Targeting MYC induces lipid droplet accumulation by upregulation of HILPDA in clear cell renal cell carcinoma.

Metabolic reprogramming is critical during clear cell renal cell carcinoma (ccRCC) tumorigenesis, manifested by accumulation of lipid droplets (LDs), organelles that have emerged as new hallmarks of cancer. Yet, regulation of their biogenesis is still poorly understood. Here, we demonstrate that MYC inhibition in ccRCC cells lacking the von Hippel Lindau (VHL) gene leads to increased triglyceride content potentiating LD formation in a glutamine-dependent manner. Importantly, the concurrent inhibition of MYC signaling and glutamine metabolism prevented LD accumulation and reduced tumor burden in vivo. Furthermore, we identified the hypoxia-inducible lipid droplet-associated protein (HILPDA) as the key driver for induction of MYC-driven LD accumulation and demonstrated that conversely, proliferation, LD formation, and tumor growth are impaired upon its downregulation. Finally, analysis of ccRCC tissue as well as healthy renal control samples postulated HILPDA as a specific ccRCC biomarker. Together, these results provide an attractive approach for development of alternative therapeutic interventions for the treatment of this type of renal cancer.

Bedtime to the brain: how infants' sleep behaviours intertwine with non-rapid eye movement sleep electroencephalography features.

Adequate sleep is critical for development and facilitates the maturation of the neurophysiological circuitries at the basis of cognitive and behavioural function. Observational research has associated early life sleep problems with worse later cognitive, psychosocial, and somatic health outcomes. Yet, the extent to which day-to-day sleep behaviours (e.g., duration, regularity) in early life relate to non-rapid eye movement (NREM) neurophysiology-acutely and the long-term-remains to be studied. We measured sleep behaviours in 32 healthy 6-month-olds assessed with actimetry and neurophysiology with high-density electroencephalography (EEG) to investigate the association between NREM sleep and habitual sleep behaviours. Our study revealed four findings: first, daytime sleep behaviours are related to EEG slow-wave activity (SWA). Second, night-time movement and awakenings from sleep are connected with spindle density. Third, habitual sleep timing is linked to neurophysiological connectivity quantified as delta coherence. And lastly, delta coherence at 6 months predicts night-time sleep duration at 12 months. These novel findings widen our understanding that infants' sleep behaviours are closely intertwined with three particular levels of neurophysiology: sleep pressure (determined by SWA), the maturation of the thalamocortical system (spindles), and the maturation of cortical connectivity (coherence). The crucial next step is to extend this concept to clinical groups to objectively characterise infants' sleep behaviours 'at risk' that foster later neurodevelopmental problems.

Functional lateralization of the medial temporal lobe in novel associative processing during creativity evaluation.

Although hemispheric lateralization of creativity has been a longstanding topic of debate, the underlying neurocognitive mechanism remains poorly understood. Here we designed 2 types of novel stimuli-"novel useful and novel useless," adapted from "familiar useful" designs taken from daily life-to demonstrate how the left and right medial temporal lobe (MTL) respond to novel designs of different usefulness. Taking the "familiar useful" design as a baseline, we found that the right MTL showed increased activation in response to "novel useful" designs, followed by "novel useless" ones, while the left MTL only showed increased activation in response to "novel useful" designs. Calculating an asymmetry index suggests that usefulness processing is predominant in the left MTL, whereas the right MTL is predominantly involved in novelty processing. Moreover, the left parahippocampal gyrus (PHG) showed stronger functional connectivity with the anterior cingulate cortex when responding to "novel useless" designs. In contrast, the right PHG showed stronger connectivity with the amygdala, midbrain, and hippocampus. Critically, multivoxel representational similarity analyses revealed that the left MTL was more effective than the right MTL at distinguishing the usefulness differences in novel stimuli, while representational patterns in the left PHG positively predicted the post-behavior evaluation of "truly creative" products. These findings suggest an apparent dissociation of the left and right MTL in integrating the novelty and usefulness information and novel associative processing during creativity evaluation, respectively. Our results provide novel insights into a longstanding and controversial question in creativity research by demonstrating functional lateralization of the MTL in processing novel associations.

An infant sleep electroencephalographic marker of thalamocortical connectivity predicts behavioral outcome in late infancy.

Infancy represents a critical period during which thalamocortical brain connections develop and mature. Deviations in the maturation of thalamocortical connectivity are linked to neurodevelopmental disorders. There is a lack of early biomarkers to detect and localize neuromaturational deviations, which can be overcome with mapping through high-density electroencephalography (hdEEG) assessed in sleep. Specifically, slow waves and spindles in non-rapid eye movement (NREM) sleep are generated by the thalamocortical system, and their characteristics, slow wave slope and spindle density, are closely related to neuroplasticity and learning. Spindles are often subdivided into slow (11.0-13.0 Hz) and fast (13.5-16.0 Hz) frequencies, for which not only different functions have been proposed, but for which also distinctive developmental trajectories have been reported across the first years of life. Recent studies further suggest that information processing during sleep underlying sleep-dependent learning is promoted by the temporal coupling of slow waves and spindles, yet slow wave-spindle coupling remains unexplored in infancy. Thus, we evaluated three potential biomarkers: 1) slow wave slope, 2) spindle density, and 3) the temporal coupling of slow waves with spindles. We use hdEEG to first examine the occurrence and spatial distribution of these three EEG features in healthy infants and second to evaluate a predictive relationship with later behavioral outcomes. We report four key findings: First, infants' EEG features appear locally: slow wave slope is maximal in occipital and frontal areas, whereas slow and fast spindle density is most pronounced frontocentrally. Second, slow waves and spindles are temporally coupled in infancy, with maximal coupling strength in the occipital areas of the brain. Third, slow wave slope, fast spindle density, and slow wave-spindle coupling are not associated with concurrent behavioral status (6 months). Fourth, fast spindle density in central and frontocentral regions at age 6 months predicts overall developmental status at age 12 months, and motor skills at age 12 and 24 months. Neither slow wave slope nor slow wave-spindle coupling predict later behavioral development. We further identified spindle frequency as a determinant of slow and fast spindle density, which accordingly, also predicts motor skills at 24 months. Our results propose fast spindle density, or alternatively spindle frequency, as early EEG biomarker for identifying thalamocortical maturation, which can potentially be used for early diagnosis of neurodevelopmental disorders in infants. These findings are in support of a role of sleep spindles in sensorimotor microcircuitry development. A crucial next step will be to evaluate whether early therapeutic interventions may be effective to reverse deviations in identified individuals at risk.

Neural correlates of sleep-induced benefits on traumatic memory processing.

Recent findings indicate that sleep after trauma compared to sleep loss inhibits intrusive memory development, possibly by promoting adequate memory consolidation and integration. However, the underlying neural mechanisms are still unknown. Here, we examined the neural correlates underlying the effects of sleep on traumatic memory development in 110 healthy participants using a trauma film paradigm and an implicit memory task with fMRI recordings in a between-subjects design. To further facilitate memory integration, we used targeted memory reactivation (TMR) to reactivate traumatic memories during sleep. We found that sleep (i.e., nap) compared to wakefulness reduced the number of intrusive traumatic memories for the experimental trauma groups. TMR during sleep only descriptively reduced the intrusions further. On the level of brain activity, increased activity in the anterior and posterior cingulate cortex, retrosplenial cortex and precuneus was found in the experimental trauma group compared to the control group after wakefulness. After sleep, on the other hand, these findings could not be found in the experimental trauma groups compared to the control group. Sleep compared to wakefulness increased activity in the cerebellum, fusiform gyrus, inferior temporal lobe, hippocampus, and amygdala during implicit retrieval of trauma memories in the experimental trauma groups. Activity in the hippocampus and the amygdala predicted subsequent intrusions. Results demonstrate the beneficial behavioral and neural effects of sleep after experimental trauma and provide indications for early neural predictor factors. This study has implications for understanding the important role of sleep for personalized treatment and prevention in posttraumatic stress disorder.

Association of transportation noise with sleep during the first year of life: A longitudinal study.

STUDY OBJECTIVES: During infancy, adequate sleep is crucial for physical and neurocognitive development. In adults and children, night-time noise exposure is associated with sleep disturbances. However, whether and to what extent infants' sleep is affected, is unknown. Thus, this study investigated the relationship between nocturnal transportation noise and actimetry-derived habitual sleep behavior across the first year of life. METHODS: In 144 healthy infants (63 girls), nocturnal (23:00-7:00) transportation noise (i.e., road, railway, and aircraft) was modelled at the infants' individual places of residence. Using actimetry, we recorded movement patterns for 11 days in a longitudinal design at 3, 6, and 12 months of age and derived the recently proposed core sleep composites of night-time sleep duration, activity, and variability. Using linear mixed-effects models, we determined associations between noise exposure and sleep composites. Sex, gestational age, parents' highest educational level, infants' age, and the existence of siblings served as control variables. RESULTS: In models without interactions, night-time transportation noise was unrelated to sleep composites across the first year of life (p > .16). Exploratory analyses of an interaction between noise and the existence of siblings yielded an association between night-time transportation noise and sleep duration in infants without siblings only (p = .004). CONCLUSION: In our study, sleep in infants during the first year of life was relatively robust against external perturbation by night-time transportation noise. However, particularly in children without siblings increasing night-time transportation noise reduced sleep duration. This suggests that the habitual noise environment may modulate individual susceptibility to adverse effects of noise on sleep.

Actigraphy in sleep research with infants and young children: Current practices and future benefits of standardized reporting.

Actigraphy is a cost-efficient method to estimate sleep-wake patterns over long periods in natural settings. However, the lack of methodological standards in actigraphy research complicates the generalization of outcomes. A rapidly growing methodological diversity is visible in the field, which increasingly necessitates the detailed reporting of methodology. We address this problem and evaluate the current state of the art and recent methodological developments in actigraphy reporting with a special focus on infants and young children. Through a systematic literature search on PubMed (keywords: sleep, actigraphy, child *, preschool, children, infant), we identified 126 recent articles (published since 2012), which were classified and evaluated for reporting of actigraphy. Results show that all studies report on the number of days/nights the actigraph was worn. Reporting was good with respect to device model, placement and sleep diary, whereas reporting was worse for epoch length, algorithm, artefact identification, data loss and definition of variables. In the studies with infants only (n = 58), the majority of articles (62.1%) reported a recording of actigraphy that was continuous across 24 hr. Of these, 23 articles (63.9%) analysed the continuous 24-hr data and merely a fifth used actigraphy to quantify daytime sleep. In comparison with an evaluation in 2012, we observed small improvements in reporting of actigraphy methodology. We propose stricter adherence to standards in reporting methodology in order to streamline actigraphy research with infants and young children, to improve comparability and to facilitate big data ventures in the sleep community.

Sleep behavior of infants with infantile hemangioma treated with propranolol-a cohort study.

Sleep problems are frequently reported in infants treated with propranolol for infantile hemangiomas, possibly serving as a marker for a negative impact on central nervous system function. In this cohort study, we objectively investigate the sleep behavior of infants with infantile hemangiomas on propranolol compared to a healthy, untreated control group. Sleep of propranolol-treated infants and controls was investigated using ankle actigraphy and a 24-h diary for 7-10 days at ages 3 and 6 months. The main outcome measures were the Number of Nighttime Awakenings and Sleep Efficiency. The main secondary outcome measures included 24-hour Total Sleep, daytime sleep behavior, and parent-rated infant sleep quality and behavioral development based on the Brief Infant Sleep Questionnaire (BISQ) and the age-appropriate Ages-and-Stages Questionnaire (ASQ), respectively. Fifty-four term-born infants were included in each cohort. No group difference in any investigated parameter was seen at age 3 months. At age 6 months, the propranolol group exhibited a decrease in Sleep Efficiency and a trend towards an increased Number of Nighttime Awakenings compared to the control group. Treated infants at 6 months also had shorter daytime waking periods. 24-hour Total Sleep was unaffected by propranolol. No negative impact of propranolol on subjective sleep quality and behavioral development was noted.Conclusion: Propranolol exerts a measurable yet mild impact on objectively assessed infants' sleep measures. Behavioral developmental scores were unaffected. Our results support propranolol as first-line therapy for complicated infantile hemangiomas. What is Known: • Sleep disorders are frequently reported in infants with infantile hemangiomas treated with propranolol and often lead to treatment discontinuation. • Investigations of the sleep pattern in this patient group using objective measures are lacking. What is New: • The sleep pattern of propranolol-treated infants is assessed using actigraphy and a 24-h sleep diary and compared to healthy, untreated controls. • Propranolol leads to a decreased sleep efficiency at night and an increased demand of daytime sleep, yet effects are mild overall.

Toxicity and Gene Expression Profiling of Copper- and Titanium-Based Nanoparticles Using Air-Liquid Interface Exposure.

To assess the toxicity of nanomaterials, most in vitro studies have been performed under submerged conditions, which do not reflect physiological conditions upon inhalation. An air-liquid interface (ALI) exposure may provide more reliable data on dosimetry and prevent interactions with cell culture media components. Therefore, an ALI exposure was combined with a high-throughput RT-qPCR approach to evaluate the toxicological potential of CuO and TiO2 nanoparticles (NP) in A549 cells. While TiO2 NP did not show any cytotoxicity or other effects compromising genomic stability up to 25.8 µg/cm2, CuO NP revealed a dose-dependent cytotoxicity, starting at 4.9 µg/cm2. Furthermore, CuO NP altered distinct gene expression patterns indicative for disturbed metal homeostasis, stress response, and DNA damage induction. Thus, induction of metal homeostasis associated genes (MT1X, MT2A) at 0.4 µg/cm2 and higher suggested uptake and intracellular dissolution of CuO NP, which was verified by a dose-dependent increase in intracellular copper concentration. Starting at 4.9 µg/cm2, oxidative stress markers (HMOX1, HSPA1A) were induced dose-dependently, supported by elevated ROS levels. Furthermore, a dose-dependent induction of genes associated with DNA damage response (DDIT3, GADD45A) was observed, in concordance with an increase in DNA strand breaks. Finally, transcriptional data suggested the induction of apoptosis at high doses, while flow cytometric analysis revealed increased numbers of either late apoptotic or necrotic cells and clearly necrotic cells at the highest concentrations. Thus, an ALI cell culture system was successfully combined with a comprehensive high-throughput RT-qPCR system, allowing the quantification of NP deposition and their impact on genomic stability. For CuO NP, in principle the data confirm observations made under submerged conditions with respect to intracellular copper ion release, as well as oxidative and genotoxic stress response. However, the results derived from ALI exposure allow the assessment of dose-response-relationships as well as the comparison of relative toxic potencies of different NP.

Which are the Central Aspects of Infant Sleep? The Dynamics of Sleep Composites across Infancy.

Sleep during infancy is important for the well-being of both infant and parent. Therefore, there is large interest in characterizing infant sleep with reliable tools, for example by combining actigraphy with 24-h-diaries. However, it is critical to select the right variables to characterize sleep. In a longitudinal investigation, we collected sleep data of 152 infants at ages 3, 6, and 12 months. Using principal component analysis, we identified five underlying sleep composites from 48 commonly-used sleep variables: Sleep Night, Sleep Day, Sleep Activity, Sleep Timing, and Sleep Variability. These composites accurately reflect known sleep dynamics throughout infancy as Sleep Day (representing naps), Sleep Activity (representing sleep efficiency and consolidation), and Sleep Variability (representing day-to-day stability) decrease across infancy, while Sleep Night (representing nighttime sleep) slightly increases, and Sleep Timing becomes earlier as one ages. We uncover interesting dynamics between the sleep composites and demonstrate that infant sleep is not only highly variable between infants but also dynamic within infants across time. Interestingly, Sleep Day is associated with behavioral development and therefore a potential marker for maturation. We recommend either the use of sleep composites or the core representative variables within each sleep composite for more reliable research.

Comparative Study of the Mode of Action of Clinically Approved Platinum-Based Chemotherapeutics.

Platinum drugs are among the most effective anticancer agents, but their mode of action is still not fully understood. We therefore carried out a systematic investigation on the cellular activities of cisplatin, carboplatin and oxaliplatin in A498 kidney cancer cells. Cytotoxicity was higher for cisplatin and oxaliplatin compared to carboplatin, with induction of apoptosis as the preferred mode of cell death. Gene expression profiling displayed modulation of genes related to DNA damage response/repair, cell cycle regulation and apoptosis which was more pronounced upon oxaliplatin treatment. Furthermore, repression of specific DNA repair genes was restricted to oxaliplatin. Transcriptional level observations were further analyzed on the functional level. Uptake studies revealed low intracellular platinum accumulation and DNA platination upon carboplatin treatment. Removal of overall DNA platination was comparable for the three drugs. However, no processing of oxaliplatin-induced interstrand crosslinks was observed. Cisplatin and carboplatin influenced cell cycle distribution comparably, while oxaliplatin had no effect. Altogether, we found a similar mode of action for cisplatin and carboplatin, while the activity of oxaliplatin appeared to differ. This might be clinically relevant as due to the difference in mode of action oxaliplatin could be active in tumors which show resistance towards cisplatin and carboplatin.

The effect of dream report collection and dream incorporation on memory consolidation during sleep.

Collecting dream reports typically requires waking subjects up from their sleep-a method that has been used to study the relationship between dreams and memory consolidation. However, it is unclear whether these awakenings influence sleep-associated memory consolidation processes. Furthermore, it is unclear how the incorporation of the learning task into dreams is related to memory consolidation. In this study we compared memory performance in a word-picture association learning task after a night with and without awakenings in 22 young and healthy participants. We then examined if the stimuli from the learning task are successfully incorporated into dreams, and if this incorporation is related to the task performance the next morning. We show that while the awakenings impaired both subjective and objective sleep quality, they did not affect sleep-associated memory consolidation. When dreams were collected during the night by awakenings, memories of the learning task were successfully incorporated into dreams. When dreams were collected in the morning, no incorporations were detected. Task incorporation into non-rapid eye movement sleep dreams, but not rapid eye movement sleep dreams positively predicted memory performance the next morning. We conclude that the method of awakenings to collect dream reports is suitable and necessary for dream and memory studies. Furthermore, our study suggests that dreams in non-rapid eye movement rather than rapid eye movement sleep might be related to processes of memory consolidation during sleep.

Modulating influences of memory strength and sensitivity of the retrieval test on the detectability of the sleep consolidation effect.

Emotionality can increase recall probability of memories as emotional information is highly relevant for future adaptive behavior. It has been proposed that memory processes acting during sleep selectively promote the consolidation of emotional memories, so that neutral memories no longer profit from sleep consolidation after learning. This appears as a selective effect of sleep for emotional memories. However, other factors contribute to the appearance of a consolidation benefit and influence this interpretation. Here we show that the strength of the memory trace before sleep and the sensitivity of the retrieval test after sleep are critical factors contributing to the detection of the benefit of sleep on memory for emotional and neutral stimuli. 228 subjects learned emotional and neutral pictures and completed a free recall after a 12-h retention interval of either sleep or wakefulness. We manipulated memory strength by including an immediate retrieval test before the retention interval in half of the participants. In addition, we varied the sensitivity of the retrieval test by including an interference learning task before retrieval testing in half of the participants. We show that a "selective" benefit of sleep for emotional memories only occurs in the condition with high memory strength. Furthermore, this "selective" benefit disappeared when we controlled for the memory strength before the retention interval and used a highly sensitive retrieval test. Our results indicate that although sleep benefits are more robust for emotional memories, neutral memories similarly profit from sleep after learning when more sensitive indicators are used. We conclude that whether sleep benefits on memory appear depends on several factors, including emotion, memory strength and sensitivity of the retrieval test.

Platinum(IV)-nitroxyl complexes as possible candidates to circumvent cisplatin resistance in RT112 bladder cancer cells.

The therapeutic efficacy of the anticancer drug cisplatin is limited by the development of resistance. We therefore investigated newly synthesized platinum-nitroxyl complexes (PNCs) for their potential to circumvent cisplatin resistance. The complexes used were PNCs with bivalent cis-PtII(R·NH2)(NH3)Cl2 and cis-PtII(DAPO)Ox and four-valent platinum cis,trans,cis-PtIV(R·NH2)(NH3)(OR)2Cl2 and cis,trans,cis-PtIV(DAPO)(OR)2Ox, where R· are TEMPO or proxyl nitroxyl radicals, DAPO is trans-3,4-diamino-2,2,6,6-tetramethylpiperidine-1-oxyl, and OR and Ox are carboxylato and oxalato ligands, respectively. The complexes were characterized by spectroscopic methods, HPLC, log P ow data and elemental analysis. We studied intracellular platinum accumulation, DNA platination and cytotoxicity upon treatment with the PNCs in a model system of the bladder cancer cell line RT112 and its cisplatin-resistant subline RT112-CP. Platinum accumulation and DNA platination were similar in RT112 and RT112-CP cells for both bivalent and four-valent PNCs, in contrast to cisplatin for which a reduction in intracellular accumulation and DNA platination was observed in the resistant subline. The PNCs were found to platinate DNA in relation to the length of their axial RO-ligands. Furthermore, the PNCs were increasingly toxic in relation to the elongation of their axial RO-ligands, with similar toxicities in RT112 and its cisplatin-resistant subline. Using a cell-free assay, we observed induction of oxidative DNA damage by cisplatin but not PNCs suggesting that cisplatin exerts its toxic action by platination and oxidative DNA damage, while cells treated with PNCs are protected against oxidatively induced lesions. Altogether, our study suggests that PNCs may provide a more effective treatment for tumors which have developed resistance toward cisplatin.

The sleeping brain's connectivity and family environment: characterizing sleep EEG coherence in an infant cohort.

Brain connectivity closely reflects brain function and behavior. Sleep EEG coherence, a measure of brain's connectivity during sleep, undergoes pronounced changes across development under the influence of environmental factors. Yet, the determinants of the developing brain's sleep EEG coherence from the child's family environment remain unknown. After characterizing high-density sleep EEG coherence in 31 healthy 6-month-old infants by detecting strongly synchronized clusters through a data-driven approach, we examined the association of sleep EEG coherence from these clusters with factors from the infant's family environment. Clusters with greatest coherence were observed over the frontal lobe. Higher delta coherence over the left frontal cortex was found in infants sleeping in their parents' room, while infants sleeping in a room shared with their sibling(s) showed greater delta coherence over the central parts of the frontal cortex, suggesting a link between local brain connectivity and co-sleeping. Finally, lower occipital delta coherence was associated with maternal anxiety regarding their infant's sleep. These interesting links between sleep EEG coherence and family factors have the potential to serve in early health interventions as a new set of targets from the child's immediate environment.

Memory reactivations during sleep: a neural basis of dream experiences?

Newly encoded memory traces are spontaneously reactivated during sleep. Since their discovery in the 1990s, these memory reactivations have been discussed as a potential neural basis for dream experiences. New results from animal and human research, as well as from the rapidly growing field of sleep and dream engineering, provide essential insights into this question, and reveal both strong parallels and disparities between the two phenomena. We suggest that, although memory reactivations may contribute to subjective experiences across different states of consciousness, they are not likely to be the primary neural basis of dreaming. We identify important limitations in current research paradigms and suggest novel strategies to address this question empirically.

Lack of association between behavioral development and simplified topographical markers of the sleep EEG in infancy.

The sleep EEG mirrors neuronal connectivity, especially during development when the brain undergoes substantial rewiring. As children grow, the slow-wave activity (SWA; 0.75-4.25 Hz) spatial distribution in their sleep EEG changes along a posterior-to-anterior gradient. Topographical SWA markers have been linked to critical neurobehavioral functions, such as motor skills, in school-aged children. However, the relationship between topographical markers in infancy and later behavioral outcomes is still unclear. This study aims to explore reliable indicators of neurodevelopment in infants by analyzing their sleep EEG patterns. Thirty-one 6-month-old infants (15 female) underwent high-density EEG recordings during nighttime sleep. We defined markers based on the topographical distribution of SWA and theta activity, including central/occipital and frontal/occipital ratios and an index derived from local EEG power variability. Linear models were applied to test whether markers relate to concurrent, later, or retrospective behavioral scores, assessed by the parent-reported Ages & Stages Questionnaire at ages 3, 6, 12, and 24 months. Results indicate that the topographical markers of the sleep EEG power in infants were not significantly linked to behavioral development at any age. Further research, such as longitudinal sleep EEG in newborns, is needed to better understand the relationship between these markers and behavioral development and assess their predictive value for individual differences.

Identification and validation of NFIA as a novel prognostic marker in renal cell carcinoma.

Prognostic tools are an essential component of the clinical management of patients with renal cell carcinoma (RCC). Although tumour stage and grade can provide important information, they fail to consider patient- and tumour-specific biology. In this study, we set out to find a novel molecular marker of RCC by using hepatocyte nuclear factor 4A (HNF4A), a transcription factor implicated in RCC progression and malignancy, as a blueprint. Through transcriptomic analyses, we show that the nuclear factor I A (NFIA)-driven transcription network is active in primary RCC and that higher levels of NFIA confer a survival benefit. We validate our findings using immunohistochemical staining and analysis of a 363-patient tissue microarray (TMA), showing for the first time that NFIA can independently predict poor cancer-specific survival in clear cell RCC (ccRCC) patients (hazard ratio = 0.46, 95% CI = 0.24-0.85, p value = 0.014). Furthermore, we confirm the association of HNF4A with higher grades and stages in ccRCC in our TMA cohort. We present novel data that show HNF4A protein expression does not confer favourable prognosis in papillary RCC, confirming our survival analysis with publicly available HNF4A RNA expression data. Further work is required to elucidate the functional role of NFIA in RCC as well as the testing of these markers on patient material from diverse multi-centre cohorts, to establish their value for the prognostication of RCC.

Learning during sleep in humans - A historical review.

Sleep helps to consolidate previously acquired memories. Whether new information such as languages and other useful skills can also be learned during sleep has been debated for over a century, however, the sporadic studies' different objectives and varied methodologies make it difficult to draw definitive conclusions. This review provides a comprehensive overview of the history of sleep learning research conducted in humans, from its empirical beginnings in the 1940s to the present day. Synthesizing the findings from 51 research papers, we show that several studies support the notion that simpler forms of learning, such as habituation and conditioning, are possible during sleep. In contrast, the findings for more complex, applied learning (e.g., learning a new language during sleep) are more divergent. While there is often an indication of processing and learning during sleep when looking at neural markers, behavioral evidence for the transfer of new knowledge to wake remains inconclusive. We close by critically examining the limitations and assumptions that have contributed to the discrepancies in the literature and highlight promising new directions in the field.

Not simply a matter of parents-Infants' sleep-wake patterns are associated with their regularity of eating.

In adults there are indications that regular eating patterns are related to better sleep quality. During early development, sleep and eating habits experience major maturational transitions. Further, the bacterial landscape of the gut microbiota undergoes a rapid increase in complexity. Yet little is known about the association between sleep, eating patterns and the gut microbiota. We first hypothesized that higher eating regularity is associated with more mature sleep patterns, and second, that this association is mediated by the maturational status of the gut microbiota. To test this hypothesis, we performed a longitudinal study in 162 infants to assess actigraphy, diaries of sleep and eating times, and stool microbiota composition at ages 3, 6 and 12 months. To comprehensively capture infants' habitual sleep-wake patterns, 5 sleep composites that characterize infants' sleep habits across multiple days in their home environment were computed. To assess timing of eating habits, we developed an Eating Regularity Index (ERI). Gut microbial composition was assessed by 16S rRNA gene amplicon sequencing, and its maturation was assessed based on alpha diversity, bacterial maturation index, and enterotype. First, our results demonstrate that increased eating regularity (higher ERI) in infants is associated with less time spent awake during the night (sleep fragmentation) and more regular sleep patterns. Second, the associations of ERI with sleep evolve with age. Third, the link between infant sleep and ERI remains significant when controlling for parents' subjectively rated importance of structuring their infant's eating and sleeping times. Finally, the gut microbial maturational markers did not account for the link between infant's sleep patterns and ERI. Thus, infants who eat more regularly have more mature sleep patterns, which is independent of the maturational status of their gut microbiota. Interventions targeting infant eating rhythm thus constitute a simple, ready-to-use anchor to improve sleep quality.