Biology subjects

Markovic, A.

Publications and source records attributed to Markovic, A..

4 recordsLinked to original sources

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↗