Biology subjects

Markovic, A.

Publications and source records attributed to Markovic, A..

10 recordsLinked to original sources

bioRxiv2026

REM Sleep Iota Oscillations Across the Lifespan

Iota oscillations are a newly discovered marker of wakefulness and rapid eye movement (REM) sleep. So far, iota in REM sleep has only been reported in the surface electroencephalography (EEG) of a small sample of young adults and in intracranial recordings of epileptic patients. Here, we investigated the presence of these oscillations in a large dataset (N=937) of high-density sleep EEG recordings from individuals 7 to 70 years old. We found that iota spectral peaks during REM sleep were between 25 and 40 Hz, slightly faster than in wake (25-35 Hz). Iota power was significantly associated with REM sleep architecture, increasing with both REM duration and across progressive sleep cycles. Iota peaks were observed in individuals of all ages, although the prevalence decreased gradually with age, from 88% in children to 44% in older adults. Most iota spectral peak properties (frequency, amplitude, timing, topography) likewise shifted with age. The most striking effect, however, was in bandwidth, such that children had narrow iota peaks, older adults had broad iota peaks, and 20-30 year olds could have either. It remains unclear whether narrowband and broadband iota are functionally equivalent. On shorter time scales (< 1 year), iota properties remained stable across measurements. Analyses of a separate dataset of monozygotic and dizygotic twins revealed high heritability of all iota peak properties except bandwidth. Overall, these results establish iota as a genetically determined trait-like marker of REM sleep with unique age-related changes. Iota oscillations open new avenues to investigate the interaction between sleep, genetics, development, and aging.

neuroscience↗

bioRxiv2026

Identification of MED13 and DDX60 as critical host factors for SARS-CoV-2 infections

The virus responsible for COVID-19, SARS-CoV-2, continues to spread through the world. The ongoing emergence of new variants with increased viral transmission and immune evasion continue to pose a challenge. Although large-scale genetic screens have identified numerous host factors required for SARS-CoV-2 infection, however the function of these hits remain incompletely understood. In this study, we performed a haploid forward genetic screen in chemically mutagenized mouse embryonic stem cells overexpressing human ACE2 and identified MED13 and DDX60 as important host factors involved in the modulation of SARS-CoV-2 infection. In this study, we have identified and characterized the function of these key element factors for SARS-CoV2 infection. Knockdown of CKM subunits--with the exception of CDK8--or the helicase DDX60 was sufficient to reduce SARS-CoV-2 infection across Vero E6, A549, and Calu-3 cells. During SARS-CoV-2 infection, MED13 was found to function downstream of the JAK/STAT interferon pathway, but also showed another function independently of the interferon response pathway. Surprisingly, while DDX60 is traditionally involved in the interferon response pathway, its knockdown reduces SARS-CoV-2 infection, suggesting DDX60 can promote SARS-CoV-2 infection Interestingly, while inactivation of MED13 or DDX60 markedly reduced SARS-CoV-2 and SARS-CoV infection, it did not affect MERS-CoV. Collectively, these results identify MED13 and DDX60 as critical host determinants for SARS-CoV-2 related-coronaviruses with pandemic potential. Impact statementUsing an unbiased haploid genetic screening approach, this study identifies for the first time MED13 and DDX60 as host factors that influence coronavirus replication through transcriptional and interferon-associated pathways. While DDX60 has previously been linked to antiviral signaling, our findings suggest it can promote coronavirus infection. Most interestingly, the effects of these factors extend beyond SARS-CoV-2 to other coronaviruses. These findings broaden the current understanding of coronavirus-host interaction by highlighting transcriptional control and interferon-associated pathways as modulators of infection rather than focusing solely on viral entry. The work provides mechanistic insight into how host regulatory networks influence coronavirus replication and suggests potential targets for host-directed therapies with activity against multiple present and future coronavirus threats. Data summaryThe authors confirm all supporting data, code and protocols have been provided within the article or through supplementary data files. RepositoriesThe data generated in this study are provided in the Supplementary Information/Source Data file. Sequencing data are available on NCBI Sequence Read Archive under the accession number BioProject PRJNA1271794. The next generation sequencing data generated in this study has been deposited in the NCBI Sequence Read Archive (SRA) under accession number SRX29485992, SRX29485993, SRX29485994, SRX29485995, SRX29485996, SRX29485997, SRX29485998, SRX29485999, SRX29486000, SRX29486001, SRX29486002, SRX29486003, SRX29486004, SRX29486005, SRX29486006, SRX29486007, SRX29486010, SRX29486011, SRX29486012, SRX29486013, SRX29486014, SRX29486015, SRX29486016, SRX29486017, SRX29486018, SRX29486019, SRX29486021, SRX29486022, SRX29486023, SRX29486024

microbiology↗

bioRxiv2025

Stool Dynamics and the Developing Gut Microbiome During Infancy

The infant gut microbiome is a dynamic ecosystem that plays a crucial role in early development, influences immune system maturation, and overall health. Recent insights reveal that the gut microbiota undergoes changes across the 24-h day, raising the possibility that it may act as "zeitgeber", helping to regulate the hosts sleep-wake organisation. Despite its importance, timing factors influencing microbiome composition are poorly understood, limiting its use as a health predictor. This study investigates the relationship between stool dynamics (interval since last defecation, collection time of the sample), sleep pressure (interval since last sleep), meal timing and the composition of the gut microbiome. Stool samples from 198 healthy infants, aged 3 to 31 months, were analysed to assess microbial diversity, richness evenness, and abundance. Our findings reveal that longer intervals since the last bowel movement are associated with increased microbial diversity, evenness, and richness. Stool timing is associated with shifts in microbial composition, especially in younger infants, indicating that diurnal microbial fluctuations may become more stable as infants mature. We found that longer periods of wakefulness were associated with increased microbial diversity in early infancy, although this effect appeared to diminish with age. Feeding schedules appeared to have a limited effect on the gut microbiome. Longer fasting before sampling showed no significant associations with most microbial parameters, except for a positive association with microbial richness. At the phylum level, results indicate that infant gut microbial composition is influenced by behaviour and physiology. Longer intervals between bowel movements were associated with shifts in bacterial abundance, with Proteobacteria decreasing and Actinobacteria increasing. Stool timing and meal timing also affected microbial diversity: later sampling times showed higher Actinobacteria levels, and longer fasting was associated with reduced Bacteroidetes. Sleep pressure showed a trend effect with Firmicutes displaying a slight decrease in infants who had been awake longer. Our findings underscore the importance of time-based factors on infant gut microbiome composition.

systems biology↗

bioRxiv2025

Tracing infant sleep neurophysiology longitudinally from 3 to 6 months: EEG insights into brain development

1.Sleep is critical for brain plasticity during early development, yet the individual maturation of sleep neurophysiology in infancy remains poorly characterized. In particular, slow wave activity (SWA) has emerged as a key marker of both cortical maturation and experience-dependent plasticity. Understanding the regional dynamics of sleep neurophysiology early in life could yield critical insights into neurodevelopmental health. We conducted a longitudinal high-density EEG study in 11 healthy infants (3-6 months) assessing non-rapid eye movement (NREM) sleep. We analyzed the maturation of SWA (0.75-4.25 Hz), theta power (4.5-7.5 Hz), and sigma power (9.75-14.75 Hz) across scalp regions and examined their association with behavioral development. From 3 to 6 months, SWA increased maximally in occipital regions, while theta power exhibited a global increase. Sigma power, initially concentrated centrally, dispersed towards frontal regions. Greater power increases over frontal regions correlated with higher motor (theta) and personal-social skill scores (sigma) at 6 months. These findings establish a framework for typical infant sleep EEG maturation, highlighting frequency-specific and regionally distinct developmental patterns. This study provides the first longitudinal evidence that early changes in sleep EEG topography reflect individual developmental trajectories, supporting its utility as a non-invasive and yet precise biomarker for early identification of atypical neurodevelopment at preverbal ages.

neuroscience↗

bioRxiv2025

The Infraslow Fluctuation of Sigma Power During Sleep in Young Individuals with Schizophrenia

A reduction in sleep spindles, a major electrophysiological characteristic of Non-Rapid Eye Movement sleep, has been suggested as a potential biomarker of schizophrenia. While research has primarily focused on the spindle quantity, recent studies have begun to explore their temporal dynamics throughout the night. In healthy individuals, sleep spindles fluctuate on an infraslow [~]50-second timescale, alternating between phases of high and low spindle activity. This fluctuation is referred to as the infraslow fluctuation of sigma power (ISFS), which is modulated by noradrenergic activity from the locus coeruleus and linked to the organization of arousal and memory reactivation processes during sleep. Given the known deficit in sleep spindles, dysregulation of noradrenergic activity, and impairments in sleep maintenance and memory in schizophrenia, this study investigates the ISFS in sleep electroencephalography data from individuals with either Childhood-Onset Schizophrenia (COS; N = 17) or Early-Onset Schizophrenia (EOS; N = 11), aged 9 to 21 years, alongside age- and sex-matched healthy controls (N = 56). The presence and strength of the ISFS were reduced in both COS and EOS groups compared to controls, particularly in central-parietal electrodes. No significant differences in these features of the ISFS were found between the two clinical groups, despite group differences in sleep spindle density and clinical characteristics. These findings suggest that the ISFS is observable but reduced in young patients with schizophrenia and support the notion that the timing of sleep spindles may inform pathomechanistic models of the disorder, as well as future diagnostic approaches and interventions.

neuroscience↗

bioRxiv2024

From womb to crib: How fetal activity patterns in utero reveal postnatal sleep behavior

ImportanceThe human circadian system, a critical biological mechanism governing the sleep-wake cycle, begins to oscillate before birth. Distinct fetal behavioral states have been described using short-duration ultrasound recordings, but the alignment of fetal activity with day and night cycles (i.e., diurnal rhythms) remains poorly understood due to the lack of long-term monitoring. Accordingly, a substantial knowledge gap exists concerning the evolution of fetal diurnal rhythms into infant sleep-wake cycles. ObjectiveTo investigate the development of fetal diurnal rhythms and their evolution into postnatal infant sleep, as well as the role of maternal factors and melatonin in shaping early circadian entrainment. MethodsIn this cohort study, conducted in 2022 and 2023, we collected over 20 000 hours of wearable acceleration and temperature data from 32 fetuses and their mothers during continuous 5-day monitoring in the third trimester of pregnancy. The cohort was subsequently followed longitudinally from the prenatal period through 6 months postpartum, with infant sleep outcomes assessed at three key time points (first postnatal weeks, 3 months, and 6 months) using sleep diaries and questionnaires. The first postnatal assessment additionally included breast milk and infant stool sample collection. ResultsMulti-level modelling revealed early diurnal rhythms in fetuses that align with maternal activity and circadian rhythms. Random Forest analyses identified fetal day/night sleep duration ratio - a simplified proxy for fetal circadian entrainment - as the strongest predictor of postnatal infant sleep, with fetuses preferring nighttime sleep maintaining this preference postnatally. Maternal sleep regularity (i.e., consistent sleep patterns characterized by low day-to-day variability in sleep timing) during pregnancy also predicted infant sleep, associating with a stronger preference for nighttime sleep in infants. Conclusions and relevanceThese findings highlight the potential influence of intrauterine and maternal factors on the evolution of circadian entrainment. Our study contributes to a broader understanding of the earliest emergence of circadian rhythms, supporting future research on their long-term health impacts. Maternal sleep regularity stands out as the earliest modifiable target for interventions, offering an actionable pathway to promote infant circadian entrainment, with potential long-term benefits for family dynamics and well-being.

developmental biology↗

bioRxiv2024

Dynamics of positional information in the vertebrate neural tube

In developing embryos, cells acquire distinct identities depending on their position in a tissue. Secreted signaling molecules, known as morphogens, act as long-range cues to provide the spatial information that controls these cell fate decisions. In several tissues, both the level and the duration of morphogen signaling appear to be important for determining cell fates. This is the case in the forming vertebrate nervous system where antiparallel morphogen gradients pattern the dorsal-ventral axis by partitioning the tissue into sharply delineated domains of molecularly distinct neural progenitors. How information in the gradients is decoded to generate precisely positioned boundaries of gene expression remains an open question. Here, we adopt tools from information theory to quantify the positional information in the neural tube and investigate how temporal changes in signaling could influence positional precision. The results reveal that the use of signaling dynamics, as well as the signaling level, substantially increases the precision possible for the estimation of position from morphogen gradients. This analysis links the dynamics of opposing morphogen gradients with precise pattern formation and provides an explanation for why time is used to impart positional information.

developmental biology↗

bioRxiv2022

Adaptation to spindle assembly checkpoint inhibition through the selection of specific aneuploidies

Both the presence of an abnormal complement of chromosomes (aneuploidy) and an increased frequency of chromosome missegregation (chromosomal instability) are hallmarks of cancer. Analyses of cancer genome data have identified certain aneuploidy patterns in tumors; however, the bases behind their selection are largely unexplored. By establishing time-resolved long-term adaptation protocols, we found that human cells adapt to persistent spindle assembly checkpoint (SAC) inhibition by acquiring specific chromosome arm gains and losses. Independently adapted populations converge on complex karyotypes, which over time are refined to contain ever smaller chromosomal changes. Of note, the frequencies of chromosome arm gains in adapted cells correlate very well with those detected in cancers, suggesting that our cellular adaptation approach recapitulates selective traits that dictate pan-cancer aneuploidy patterns. We further engineered specific aneuploidies to determine the genetic basis behind the observed karyotype patterns. These experiments demonstrated that the adapted and engineered aneuploid cell lines limit CIN by extending mitotic duration. Heterozygous deletions of key SAC and APC/C genes recapitulated the rescue phenotypes of the monosomic chromosomes. We conclude that aneuploidy-induced gene dosage imbalances of individual mitotic regulators are sufficient for altering mitotic timing to reduce CIN.

cell biology↗

bioRxiv2021

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. 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 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, spindle density, and slow wave-spindle coupling are not associated with concurrent behavioral status (6 months). Fourth, spindle density in central and frontocentral regions at age 6 months predicts later behavioral outcomes at 12 and 24 months. Neither slow wave slope nor slow wave-spindle coupling predict behavioral development. Our results propose spindle density as an early EEG biomarker for identifying thalamocortical maturation, which can potentially be used for early diagnosis of neurodevelopmental disorders in infants. These findings are complemented by our companion paper that demonstrates the linkage of spindle density to infant nighttime movement, framing the possible role of spindles in sensorimotor microcircuitry development. Together, our studies suggest that early sleep habits, thalamocortical maturation, and behavioral outcome are closely interwoven. A crucial next step will be to evaluate whether early therapeutic interventions may be effective to reverse deviations in identified individuals at risk. HighlightsO_LISlow waves and spindles occur in a temporally coupled manner in infancy C_LIO_LISlow wave slope, spindle density, and slow wave-spindle coupling are not related to concurrent behavioral development C_LIO_LISpindle density at 6 months predicts behavioral status at 12 and 24 months C_LIO_LISlow wave slope and slow wave-spindle coupling are not predictive of behavioral development C_LI

neuroscience↗

bioRxiv2021

Bedtime to the brain: How infants sleep habits intertwine with sleep neurophysiology

Adequate sleep is critical for development and facilitates the maturation of the neurophysiological circuitries at the basis of cognitive and behavioral function. Observational research has associated sleep problems in early life with worse later cognitive, psychosocial, and somatic health outcomes. Yet, the extent to which day-to-day sleep habits in early life relate to neurophysiology - acutely and long-term - remains to be explored. Here, we report that sleep habits in 32 healthy 6-month-olds assessed with actimetry are linked to fundamental aspects of their neurophysiology measured with high-density electroencephalography (hdEEG). Our study reveals four key findings: First, daytime sleep habits are linked to EEG slow wave activity (SWA). Second, habits of nighttime 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 age 6 months predicts nighttime sleep duration at age 12 months. These novel findings widen our understanding that infants sleep habits 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). Our companion paper complements this insight in the perspective of later developmental outcomes: early thalamocortical connectivity (spindle density) at age 6 months predicts later behavioural status at 12 and 24 months. The crucial next step is to extend this concept to clinical groups to objectively characterize infants sleep habits "at risk" that foster later neurodevelopmental problems. HighlightsO_LIInfants habitual sleep behavior (actimetry) is linked with their sleep neurophysiology (EEG) C_LIO_LIHabits of daytime sleeping (naps) are related to slow wave activity C_LIO_LIInfants movements and awakenings at nighttime are linked to their sleep spindles C_LIO_LISleep timing (infants bedtimes) is associated with cortical connectivity in the EEG C_LI

neuroscience↗