines and provide novel insights into behavior-trait factors that modulate the use of experience when building adaptive repertoires.

Reducing DNS Traffic to Enhance Home IoT Device Privacy.

The deployment of Internet of Things (IoT) devices is widespread in different environments, including homes. Although security is incorporated, homes can become targets for cyberattacks because of their vulnerabilities. IoT devices generate Domain Name Server (DNS) traffic primarily for communication with Internet servers. In this paper, we present a detailed analysis of DNS traffic from IoT devices. The queried domains are highly distinctive, enabling attackers to easily identify the IoT device. In addition, we observed an unexpectedly high volume of queries. The analysis reveals that the same domains are repeatedly queried, DNS queries are transmitted in plain text over User Datagram Protocol (UDP) port 53 (Do53), and the excessive generation of traffic poses a security risk by amplifying an attacker's ability to identify IoT devices and execute more precise, targeted attacks, consequently escalating the potential compromise of the entire IoT ecosystem. We propose a simple measure that can be taken to reduce DNS traffic generated by IoT devices, thus preventing it from being used as a vector to identify the types of devices present in the network. This measure is based on the implementation of the DNS cache in the devices; caching few resources increases privacy considerably.

Improved Efficacy of Delayed Treatment with Human Bone Marrow-Derived Stromal Cells Evaluated in Rats with Spinal Cord Injury.

The treatment of spinal cord injury (SCI) with uncultivated human bone marrow-derived stromal cells (bmSCs) prepared by negative selection has been proposed to be therapeutically superior to treatment with stem cells that were expanded in vitro. To explore their use in clinical trials, we studied the functional effects of delayed application at 7 days after SCI by testing different doses of bmSCs. Spinal cord contusion injury was induced in adult male Wistar rats at the thoracic level T9. Human bmSCs were prepared by negative selection without expansion in vitro (NeuroCellsTM). Treatment consisted of one 150 µL injection into the cisterna magna containing 0.5 or 2.5 million fresh bmSCs or 2.5 million bmSCs. The recovery of motor functions was evaluated during a surveillance period of six weeks (6 W), during which spinal cords were assessed histologically. Treatment resulted in a significant, dose-dependent therapeutic effect on the recovery of motor performance. The histological analysis revealed a lower degree of axonal degeneration and better survival of neurons and oligodendrocytes in bmSCs treated rats. Our results support delayed intrathecal application of bmSCs prepared by negative selection without expansion in vitro as a treatment of SCI.

Evidence for adaptive myelination of subcortical shortcuts for visual motion perception in healthy adults.

Conscious visual motion information follows a cortical pathway from the retina to the lateral geniculate nucleus (LGN) and on to the primary visual cortex (V1) before arriving at the middle temporal visual area (MT/V5). Alternative subcortical pathways that bypass V1 are thought to convey unconscious visual information. One flows from the retina to the pulvinar (PUL) and on to medial temporal visual area (MT); while the other directly connects the LGN to MT. Evidence for these pathways comes from non-human primates and modest-sized studies in humans with brain lesions. Thus, the aim of the current study was to reconstruct these pathways in a large sample of neurotypical individuals and to determine the degree to which these pathways are myelinated, suggesting information flow is rapid. We used the publicly available 7T (N = 98; 'discovery') and 3T (N = 381; 'validation') diffusion magnetic resonance imaging datasets from the Human Connectome Project to reconstruct the PUL-MT (including all subcompartments of the PUL) and LGN-MT pathways. We found more fibre tracts with greater density in the left hemisphere. Although the left PUL-MT path was denser, the bilateral LGN-MT tracts were more heavily myelinated, suggesting faster signal transduction. We suggest that this apparent discrepancy may be due to 'adaptive myelination' caused by more frequent use of the LGN-MT pathway that leads to greater myelination and faster overall signal transmission.

Anxiety attenuates learning advantages conferred by statistical stability and induces loss of volatility-attuning in brain activity.

Anxiety can alter an individual's perception of their external sensory environment. Previous studies suggest that anxiety can increase the magnitude of neural responses to unexpected (or surprising) stimuli. Additionally, surprise responses are reported to be boosted during stable compared to volatile environments. Few studies, however, have examined how learning is impacted by both threat and volatility. To investigate these effects, we used threat-of-shock to transiently increase subjective anxiety in healthy adults while they performed an auditory oddball task under stable and volatile environments and while undergoing functional Magnetic Resonance Imaging (fMRI) scanning. We then used Bayesian Model Selection (BMS) mapping to identify the brain areas where different models of anxiety displayed the highest evidence. Behaviourally, we found that threat-of-shock eliminated the accuracy advantage conferred by environmental stability over volatility. Neurally, we found that threat-of-shock led to attenuation and loss of volatility-attuning of brain activity evoked by surprising sounds across most subcortical and limbic regions including the thalamus, basal ganglia, claustrum, insula, anterior cingulate, hippocampal gyrus and the superior temporal gyrus. Taken together, our findings suggest that threat eliminates learning advantages conferred by statistical stability compared to volatility. Thus, we propose that anxiety disrupts behavioural adaptation to environmental statistics, and that multiple subcortical and limbic regions are implicated in this process.

Integrin alpha9 emerges as a key therapeutic target to reduce metastasis in rhabdomyosarcoma and neuroblastoma.

The majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis. This is a paradox, since more than 90% of cancer deaths are attributable to metastatic progression. Integrin alpha9 (ITGA9) has been previously described as playing an essential role in metastasis; however, little is known about the mechanism that links this protein to this process, being one of the less studied integrins. We have now deciphered the importance of ITGA9 in metastasis and provide evidence demonstrating its essentiality for metastatic dissemination in rhabdomyosarcoma and neuroblastoma. However, the most translational advance of this study is to reveal, for the first time, the possibility of reducing metastasis by pharmacological inhibition of ITGA9 with a synthetic peptide simulating a key interaction domain of ADAM proteins, in experimental metastasis models, not only in childhood cancers but also in a breast cancer model.

Temporal stability of Bayesian belief updating in perceptual decision-making.

Bayesian inference suggests that perception is inferred from a weighted integration of prior contextual beliefs with current sensory evidence (likelihood) about the world around us. The perceived precision or uncertainty associated with prior and likelihood information is used to guide perceptual decision-making, such that more weight is placed on the source of information with greater precision. This provides a framework for understanding a spectrum of clinical transdiagnostic symptoms associated with aberrant perception, as well as individual differences in the general population. While behavioral paradigms are commonly used to characterize individual differences in perception as a stable characteristic, measurement reliability in these behavioral tasks is rarely assessed. To remedy this gap, we empirically evaluate the reliability of a perceptual decision-making task that quantifies individual differences in Bayesian belief updating in terms of the relative precision weighting afforded to prior and likelihood information (i.e., sensory weight). We analyzed data from participants (n = 37) who performed this task twice. We found that the precision afforded to prior and likelihood information showed high internal consistency and good test-retest reliability (ICC = 0.73, 95% CI [0.53, 0.85]) when averaged across participants, as well as at the individual level using hierarchical modeling. Our results provide support for the assumption that Bayesian belief updating operates as a stable characteristic in perceptual decision-making. We discuss the utility and applicability of reliable perceptual decision-making paradigms as a measure of individual differences in the general population, as well as a diagnostic tool in psychiatric research.

Neural and computational processes of accelerated perceptual awareness and decisions: A 7T fMRI study.

Rapidly detecting salient information in our environments is critical for survival. Visual processing in subcortical areas like the pulvinar and amygdala has been shown to facilitate unconscious processing of salient stimuli. It is unknown, however, if and how these areas might interact with cortical regions to facilitate faster conscious perception of salient stimuli. Here we investigated these neural processes using 7T functional magnetic resonance imaging (fMRI) in concert with computational modelling while participants (n = 33) engaged in a breaking continuous flash suppression paradigm (bCFS) in which fearful and neutral faces are initially suppressed from conscious perception but then eventually 'breakthrough' into awareness. Participants reported faster breakthrough times for fearful faces compared with neutral faces. Drift-diffusion modelling suggested that perceptual evidence was accumulated at a faster rate for fearful faces compared with neutral faces. For both neutral and fearful faces, faster response times were associated with greater activity in the amygdala (specifically within its subregions, including superficial, basolateral and amygdalo-striatal transition area) and the insula. Faster rates of evidence accumulation coincided with greater activity in frontoparietal regions and occipital lobe, as well as the amygdala. A lower decision-boundary correlated with activity in the insula and the posterior cingulate cortex (PCC), but not with the amygdala. Overall, our findings suggest that hastened perceptual awareness of salient stimuli recruits the amygdala and, more specifically, is driven by accelerated evidence accumulation in fronto-parietal and visual areas. In sum, we have mapped distinct neural computations that accelerate perceptual awareness of visually suppressed faces.

Correction: Attention promotes the neural encoding of prediction errors.

[This corrects the article DOI: 10.1371/journal.pbio.2006812.].

Attention promotes the neural encoding of prediction errors.

The encoding of sensory information in the human brain is thought to be optimised by two principal processes: 'prediction' uses stored information to guide the interpretation of forthcoming sensory events, and 'attention' prioritizes these events according to their behavioural relevance. Despite the ubiquitous contributions of attention and prediction to various aspects of perception and cognition, it remains unknown how they interact to modulate information processing in the brain. A recent extension of predictive coding theory suggests that attention optimises the expected precision of predictions by modulating the synaptic gain of prediction error units. Because prediction errors code for the difference between predictions and sensory signals, this model would suggest that attention increases the selectivity for mismatch information in the neural response to a surprising stimulus. Alternative predictive coding models propose that attention increases the activity of prediction (or 'representation') neurons and would therefore suggest that attention and prediction synergistically modulate selectivity for 'feature information' in the brain. Here, we applied forward encoding models to neural activity recorded via electroencephalography (EEG) as human observers performed a simple visual task to test for the effect of attention on both mismatch and feature information in the neural response to surprising stimuli. Participants attended or ignored a periodic stream of gratings, the orientations of which could be either predictable, surprising, or unpredictable. We found that surprising stimuli evoked neural responses that were encoded according to the difference between predicted and observed stimulus features, and that attention facilitated the encoding of this type of information in the brain. These findings advance our understanding of how attention and prediction modulate information processing in the brain, as well as support the theory that attention optimises precision expectations during hierarchical inference by increasing the gain of prediction errors.

IκBα deficiency imposes a fetal phenotype to intestinal stem cells.

The intestinal epithelium is a paradigm of adult tissue in constant regeneration that is supported by intestinal stem cells (ISCs). The mechanisms regulating ISC homeostasis after injury are poorly understood. We previously demonstrated that IκBα, the main regulator of NF-κB, exerts alternative nuclear functions as cytokine sensor in a subset of PRC2-regulated genes. Here, we show that nuclear IκBα is present in the ISC compartment. Mice deficient for IκBα show altered intestinal cell differentiation with persistence of a fetal-like ISC phenotype, associated with aberrant PRC2 activity at specific loci. Moreover, IκBα-deficient intestinal cells produce morphologically aberrant organoids carrying a PRC2-dependent fetal-like transcriptional signature. DSS treatment, which induces acute damage in the colonic epithelium of mice, results in a temporary loss of nuclear P-IκBα and its subsequent accumulation in early CD44-positive regenerating areas. Importantly, IκBα-deficient mice show higher resistance to damage, likely due to the persistent fetal-like ISC phenotype. These results highlight intestinal IκBα as a chromatin sensor of inflammation in the ISC compartment.

Diverse mutations and structural variations contribute to Notch signaling deregulation in paediatric T-cell lymphoblastic lymphoma.

BACKGROUND: T-cell lymphoblastic lymphoma (T-LBL) is an aggressive neoplasm closely related to T-cell acute lymphoblastic leukaemia (T-ALL). Despite their similarities, and contrary to T-ALL, studies on paediatric T-LBL are scarce and, therefore, its molecular landscape has not yet been fully elucidated. Thus, the aims of this study were to characterize the genetic and molecular heterogeneity of paediatric T-LBL and to evaluate novel molecular markers differentiating this entity from T-ALL. PROCEDURE: Thirty-three paediatric T-LBL patients were analyzed using an integrated approach, including targeted next-generation sequencing, RNA-sequencing transcriptome analysis and copy-number arrays. RESULTS: Copy number and mutational analyses allowed the detection of recurrent homozygous deletions of 9p/CDKN2A (78%), trisomy 20 (19%) and gains of 17q24-q25 (16%), as well as frequent mutations of NOTCH1 (62%), followed by the BCL11B (23%), WT1 (19%) and FBXW7, PHF6 and RPL10 genes (15%, respectively). This genetic profile did not differ from that described in T-ALL in terms of mutation incidence and global genomic complexity level, but unveiled virtually exclusive 17q25 gains and trisomy 20 in T-LBL. Additionally, we identified novel gene fusions in paediatric T-LBL, including NOTCH1-IKZF2, RNGTT-SNAP91 and DDX3X-MLLT10, the last being the only one previously described in T-ALL. Moreover, clinical correlations highlighted the presence of Notch pathway alterations as a factor related to favourable outcome. CONCLUSIONS: In summary, the genomic landscape of paediatric T-LBL is similar to that observed in T-ALL, and Notch signaling pathway deregulation remains the cornerstone in its pathogenesis, including not only mutations but fusion genes targeting NOTCH1.

Differences between genetic dilated cardiomyopathy and myocarditis in children presenting with severe cardiac dysfunction.

Acute myocarditis is an inflammatory disease of the myocardium, and it can present as severe heart failure in children. Differential diagnosis with genetic cardiomyopathy can be difficult. The objective of this study is to identify patterns of clinical presentation and to assess invasive and non-invasive measures to differentiate patients with acute myocarditis from patients with dilated genetic cardiomyopathy. We performed a retrospective descriptive study of all paediatric patients (0-16 years old) that presented with new-onset heart failure with left ventricle ejection fraction < 35% in whom we performed an endomyocardial biopsy (EMB) during the period from April 2007 to December 2020. The patients were classified into two groups: Group 1 included 18 patients with myocarditis. Group 2 included 9 patients with genetic cardiomyopathy. Findings favouring a diagnosis of myocarditis included a fulminant or acute presentation (77.8% vs 33.3%, p = 0.01), higher degree of cardiac enzyme elevation (p = 0.011), lower left ventricular dimension z-score (2.2 vs 5.4, p = 0.03) increase of ventricular wall thickness (88.8% vs 33.3%, p = 0.03) and oedema in the EMB. Seven (77.8%) patients with genetic cardiomyopathy had inflammation in the endomyocardial biopsy fulfilling the diagnostic criteria of inflammatory cardiomyopathy.Conclusion: Differentiating patients with a myocarditis from those with genetic cardiomyopathy can be challenging, even performing an EMB. Some patients with genetic cardiomyopathy fulfil the diagnostic criteria of inflammatory cardiomyopathy. Using invasive and non-invasive measures may be useful to develop a predictive model to differentiate myocarditis from genetic cardiomyopathy. What is Known: • Acute myocarditis could present with cardiogenic shock in paediatric patients. • Parvovirus B19 is the main cause of myocarditis in this population. What is New: • Current diagnostic criteria for myocarditis have limited use in paediatric patients presenting with new-onset heart failure. • Some patients with a genetic cardiomyopathy and a new-onset heart failure fulfill the diagnostic criteria of inflammatory cardiomyopathy.

People with tobacco use disorder exhibit more prefrontal activity during preparatory control but reduced anterior cingulate activity during reactive control.

Reduced inhibitory control and a hypersensitivity to reward are key deficits in drug dependents; however, they tend to be studied in isolation. Here, we seek to understand the neural processes underlying control over reward and how this is different in people with a tobacco use disorder (pTUD). A novel variant of the monetary incentive delay task was performed by pTUD (n = 20) and non-smokers (n = 20), where we added a stop-signal component such that participants had to inhibit prepotent responses to earn a larger monetary reward. Brain activity was recorded using functional magnetic resonance imaging (fMRI). We estimated stop signal reaction times (SSRTs), an indicator of impulsivity, and correlated these with brain activity. Inhibitory accuracy scores did not differ between the control group and pTUD. However, pTUD had slower SSRTs, suggesting that they may find it harder to inhibit responses. Brain data revealed that pTUD had greater preparatory control activity in the middle frontal gyrus and inferior frontal gyrus prior to successful inhibitions over reward. In contrast, non-smokers had greater reactive control associated with more activity in the anterior cingulate cortex during these successful inhibitions. SSRT-brain activity correlations revealed that pTUD engaged more control-related prefrontal brain regions when SSRTs are slower. Overall, while the inhibition accuracy scores were similar between groups, differential neural processes and strategies were used to successfully inhibit a prepotent response. The findings suggest that increasing preparatory control in pTUD may be one possible treatment target in order to increase inhibitory control over reward.